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Fueling the Alzheimer’s brain with fat
LONDON – A 3-month diet comprised of 70% fat improved cognition in Alzheimer’s disease patients better than any anti-amyloid drug that has ever been tested.
In a small pilot study, Alzheimer’s patients who followed the University of Kansas’s ketogenic diet program improved an average of 4 points on one of the most important cognitive assessments in dementia care, the Alzheimer’s Disease Assessment Scale–cognitive domain (ADAS-cog). Not only was this gain statistically significant, but it reached a level that clinical trialists believe to be clinically meaningful, and it was similar to the gains that won Food and Drug Administration approval for donepezil in 1996, according to Russell Swerdlow, MD, director of the University of Kansas Alzheimer’s Disease Center in Fairway.
To put the results in perspective, donepezil was approved on a 4-point spread between the active and placebo arm over 3 months, said Dr. Swerdlow, who is also the Gene and Marge Sweeney Professor of Neurology at the university. Part of this difference was driven by a 2-point decline in the placebo group. Relative to its baseline, the treatment group improved, on average, by about 2 points.
But in the Ketogenic Diet Retention and Feasibility Trail (KDRAFT), also 3 months long, patients’ ADAS-cog scores didn’t decline at all. Everyone who stayed with the diet and kept on their baseline medications improved, although to varying degrees.
KDRAFT was very small, with just 10 patients completing the intervention, and lacked a comparator group, so the results should be interpreted extremely cautiously, Dr. Swerdlow said in an interview. “We have to very careful about overinterpreting these findings. It’s a pilot study, and a small group, so we don’t know how genuine the finding is. But if it is true, it’s a big deal.”
Diet and dementia
Emerging evidence suggests that modifying diet can help prevent Alzheimer’s and may even help AD patients think and function better. But this research has largely focused on the heart-healthy diets already proven successful in preventing and treating hypertension, diabetes, and cardiovascular disease. Most notably, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet cut the risk of AD by up to 53% (Alzheimers Dement. 2015 Sep;11[9]:1007-14) and also slowed aging-related cognitive decline (Alzheimers Dement. 2015 Sep; 11[9]:1015-22).
MIND is a combination of the low-salt, plant-focused DASH diet, and the heart-healthy Mediterranean diet. It is a moderate-fat plan, with a ratio of 33% fat, 38% carbohydrates, and 26% protein. Ideally, only 3% of the fat should be saturated, so MIND draws on olive oil, nuts, and other foods with monounsaturated fats, largely eschewing animal fats. It’s generally considered fairly easy to follow, since it allows a wide variety of whole grains, beans, nuts, fruits, vegetables, salads, fish, and poultry. Butter, red meat, fried foods, full-fat dairy, and fast foods are strict no-nos.
A ketogenic diet, however, turns MIND on its head. With a 70% fat, 20% protein, 10% carbohydrate ratio, a typical ketogenic diet nearly eliminates most fruits, and virtually all starchy vegetables, beans, and grains. It does, however, incorporate a large amount of fat from many sources, including olive oil, butter, cream, eggs, nuts, all kinds of meat, and fish. For a ketogenic diet, Dr. Swerdlow said, the ratio of fat to protein and carbs is more critical than the source of the fat.
MIND was designed to prevent the cardiovascular and endocrine disorders than predispose to dementia over the long term. But a ketogenic diet for patients with Alzheimer’s acutely manipulates the brain’s energy metabolism system, forcing it to use ketone bodies instead of glucose for fuel.
In normal energy metabolism, carbohydrates provide a ready supply of glucose, the brain’s primary fuel. When carbs are limited or absent, serum insulin decreases and glucagon increases. This promotes lipolysis. Ketones (primarily beta-hydroxybutyrate and acetoacetate) are formed in the liver from the newly released fatty acids, and released into the circulation, including into the brain during times of decreased glucose availability – a state characteristic of Alzheimer’s disease.
Induced ketogenesis trial
Inducing ketosis through diet seems to help correct the normal, age-related decline in the brain’s ability to use glucose, said Stephen Cunnane, PhD, who also presented ketogenic intervention results at AAIC. “Cognitively normal, healthy older adults experience a 10% reduction in the brain’s ability to metabolize glucose compared to healthy young people,” he said in an interview. But this decline accelerates as Alzheimer’s hits. Those with early AD have a 20% decrement in glucose utilization, compared with healthy elders.
Changes in brain glucose metabolism can develop years before any cognitive symptoms manifest and seem to increase the risk of Alzheimer’s, said Dr. Cunnane of Sherbrooke University, Que.
“We propose that this vicious cycle of presymptomatic glucose hypometabolism causes chronic brain energy deprivation, and might contribute to deteriorating neuronal function. That could cause a further decrease in the demand for glucose, leading to cognitive decline.”
“What doesn’t change, though, is the brain’s ability to take up ketone bodies,” he said. If anything, the brain appears to use ketones more efficiently as AD becomes established. “It’s almost like the brain is trying to rescue itself. If those cells were dead, they would not be able to take up ketones. Because they do, we think they are instead starving because of their inability to use glucose and that maybe we can rescue them with ketones before they die.”
At AAIC, Dr. Cunnane reported interim results of an investigation of induced ketogenesis in patients with mild cognitive impairment (MCI). The 6-month BENEFIC trial comprises 50 patients, randomized to either a daily nutritional supplement with 30 g medium chain triglycerides (MCT) in a unflavored, nondairy emulsion, or a fat-equivalent placebo drink. When consumed, the liver very quickly converts MCT fatty acids into ketone bodies, which then circulate throughout the body, including passing the blood-brain barrier.
All of the participants in the BENEFIC trial underwent brain PET scanning for both glucose and ketone uptake. Early results clearly showed that the MCI brains took up just as much acetoacetate as did the brains of cognitively normal young adults. And although the study wasn’t powered for a full cognitive assessment, Dr. Cunnane did present 6-month data on three measures in the MCI group: trail making time, verbal fluency, and the Boston Naming Test. In the active group on MCT, scores on all three measures improved “modestly” in direct correlation with brain ketone uptake. In the placebo group, scores remained unchanged.
“We don’t have enough people in the study to make any definitive statement about cognition, but it’s nice to see the trend going in the right direction, Dr. Cunnane said. “I really think of this as a dose-finding study and a chance to demonstrate the safety and tolerability of a liquid MCT supplement in people with MCI. Our next study will use a 45 g per day supplement of MCT.”
Details of the KDRAFT study
The BENEFIC study looked only at the effects of an MCT supplement, which may not deliver all the metabolic benefits of a ketogenic diet. KDRAFT, however, employed both, and assessed not only cognitive outcomes and adverse effects, but the practical matter of whether AD patients and their caregivers could implement the diet and stick to it.
Couples recruited into the trial met with a dietitian who explained the importance of sticking with the strict fat:carb:protein ratio. It’s not easy to stay in that zone, Dr. Swerdlow said, and the MCT supplement really helps there.
“Adding the MCT, which is typically done for the ketogenic diet in epilepsy, increases the fat intake so you can tolerate a bit more carbohydrate and still remain in ketosis. MCT therefore makes it easier to successfully do the diet, if we define success by time in ketosis. Ultimately, it is an iterative diet. You check your urine, and if you are in ketosis, you are doing well. If you are not in ketosis, you have to increase your fat intake, decrease your carb intake, or both.”
The study comprised 15 patients (7 with very mild AD, 4 with mild, and 4 with moderate disease). All patients were instructed to remain on their current medications for Alzheimer’s disease for the duration of the study if they were taking any. All of the patients with moderate AD and one with very mild AD dropped out of the study within the first month, citing caregiver burden. The supplement was in the form of an oil, not an emulsion like the BENEFIC supplement, and it caused diarrhea and nausea in five subjects, although none discontinued because of that.
“We found that a slow titration of the oil could deal with the GI issues. Rather, the primary deal-breaker seemed to be the stress of planning the menus and preparing the meals.”
One patient discontinued his cholinesterase inhibitor during the study, for unknown reasons. His cognitive scores declined, but was still included in the diet-compliant analysis.
The diet didn’t affect weight, blood pressure, insulin sensitivity or resistance, or glucose level, but the intervention was short-lived. Nor were there any significant changes in high-density, low-density, or total cholesterol. Liver enzymes were stable, too.
“The only thing that changed was that they really did increase their fat and decrease their carb intake,” Dr. Swerdlow said. Daily fat jumped from 91 g to 167 g, and carbs dropped from 201 g to 46 g.
Almost everyone who stuck with the diet achieved and maintained ketosis during the study, although with varying degrees of success. “Many only had a trace amount of urinary ketones,” Dr. Swerdlow said. The investigators tracked serum beta hydroxybutyrate levels every month as well, and those measures also confirmed ketosis in the group as a whole, although some patients fluctuated in and out of the state.
The cognitive changes were striking, he said. In the 10-patient analysis, ADAS-cog scores improved by an average of 4.1 points. The results were better when Dr. Swerdlow excluded the patient who stopped his cholinesterase inhibitor medication. In that nine-patient group, the ADAS-cog improved an average of 5.3 points.
While urging caution over the small sample size and lack of a control comparator, Dr. Swerdlow expressed deep satisfaction over the outcomes. A clinician as well as a researcher, he is accustomed to the slow but inexorable decline of AD patients.
“I’m going to try to relate the impression you get in the clinic with these scores,” he said. “Very rarely, but sometimes, with a cholinesterase inhibitor in patients, we’ll see something like a 7-point change. That’s a fantastic response, an improvement you can see across the room. A change of 2 points really doesn’t look that much different, although caregivers will tell you there is a subtle change, maybe a little more focus. The average we got in our 10 subjects was a 4-point improvement. That’s impressive. And a 5-point change is like rolling the clock back by a year.”
The improvements didn’t last, though. A 1-month washout period followed the intervention. By the end, both ADAS-cog and Mini-Mental State Examination scores had returned to their baseline levels. At the end of the study, a few of the patients and their partners expressed their intent to resume the diet, but the investigators do not know whether this indeed happened. Still, the results are encouraging enough that, like Dr. Cunnane, Dr. Swerdlow hopes to conduct a larger, longer study – one that would include a control group.
Future investigations of the ketogenic diet in AD might do well to also include an exercise component, both researchers mentioned. In addition to starvation, ketogenic dieting, and MCT supplementation, exercise is an effective way to induce ketogenesis.
“Exercise produces ketones, but most importantly, it increases the capacity of the brain to use ketones,” Dr. Cunnane said. The connection may help explain some of the cognitive benefits seen in exercise trials in patients with MCI and AD.
“This raises the possibility that if in fact exercise benefits the brain, ketone bodies may mediate some of that effect,” Dr. Swerdlow said. “Could exercise potentiate the ketosis from the diet? That is possible, and maybe using these interventions in conjunction would be synergistic. At this point, we are just happy to show the diet is feasible, if even for a limited period.”
Implementing KDRAFT: Research team dishes the skinny on fats
The KDRAFT study diet is surprisingly flexible despite its strict ratio of fat to protein and carbohydrate, according to the University of Kansas research team that implemented it. It only took a few counseling sessions to get most study participants enthusiastically embracing the new eating plan, even one so radically different from the way they were accustomed to eating.
“We focused mainly on the macronutrient makeup,” said Matthew Taylor, PhD, who supervised the diet study on a day-to-day basis. Instead of distributing a rigid diet plan, with prespecified meals and snacks, “We talked more in general about foods they could have and foods they couldn’t have.”
“When people think ‘ketogenic,’ they think bacon, eggs, oil, butter and cream, and may have an automatic negative connotation that this is unhealthy eating,” Dr. Taylor said in an interview. “But yes, eggs were in there and, because a lot of people really like bacon, there was bacon, too!”
The educational sessions did include teaching about healthy and unhealthy fats, and Dr. Taylor “tried to steer people toward the healthier ones, like olive oil, avocados, and nuts. But I didn’t say, ‘Eat this one and not that one.’ If it took melting butter on vegetables to get to that fat ratio, I was not as concerned about where the fat came from as about getting there and maintaining ketosis.”
KDRAFT also had a twist that’s becoming more common among ketogenic eating plans: lots of vegetables. Dr. Taylor asked participants to concentrate on nonstarchy vegetables and forgo potatoes, corn, beans, and lima beans, although some people did enjoy peas occasionally.
“We used to be think we had to restrict vegetables or people would go out of ketosis more easily. But that doesn’t seem to be true. We focused a lot on eating vegetables, and everyone increased their vegetable intake dramatically. We actually tried to use vegetables as a vehicle for fat. For example, people would roast Brussels sprouts or broccoli in olive oil and then put melted butter on it. It was pretty much, ‘Eat all the vegetables you can and put fat on them.’”
Fruits are full of sugar, so they are not liberally used in most ketogenic diets, but KDRAFT did allow one type: berries, and blueberries in particular. “We had people eating a couple of small handfuls of berries throughout the day and still being able to maintain ketosis. We did severely cut back on the amount and type of fruit people could have, but berries seemed to work well.”
Whipping cream had a place, too. “It fit really well in the diet, because it’s basically all fat,” Dr. Taylor said. “It’s used more often in pediatric ketogenic diets as a milk substitute. One thing our subjects liked to do was use it to make a sweet snack. All it takes is a packet of [stevia] sweetener and some vanilla. Then you whip and freeze it and it’s like an ice cream dessert.”
After the initial drop-outs, the remaining study pairs embraced the intervention enthusiastically.
“When the study partner took the diet on too, we had our best success. One of our last pairs had an entire family join in – children, grandchildren, everyone decided to follow the diet. That is a very helpful piece to this. It’s difficult to always say, ‘Here’s our normal food and here’s the keto food over here.’”
The dropouts occurred very early. These study pairs, all of whom included patients with moderate Alzheimer’s, never embraced the plan at all, and this is a telling point, Dr. Taylor noted.
“When you get to a level of dementia there are so many other things in the caregiving process that taking on big behavioral changes is very difficult.”
Although the study showed that the diet wasn’t practical for sicker patients at home, it still might be beneficial in other settings, said Debra Sullivan, PhD, RD. Dr. Sullivan chairs the department of dietetics and nutrition at the University of Kansas Medical Center and holds the Midwest Dairy Council Endowed Professorship in Clinical Nutrition.
“I think that we might be able to create a version of the diet that could be used in an institutional setting for our more advanced patients,” she said. “But there’s no denying that this can be challenging. It’s a big change from the way the typical American eats.”
None of the KDRAFT participants experienced any lipid changes, for either better or worse. The 3-month intervention was long enough to have picked up such changes if they were in the offing, said principal investigator Russell Swerdlow, MD. While there are mixed data on ketogenic diets’ atherogenic effects, many people respond positively, with improved cholesterol.
“Much of what it comes down to is, are you in a catabolic or anabolic states? Are you building up or tearing down? Excessive cholesterol is a sign of being overfed and laying down energy supplies. You take in carbon and turn it into cholesterol. But if you can trick your body into a catabolic state – essentially make it think it’s starving, which a ketogenic diet does – then you have consistently low insulin levels, and you don’t turn on the cholesterol synthesis pathway. You may increase your cholesterol intake through diet, but you’re not synthesizing it in your body, and that synthesis is what really drives your cholesterol level. If you’re not overeating, your body’s production goes down.”
Brain Energy and Memory (BEAM) study
Dr. Swerdlow isn’t the only clinician researcher looking at how a ketogenic diet might influence cognition. Suzanne Craft, PhD, well known for her investigations of the role of insulin signaling and therapy in AD, is running a ketogenic diet trial as well.
As noted on clinicaltrials.gov, the 24-week Brain Energy and Memory (BEAM) study aimed to recruit 25 subjects in two cohorts: adults with mild memory complaints, and cognitively normal adults with prediabetes. A comparator group of healthy controls will contribute cognitive assessments, blood and stool sample collection, neuroimaging, and lumbar puncture at baseline.
Both active groups will be randomized to 6 weeks of either a low-fat, high-carbohydrate diet, with carbs making up 50%-60% of daily caloric intake, or a modified ketogenic-Mediterranean Diet with carbs comprising less than 10% of daily caloric intake.
BEAM’s primary outcome will be changes in the AD cerebrospinal fluid biomarkers beta-amyloid and tau. Secondary endpoints include cognitive assessments, brain ketone uptake on PET scanning, and insulin sensitivity.
Dr. Cunnane has no financial interest in the MCT emulsion, which was supplied by Abitec. He reported conference travel support from Abitec, Nisshin OilliO, and Pruvit. He also reported receiving research project funding from Nestlé and Bulletproof.
Dr. Swerdlow had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
In Alzheimer’s disease (AD), there are early significant deficits in glucose utilization that become increasingly severe as disease progresses.
Most reports from early-onset AD animal models find that these energy deficits are largely due to defects in mitochondrial complex IV and V, and possibly related to mitochondrial fusion and fission regulators. Animal models of tauopathy demonstrate Complex I deficits.
In AD-vulnerable brain regions with early glucose utilization deficits, surviving neurons show large reductions in mitochondrial complex I, IV, and V gene expression and proteins. These changes appear sufficient to contribute to cognitive deficits. These are not shared by nondemented individuals, even in the presences of AD pathology.
The precise causes of reduced glucose utilization in AD are unknown, but may reflect these mitochondrial deficits, as well as defective insulin signaling. These changes lead to adenosine triphosphate deficits and disruptions in the balance of NAD+/NADH, both of which are already altered by normal aging.
However, because metabolism is coupled to synaptic activity, it is difficult to ascertain whether these “bioenergetic” deficits are simply secondary to progressive neuron and synapse loss or a contributing factor to neuron and synapse loss and cognitive deficits.
One of the best ways to discern the contribution of bioenergetics deficits is to treat them. Many animal models and some small trials appear to show possible benefits from supplements directed at improving energy metabolism.
In the context of these known deficits in Alzheimer’s, the new positive results with ketogenic diet reported by Dr. Swerdlow should not be ignored despite the small sample size and open-label design with the diet. The impressive 4-5 point increase in ADAS-cog that they saw is not easily achieved, and the rapid loss with washout suggests a real benefit with a large effect size.
Similarly, despite the study’s limitations with dose and size, Dr. Cunnane’s imaging of ketone body uptake and its correlation with cognitive improvement suggests that ameliorating energy deficits can be a real target capable of producing substantial short-term benefits for patients with Alzheimer’s.
Given the rapid results and large effect size, this is an area that needs to see more trials.
Gregory Cole, PhD , is a professor of neurology at the University of California, Los Angeles, and interim director of the Mary S. Easton Alzheimer Center. He had no relevant financial disclosures.
In Alzheimer’s disease (AD), there are early significant deficits in glucose utilization that become increasingly severe as disease progresses.
Most reports from early-onset AD animal models find that these energy deficits are largely due to defects in mitochondrial complex IV and V, and possibly related to mitochondrial fusion and fission regulators. Animal models of tauopathy demonstrate Complex I deficits.
In AD-vulnerable brain regions with early glucose utilization deficits, surviving neurons show large reductions in mitochondrial complex I, IV, and V gene expression and proteins. These changes appear sufficient to contribute to cognitive deficits. These are not shared by nondemented individuals, even in the presences of AD pathology.
The precise causes of reduced glucose utilization in AD are unknown, but may reflect these mitochondrial deficits, as well as defective insulin signaling. These changes lead to adenosine triphosphate deficits and disruptions in the balance of NAD+/NADH, both of which are already altered by normal aging.
However, because metabolism is coupled to synaptic activity, it is difficult to ascertain whether these “bioenergetic” deficits are simply secondary to progressive neuron and synapse loss or a contributing factor to neuron and synapse loss and cognitive deficits.
One of the best ways to discern the contribution of bioenergetics deficits is to treat them. Many animal models and some small trials appear to show possible benefits from supplements directed at improving energy metabolism.
In the context of these known deficits in Alzheimer’s, the new positive results with ketogenic diet reported by Dr. Swerdlow should not be ignored despite the small sample size and open-label design with the diet. The impressive 4-5 point increase in ADAS-cog that they saw is not easily achieved, and the rapid loss with washout suggests a real benefit with a large effect size.
Similarly, despite the study’s limitations with dose and size, Dr. Cunnane’s imaging of ketone body uptake and its correlation with cognitive improvement suggests that ameliorating energy deficits can be a real target capable of producing substantial short-term benefits for patients with Alzheimer’s.
Given the rapid results and large effect size, this is an area that needs to see more trials.
Gregory Cole, PhD , is a professor of neurology at the University of California, Los Angeles, and interim director of the Mary S. Easton Alzheimer Center. He had no relevant financial disclosures.
In Alzheimer’s disease (AD), there are early significant deficits in glucose utilization that become increasingly severe as disease progresses.
Most reports from early-onset AD animal models find that these energy deficits are largely due to defects in mitochondrial complex IV and V, and possibly related to mitochondrial fusion and fission regulators. Animal models of tauopathy demonstrate Complex I deficits.
In AD-vulnerable brain regions with early glucose utilization deficits, surviving neurons show large reductions in mitochondrial complex I, IV, and V gene expression and proteins. These changes appear sufficient to contribute to cognitive deficits. These are not shared by nondemented individuals, even in the presences of AD pathology.
The precise causes of reduced glucose utilization in AD are unknown, but may reflect these mitochondrial deficits, as well as defective insulin signaling. These changes lead to adenosine triphosphate deficits and disruptions in the balance of NAD+/NADH, both of which are already altered by normal aging.
However, because metabolism is coupled to synaptic activity, it is difficult to ascertain whether these “bioenergetic” deficits are simply secondary to progressive neuron and synapse loss or a contributing factor to neuron and synapse loss and cognitive deficits.
One of the best ways to discern the contribution of bioenergetics deficits is to treat them. Many animal models and some small trials appear to show possible benefits from supplements directed at improving energy metabolism.
In the context of these known deficits in Alzheimer’s, the new positive results with ketogenic diet reported by Dr. Swerdlow should not be ignored despite the small sample size and open-label design with the diet. The impressive 4-5 point increase in ADAS-cog that they saw is not easily achieved, and the rapid loss with washout suggests a real benefit with a large effect size.
Similarly, despite the study’s limitations with dose and size, Dr. Cunnane’s imaging of ketone body uptake and its correlation with cognitive improvement suggests that ameliorating energy deficits can be a real target capable of producing substantial short-term benefits for patients with Alzheimer’s.
Given the rapid results and large effect size, this is an area that needs to see more trials.
Gregory Cole, PhD , is a professor of neurology at the University of California, Los Angeles, and interim director of the Mary S. Easton Alzheimer Center. He had no relevant financial disclosures.
LONDON – A 3-month diet comprised of 70% fat improved cognition in Alzheimer’s disease patients better than any anti-amyloid drug that has ever been tested.
In a small pilot study, Alzheimer’s patients who followed the University of Kansas’s ketogenic diet program improved an average of 4 points on one of the most important cognitive assessments in dementia care, the Alzheimer’s Disease Assessment Scale–cognitive domain (ADAS-cog). Not only was this gain statistically significant, but it reached a level that clinical trialists believe to be clinically meaningful, and it was similar to the gains that won Food and Drug Administration approval for donepezil in 1996, according to Russell Swerdlow, MD, director of the University of Kansas Alzheimer’s Disease Center in Fairway.
To put the results in perspective, donepezil was approved on a 4-point spread between the active and placebo arm over 3 months, said Dr. Swerdlow, who is also the Gene and Marge Sweeney Professor of Neurology at the university. Part of this difference was driven by a 2-point decline in the placebo group. Relative to its baseline, the treatment group improved, on average, by about 2 points.
But in the Ketogenic Diet Retention and Feasibility Trail (KDRAFT), also 3 months long, patients’ ADAS-cog scores didn’t decline at all. Everyone who stayed with the diet and kept on their baseline medications improved, although to varying degrees.
KDRAFT was very small, with just 10 patients completing the intervention, and lacked a comparator group, so the results should be interpreted extremely cautiously, Dr. Swerdlow said in an interview. “We have to very careful about overinterpreting these findings. It’s a pilot study, and a small group, so we don’t know how genuine the finding is. But if it is true, it’s a big deal.”
Diet and dementia
Emerging evidence suggests that modifying diet can help prevent Alzheimer’s and may even help AD patients think and function better. But this research has largely focused on the heart-healthy diets already proven successful in preventing and treating hypertension, diabetes, and cardiovascular disease. Most notably, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet cut the risk of AD by up to 53% (Alzheimers Dement. 2015 Sep;11[9]:1007-14) and also slowed aging-related cognitive decline (Alzheimers Dement. 2015 Sep; 11[9]:1015-22).
MIND is a combination of the low-salt, plant-focused DASH diet, and the heart-healthy Mediterranean diet. It is a moderate-fat plan, with a ratio of 33% fat, 38% carbohydrates, and 26% protein. Ideally, only 3% of the fat should be saturated, so MIND draws on olive oil, nuts, and other foods with monounsaturated fats, largely eschewing animal fats. It’s generally considered fairly easy to follow, since it allows a wide variety of whole grains, beans, nuts, fruits, vegetables, salads, fish, and poultry. Butter, red meat, fried foods, full-fat dairy, and fast foods are strict no-nos.
A ketogenic diet, however, turns MIND on its head. With a 70% fat, 20% protein, 10% carbohydrate ratio, a typical ketogenic diet nearly eliminates most fruits, and virtually all starchy vegetables, beans, and grains. It does, however, incorporate a large amount of fat from many sources, including olive oil, butter, cream, eggs, nuts, all kinds of meat, and fish. For a ketogenic diet, Dr. Swerdlow said, the ratio of fat to protein and carbs is more critical than the source of the fat.
MIND was designed to prevent the cardiovascular and endocrine disorders than predispose to dementia over the long term. But a ketogenic diet for patients with Alzheimer’s acutely manipulates the brain’s energy metabolism system, forcing it to use ketone bodies instead of glucose for fuel.
In normal energy metabolism, carbohydrates provide a ready supply of glucose, the brain’s primary fuel. When carbs are limited or absent, serum insulin decreases and glucagon increases. This promotes lipolysis. Ketones (primarily beta-hydroxybutyrate and acetoacetate) are formed in the liver from the newly released fatty acids, and released into the circulation, including into the brain during times of decreased glucose availability – a state characteristic of Alzheimer’s disease.
Induced ketogenesis trial
Inducing ketosis through diet seems to help correct the normal, age-related decline in the brain’s ability to use glucose, said Stephen Cunnane, PhD, who also presented ketogenic intervention results at AAIC. “Cognitively normal, healthy older adults experience a 10% reduction in the brain’s ability to metabolize glucose compared to healthy young people,” he said in an interview. But this decline accelerates as Alzheimer’s hits. Those with early AD have a 20% decrement in glucose utilization, compared with healthy elders.
Changes in brain glucose metabolism can develop years before any cognitive symptoms manifest and seem to increase the risk of Alzheimer’s, said Dr. Cunnane of Sherbrooke University, Que.
“We propose that this vicious cycle of presymptomatic glucose hypometabolism causes chronic brain energy deprivation, and might contribute to deteriorating neuronal function. That could cause a further decrease in the demand for glucose, leading to cognitive decline.”
“What doesn’t change, though, is the brain’s ability to take up ketone bodies,” he said. If anything, the brain appears to use ketones more efficiently as AD becomes established. “It’s almost like the brain is trying to rescue itself. If those cells were dead, they would not be able to take up ketones. Because they do, we think they are instead starving because of their inability to use glucose and that maybe we can rescue them with ketones before they die.”
At AAIC, Dr. Cunnane reported interim results of an investigation of induced ketogenesis in patients with mild cognitive impairment (MCI). The 6-month BENEFIC trial comprises 50 patients, randomized to either a daily nutritional supplement with 30 g medium chain triglycerides (MCT) in a unflavored, nondairy emulsion, or a fat-equivalent placebo drink. When consumed, the liver very quickly converts MCT fatty acids into ketone bodies, which then circulate throughout the body, including passing the blood-brain barrier.
All of the participants in the BENEFIC trial underwent brain PET scanning for both glucose and ketone uptake. Early results clearly showed that the MCI brains took up just as much acetoacetate as did the brains of cognitively normal young adults. And although the study wasn’t powered for a full cognitive assessment, Dr. Cunnane did present 6-month data on three measures in the MCI group: trail making time, verbal fluency, and the Boston Naming Test. In the active group on MCT, scores on all three measures improved “modestly” in direct correlation with brain ketone uptake. In the placebo group, scores remained unchanged.
“We don’t have enough people in the study to make any definitive statement about cognition, but it’s nice to see the trend going in the right direction, Dr. Cunnane said. “I really think of this as a dose-finding study and a chance to demonstrate the safety and tolerability of a liquid MCT supplement in people with MCI. Our next study will use a 45 g per day supplement of MCT.”
Details of the KDRAFT study
The BENEFIC study looked only at the effects of an MCT supplement, which may not deliver all the metabolic benefits of a ketogenic diet. KDRAFT, however, employed both, and assessed not only cognitive outcomes and adverse effects, but the practical matter of whether AD patients and their caregivers could implement the diet and stick to it.
Couples recruited into the trial met with a dietitian who explained the importance of sticking with the strict fat:carb:protein ratio. It’s not easy to stay in that zone, Dr. Swerdlow said, and the MCT supplement really helps there.
“Adding the MCT, which is typically done for the ketogenic diet in epilepsy, increases the fat intake so you can tolerate a bit more carbohydrate and still remain in ketosis. MCT therefore makes it easier to successfully do the diet, if we define success by time in ketosis. Ultimately, it is an iterative diet. You check your urine, and if you are in ketosis, you are doing well. If you are not in ketosis, you have to increase your fat intake, decrease your carb intake, or both.”
The study comprised 15 patients (7 with very mild AD, 4 with mild, and 4 with moderate disease). All patients were instructed to remain on their current medications for Alzheimer’s disease for the duration of the study if they were taking any. All of the patients with moderate AD and one with very mild AD dropped out of the study within the first month, citing caregiver burden. The supplement was in the form of an oil, not an emulsion like the BENEFIC supplement, and it caused diarrhea and nausea in five subjects, although none discontinued because of that.
“We found that a slow titration of the oil could deal with the GI issues. Rather, the primary deal-breaker seemed to be the stress of planning the menus and preparing the meals.”
One patient discontinued his cholinesterase inhibitor during the study, for unknown reasons. His cognitive scores declined, but was still included in the diet-compliant analysis.
The diet didn’t affect weight, blood pressure, insulin sensitivity or resistance, or glucose level, but the intervention was short-lived. Nor were there any significant changes in high-density, low-density, or total cholesterol. Liver enzymes were stable, too.
“The only thing that changed was that they really did increase their fat and decrease their carb intake,” Dr. Swerdlow said. Daily fat jumped from 91 g to 167 g, and carbs dropped from 201 g to 46 g.
Almost everyone who stuck with the diet achieved and maintained ketosis during the study, although with varying degrees of success. “Many only had a trace amount of urinary ketones,” Dr. Swerdlow said. The investigators tracked serum beta hydroxybutyrate levels every month as well, and those measures also confirmed ketosis in the group as a whole, although some patients fluctuated in and out of the state.
The cognitive changes were striking, he said. In the 10-patient analysis, ADAS-cog scores improved by an average of 4.1 points. The results were better when Dr. Swerdlow excluded the patient who stopped his cholinesterase inhibitor medication. In that nine-patient group, the ADAS-cog improved an average of 5.3 points.
While urging caution over the small sample size and lack of a control comparator, Dr. Swerdlow expressed deep satisfaction over the outcomes. A clinician as well as a researcher, he is accustomed to the slow but inexorable decline of AD patients.
“I’m going to try to relate the impression you get in the clinic with these scores,” he said. “Very rarely, but sometimes, with a cholinesterase inhibitor in patients, we’ll see something like a 7-point change. That’s a fantastic response, an improvement you can see across the room. A change of 2 points really doesn’t look that much different, although caregivers will tell you there is a subtle change, maybe a little more focus. The average we got in our 10 subjects was a 4-point improvement. That’s impressive. And a 5-point change is like rolling the clock back by a year.”
The improvements didn’t last, though. A 1-month washout period followed the intervention. By the end, both ADAS-cog and Mini-Mental State Examination scores had returned to their baseline levels. At the end of the study, a few of the patients and their partners expressed their intent to resume the diet, but the investigators do not know whether this indeed happened. Still, the results are encouraging enough that, like Dr. Cunnane, Dr. Swerdlow hopes to conduct a larger, longer study – one that would include a control group.
Future investigations of the ketogenic diet in AD might do well to also include an exercise component, both researchers mentioned. In addition to starvation, ketogenic dieting, and MCT supplementation, exercise is an effective way to induce ketogenesis.
“Exercise produces ketones, but most importantly, it increases the capacity of the brain to use ketones,” Dr. Cunnane said. The connection may help explain some of the cognitive benefits seen in exercise trials in patients with MCI and AD.
“This raises the possibility that if in fact exercise benefits the brain, ketone bodies may mediate some of that effect,” Dr. Swerdlow said. “Could exercise potentiate the ketosis from the diet? That is possible, and maybe using these interventions in conjunction would be synergistic. At this point, we are just happy to show the diet is feasible, if even for a limited period.”
Implementing KDRAFT: Research team dishes the skinny on fats
The KDRAFT study diet is surprisingly flexible despite its strict ratio of fat to protein and carbohydrate, according to the University of Kansas research team that implemented it. It only took a few counseling sessions to get most study participants enthusiastically embracing the new eating plan, even one so radically different from the way they were accustomed to eating.
“We focused mainly on the macronutrient makeup,” said Matthew Taylor, PhD, who supervised the diet study on a day-to-day basis. Instead of distributing a rigid diet plan, with prespecified meals and snacks, “We talked more in general about foods they could have and foods they couldn’t have.”
“When people think ‘ketogenic,’ they think bacon, eggs, oil, butter and cream, and may have an automatic negative connotation that this is unhealthy eating,” Dr. Taylor said in an interview. “But yes, eggs were in there and, because a lot of people really like bacon, there was bacon, too!”
The educational sessions did include teaching about healthy and unhealthy fats, and Dr. Taylor “tried to steer people toward the healthier ones, like olive oil, avocados, and nuts. But I didn’t say, ‘Eat this one and not that one.’ If it took melting butter on vegetables to get to that fat ratio, I was not as concerned about where the fat came from as about getting there and maintaining ketosis.”
KDRAFT also had a twist that’s becoming more common among ketogenic eating plans: lots of vegetables. Dr. Taylor asked participants to concentrate on nonstarchy vegetables and forgo potatoes, corn, beans, and lima beans, although some people did enjoy peas occasionally.
“We used to be think we had to restrict vegetables or people would go out of ketosis more easily. But that doesn’t seem to be true. We focused a lot on eating vegetables, and everyone increased their vegetable intake dramatically. We actually tried to use vegetables as a vehicle for fat. For example, people would roast Brussels sprouts or broccoli in olive oil and then put melted butter on it. It was pretty much, ‘Eat all the vegetables you can and put fat on them.’”
Fruits are full of sugar, so they are not liberally used in most ketogenic diets, but KDRAFT did allow one type: berries, and blueberries in particular. “We had people eating a couple of small handfuls of berries throughout the day and still being able to maintain ketosis. We did severely cut back on the amount and type of fruit people could have, but berries seemed to work well.”
Whipping cream had a place, too. “It fit really well in the diet, because it’s basically all fat,” Dr. Taylor said. “It’s used more often in pediatric ketogenic diets as a milk substitute. One thing our subjects liked to do was use it to make a sweet snack. All it takes is a packet of [stevia] sweetener and some vanilla. Then you whip and freeze it and it’s like an ice cream dessert.”
After the initial drop-outs, the remaining study pairs embraced the intervention enthusiastically.
“When the study partner took the diet on too, we had our best success. One of our last pairs had an entire family join in – children, grandchildren, everyone decided to follow the diet. That is a very helpful piece to this. It’s difficult to always say, ‘Here’s our normal food and here’s the keto food over here.’”
The dropouts occurred very early. These study pairs, all of whom included patients with moderate Alzheimer’s, never embraced the plan at all, and this is a telling point, Dr. Taylor noted.
“When you get to a level of dementia there are so many other things in the caregiving process that taking on big behavioral changes is very difficult.”
Although the study showed that the diet wasn’t practical for sicker patients at home, it still might be beneficial in other settings, said Debra Sullivan, PhD, RD. Dr. Sullivan chairs the department of dietetics and nutrition at the University of Kansas Medical Center and holds the Midwest Dairy Council Endowed Professorship in Clinical Nutrition.
“I think that we might be able to create a version of the diet that could be used in an institutional setting for our more advanced patients,” she said. “But there’s no denying that this can be challenging. It’s a big change from the way the typical American eats.”
None of the KDRAFT participants experienced any lipid changes, for either better or worse. The 3-month intervention was long enough to have picked up such changes if they were in the offing, said principal investigator Russell Swerdlow, MD. While there are mixed data on ketogenic diets’ atherogenic effects, many people respond positively, with improved cholesterol.
“Much of what it comes down to is, are you in a catabolic or anabolic states? Are you building up or tearing down? Excessive cholesterol is a sign of being overfed and laying down energy supplies. You take in carbon and turn it into cholesterol. But if you can trick your body into a catabolic state – essentially make it think it’s starving, which a ketogenic diet does – then you have consistently low insulin levels, and you don’t turn on the cholesterol synthesis pathway. You may increase your cholesterol intake through diet, but you’re not synthesizing it in your body, and that synthesis is what really drives your cholesterol level. If you’re not overeating, your body’s production goes down.”
Brain Energy and Memory (BEAM) study
Dr. Swerdlow isn’t the only clinician researcher looking at how a ketogenic diet might influence cognition. Suzanne Craft, PhD, well known for her investigations of the role of insulin signaling and therapy in AD, is running a ketogenic diet trial as well.
As noted on clinicaltrials.gov, the 24-week Brain Energy and Memory (BEAM) study aimed to recruit 25 subjects in two cohorts: adults with mild memory complaints, and cognitively normal adults with prediabetes. A comparator group of healthy controls will contribute cognitive assessments, blood and stool sample collection, neuroimaging, and lumbar puncture at baseline.
Both active groups will be randomized to 6 weeks of either a low-fat, high-carbohydrate diet, with carbs making up 50%-60% of daily caloric intake, or a modified ketogenic-Mediterranean Diet with carbs comprising less than 10% of daily caloric intake.
BEAM’s primary outcome will be changes in the AD cerebrospinal fluid biomarkers beta-amyloid and tau. Secondary endpoints include cognitive assessments, brain ketone uptake on PET scanning, and insulin sensitivity.
Dr. Cunnane has no financial interest in the MCT emulsion, which was supplied by Abitec. He reported conference travel support from Abitec, Nisshin OilliO, and Pruvit. He also reported receiving research project funding from Nestlé and Bulletproof.
Dr. Swerdlow had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – A 3-month diet comprised of 70% fat improved cognition in Alzheimer’s disease patients better than any anti-amyloid drug that has ever been tested.
In a small pilot study, Alzheimer’s patients who followed the University of Kansas’s ketogenic diet program improved an average of 4 points on one of the most important cognitive assessments in dementia care, the Alzheimer’s Disease Assessment Scale–cognitive domain (ADAS-cog). Not only was this gain statistically significant, but it reached a level that clinical trialists believe to be clinically meaningful, and it was similar to the gains that won Food and Drug Administration approval for donepezil in 1996, according to Russell Swerdlow, MD, director of the University of Kansas Alzheimer’s Disease Center in Fairway.
To put the results in perspective, donepezil was approved on a 4-point spread between the active and placebo arm over 3 months, said Dr. Swerdlow, who is also the Gene and Marge Sweeney Professor of Neurology at the university. Part of this difference was driven by a 2-point decline in the placebo group. Relative to its baseline, the treatment group improved, on average, by about 2 points.
But in the Ketogenic Diet Retention and Feasibility Trail (KDRAFT), also 3 months long, patients’ ADAS-cog scores didn’t decline at all. Everyone who stayed with the diet and kept on their baseline medications improved, although to varying degrees.
KDRAFT was very small, with just 10 patients completing the intervention, and lacked a comparator group, so the results should be interpreted extremely cautiously, Dr. Swerdlow said in an interview. “We have to very careful about overinterpreting these findings. It’s a pilot study, and a small group, so we don’t know how genuine the finding is. But if it is true, it’s a big deal.”
Diet and dementia
Emerging evidence suggests that modifying diet can help prevent Alzheimer’s and may even help AD patients think and function better. But this research has largely focused on the heart-healthy diets already proven successful in preventing and treating hypertension, diabetes, and cardiovascular disease. Most notably, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet cut the risk of AD by up to 53% (Alzheimers Dement. 2015 Sep;11[9]:1007-14) and also slowed aging-related cognitive decline (Alzheimers Dement. 2015 Sep; 11[9]:1015-22).
MIND is a combination of the low-salt, plant-focused DASH diet, and the heart-healthy Mediterranean diet. It is a moderate-fat plan, with a ratio of 33% fat, 38% carbohydrates, and 26% protein. Ideally, only 3% of the fat should be saturated, so MIND draws on olive oil, nuts, and other foods with monounsaturated fats, largely eschewing animal fats. It’s generally considered fairly easy to follow, since it allows a wide variety of whole grains, beans, nuts, fruits, vegetables, salads, fish, and poultry. Butter, red meat, fried foods, full-fat dairy, and fast foods are strict no-nos.
A ketogenic diet, however, turns MIND on its head. With a 70% fat, 20% protein, 10% carbohydrate ratio, a typical ketogenic diet nearly eliminates most fruits, and virtually all starchy vegetables, beans, and grains. It does, however, incorporate a large amount of fat from many sources, including olive oil, butter, cream, eggs, nuts, all kinds of meat, and fish. For a ketogenic diet, Dr. Swerdlow said, the ratio of fat to protein and carbs is more critical than the source of the fat.
MIND was designed to prevent the cardiovascular and endocrine disorders than predispose to dementia over the long term. But a ketogenic diet for patients with Alzheimer’s acutely manipulates the brain’s energy metabolism system, forcing it to use ketone bodies instead of glucose for fuel.
In normal energy metabolism, carbohydrates provide a ready supply of glucose, the brain’s primary fuel. When carbs are limited or absent, serum insulin decreases and glucagon increases. This promotes lipolysis. Ketones (primarily beta-hydroxybutyrate and acetoacetate) are formed in the liver from the newly released fatty acids, and released into the circulation, including into the brain during times of decreased glucose availability – a state characteristic of Alzheimer’s disease.
Induced ketogenesis trial
Inducing ketosis through diet seems to help correct the normal, age-related decline in the brain’s ability to use glucose, said Stephen Cunnane, PhD, who also presented ketogenic intervention results at AAIC. “Cognitively normal, healthy older adults experience a 10% reduction in the brain’s ability to metabolize glucose compared to healthy young people,” he said in an interview. But this decline accelerates as Alzheimer’s hits. Those with early AD have a 20% decrement in glucose utilization, compared with healthy elders.
Changes in brain glucose metabolism can develop years before any cognitive symptoms manifest and seem to increase the risk of Alzheimer’s, said Dr. Cunnane of Sherbrooke University, Que.
“We propose that this vicious cycle of presymptomatic glucose hypometabolism causes chronic brain energy deprivation, and might contribute to deteriorating neuronal function. That could cause a further decrease in the demand for glucose, leading to cognitive decline.”
“What doesn’t change, though, is the brain’s ability to take up ketone bodies,” he said. If anything, the brain appears to use ketones more efficiently as AD becomes established. “It’s almost like the brain is trying to rescue itself. If those cells were dead, they would not be able to take up ketones. Because they do, we think they are instead starving because of their inability to use glucose and that maybe we can rescue them with ketones before they die.”
At AAIC, Dr. Cunnane reported interim results of an investigation of induced ketogenesis in patients with mild cognitive impairment (MCI). The 6-month BENEFIC trial comprises 50 patients, randomized to either a daily nutritional supplement with 30 g medium chain triglycerides (MCT) in a unflavored, nondairy emulsion, or a fat-equivalent placebo drink. When consumed, the liver very quickly converts MCT fatty acids into ketone bodies, which then circulate throughout the body, including passing the blood-brain barrier.
All of the participants in the BENEFIC trial underwent brain PET scanning for both glucose and ketone uptake. Early results clearly showed that the MCI brains took up just as much acetoacetate as did the brains of cognitively normal young adults. And although the study wasn’t powered for a full cognitive assessment, Dr. Cunnane did present 6-month data on three measures in the MCI group: trail making time, verbal fluency, and the Boston Naming Test. In the active group on MCT, scores on all three measures improved “modestly” in direct correlation with brain ketone uptake. In the placebo group, scores remained unchanged.
“We don’t have enough people in the study to make any definitive statement about cognition, but it’s nice to see the trend going in the right direction, Dr. Cunnane said. “I really think of this as a dose-finding study and a chance to demonstrate the safety and tolerability of a liquid MCT supplement in people with MCI. Our next study will use a 45 g per day supplement of MCT.”
Details of the KDRAFT study
The BENEFIC study looked only at the effects of an MCT supplement, which may not deliver all the metabolic benefits of a ketogenic diet. KDRAFT, however, employed both, and assessed not only cognitive outcomes and adverse effects, but the practical matter of whether AD patients and their caregivers could implement the diet and stick to it.
Couples recruited into the trial met with a dietitian who explained the importance of sticking with the strict fat:carb:protein ratio. It’s not easy to stay in that zone, Dr. Swerdlow said, and the MCT supplement really helps there.
“Adding the MCT, which is typically done for the ketogenic diet in epilepsy, increases the fat intake so you can tolerate a bit more carbohydrate and still remain in ketosis. MCT therefore makes it easier to successfully do the diet, if we define success by time in ketosis. Ultimately, it is an iterative diet. You check your urine, and if you are in ketosis, you are doing well. If you are not in ketosis, you have to increase your fat intake, decrease your carb intake, or both.”
The study comprised 15 patients (7 with very mild AD, 4 with mild, and 4 with moderate disease). All patients were instructed to remain on their current medications for Alzheimer’s disease for the duration of the study if they were taking any. All of the patients with moderate AD and one with very mild AD dropped out of the study within the first month, citing caregiver burden. The supplement was in the form of an oil, not an emulsion like the BENEFIC supplement, and it caused diarrhea and nausea in five subjects, although none discontinued because of that.
“We found that a slow titration of the oil could deal with the GI issues. Rather, the primary deal-breaker seemed to be the stress of planning the menus and preparing the meals.”
One patient discontinued his cholinesterase inhibitor during the study, for unknown reasons. His cognitive scores declined, but was still included in the diet-compliant analysis.
The diet didn’t affect weight, blood pressure, insulin sensitivity or resistance, or glucose level, but the intervention was short-lived. Nor were there any significant changes in high-density, low-density, or total cholesterol. Liver enzymes were stable, too.
“The only thing that changed was that they really did increase their fat and decrease their carb intake,” Dr. Swerdlow said. Daily fat jumped from 91 g to 167 g, and carbs dropped from 201 g to 46 g.
Almost everyone who stuck with the diet achieved and maintained ketosis during the study, although with varying degrees of success. “Many only had a trace amount of urinary ketones,” Dr. Swerdlow said. The investigators tracked serum beta hydroxybutyrate levels every month as well, and those measures also confirmed ketosis in the group as a whole, although some patients fluctuated in and out of the state.
The cognitive changes were striking, he said. In the 10-patient analysis, ADAS-cog scores improved by an average of 4.1 points. The results were better when Dr. Swerdlow excluded the patient who stopped his cholinesterase inhibitor medication. In that nine-patient group, the ADAS-cog improved an average of 5.3 points.
While urging caution over the small sample size and lack of a control comparator, Dr. Swerdlow expressed deep satisfaction over the outcomes. A clinician as well as a researcher, he is accustomed to the slow but inexorable decline of AD patients.
“I’m going to try to relate the impression you get in the clinic with these scores,” he said. “Very rarely, but sometimes, with a cholinesterase inhibitor in patients, we’ll see something like a 7-point change. That’s a fantastic response, an improvement you can see across the room. A change of 2 points really doesn’t look that much different, although caregivers will tell you there is a subtle change, maybe a little more focus. The average we got in our 10 subjects was a 4-point improvement. That’s impressive. And a 5-point change is like rolling the clock back by a year.”
The improvements didn’t last, though. A 1-month washout period followed the intervention. By the end, both ADAS-cog and Mini-Mental State Examination scores had returned to their baseline levels. At the end of the study, a few of the patients and their partners expressed their intent to resume the diet, but the investigators do not know whether this indeed happened. Still, the results are encouraging enough that, like Dr. Cunnane, Dr. Swerdlow hopes to conduct a larger, longer study – one that would include a control group.
Future investigations of the ketogenic diet in AD might do well to also include an exercise component, both researchers mentioned. In addition to starvation, ketogenic dieting, and MCT supplementation, exercise is an effective way to induce ketogenesis.
“Exercise produces ketones, but most importantly, it increases the capacity of the brain to use ketones,” Dr. Cunnane said. The connection may help explain some of the cognitive benefits seen in exercise trials in patients with MCI and AD.
“This raises the possibility that if in fact exercise benefits the brain, ketone bodies may mediate some of that effect,” Dr. Swerdlow said. “Could exercise potentiate the ketosis from the diet? That is possible, and maybe using these interventions in conjunction would be synergistic. At this point, we are just happy to show the diet is feasible, if even for a limited period.”
Implementing KDRAFT: Research team dishes the skinny on fats
The KDRAFT study diet is surprisingly flexible despite its strict ratio of fat to protein and carbohydrate, according to the University of Kansas research team that implemented it. It only took a few counseling sessions to get most study participants enthusiastically embracing the new eating plan, even one so radically different from the way they were accustomed to eating.
“We focused mainly on the macronutrient makeup,” said Matthew Taylor, PhD, who supervised the diet study on a day-to-day basis. Instead of distributing a rigid diet plan, with prespecified meals and snacks, “We talked more in general about foods they could have and foods they couldn’t have.”
“When people think ‘ketogenic,’ they think bacon, eggs, oil, butter and cream, and may have an automatic negative connotation that this is unhealthy eating,” Dr. Taylor said in an interview. “But yes, eggs were in there and, because a lot of people really like bacon, there was bacon, too!”
The educational sessions did include teaching about healthy and unhealthy fats, and Dr. Taylor “tried to steer people toward the healthier ones, like olive oil, avocados, and nuts. But I didn’t say, ‘Eat this one and not that one.’ If it took melting butter on vegetables to get to that fat ratio, I was not as concerned about where the fat came from as about getting there and maintaining ketosis.”
KDRAFT also had a twist that’s becoming more common among ketogenic eating plans: lots of vegetables. Dr. Taylor asked participants to concentrate on nonstarchy vegetables and forgo potatoes, corn, beans, and lima beans, although some people did enjoy peas occasionally.
“We used to be think we had to restrict vegetables or people would go out of ketosis more easily. But that doesn’t seem to be true. We focused a lot on eating vegetables, and everyone increased their vegetable intake dramatically. We actually tried to use vegetables as a vehicle for fat. For example, people would roast Brussels sprouts or broccoli in olive oil and then put melted butter on it. It was pretty much, ‘Eat all the vegetables you can and put fat on them.’”
Fruits are full of sugar, so they are not liberally used in most ketogenic diets, but KDRAFT did allow one type: berries, and blueberries in particular. “We had people eating a couple of small handfuls of berries throughout the day and still being able to maintain ketosis. We did severely cut back on the amount and type of fruit people could have, but berries seemed to work well.”
Whipping cream had a place, too. “It fit really well in the diet, because it’s basically all fat,” Dr. Taylor said. “It’s used more often in pediatric ketogenic diets as a milk substitute. One thing our subjects liked to do was use it to make a sweet snack. All it takes is a packet of [stevia] sweetener and some vanilla. Then you whip and freeze it and it’s like an ice cream dessert.”
After the initial drop-outs, the remaining study pairs embraced the intervention enthusiastically.
“When the study partner took the diet on too, we had our best success. One of our last pairs had an entire family join in – children, grandchildren, everyone decided to follow the diet. That is a very helpful piece to this. It’s difficult to always say, ‘Here’s our normal food and here’s the keto food over here.’”
The dropouts occurred very early. These study pairs, all of whom included patients with moderate Alzheimer’s, never embraced the plan at all, and this is a telling point, Dr. Taylor noted.
“When you get to a level of dementia there are so many other things in the caregiving process that taking on big behavioral changes is very difficult.”
Although the study showed that the diet wasn’t practical for sicker patients at home, it still might be beneficial in other settings, said Debra Sullivan, PhD, RD. Dr. Sullivan chairs the department of dietetics and nutrition at the University of Kansas Medical Center and holds the Midwest Dairy Council Endowed Professorship in Clinical Nutrition.
“I think that we might be able to create a version of the diet that could be used in an institutional setting for our more advanced patients,” she said. “But there’s no denying that this can be challenging. It’s a big change from the way the typical American eats.”
None of the KDRAFT participants experienced any lipid changes, for either better or worse. The 3-month intervention was long enough to have picked up such changes if they were in the offing, said principal investigator Russell Swerdlow, MD. While there are mixed data on ketogenic diets’ atherogenic effects, many people respond positively, with improved cholesterol.
“Much of what it comes down to is, are you in a catabolic or anabolic states? Are you building up or tearing down? Excessive cholesterol is a sign of being overfed and laying down energy supplies. You take in carbon and turn it into cholesterol. But if you can trick your body into a catabolic state – essentially make it think it’s starving, which a ketogenic diet does – then you have consistently low insulin levels, and you don’t turn on the cholesterol synthesis pathway. You may increase your cholesterol intake through diet, but you’re not synthesizing it in your body, and that synthesis is what really drives your cholesterol level. If you’re not overeating, your body’s production goes down.”
Brain Energy and Memory (BEAM) study
Dr. Swerdlow isn’t the only clinician researcher looking at how a ketogenic diet might influence cognition. Suzanne Craft, PhD, well known for her investigations of the role of insulin signaling and therapy in AD, is running a ketogenic diet trial as well.
As noted on clinicaltrials.gov, the 24-week Brain Energy and Memory (BEAM) study aimed to recruit 25 subjects in two cohorts: adults with mild memory complaints, and cognitively normal adults with prediabetes. A comparator group of healthy controls will contribute cognitive assessments, blood and stool sample collection, neuroimaging, and lumbar puncture at baseline.
Both active groups will be randomized to 6 weeks of either a low-fat, high-carbohydrate diet, with carbs making up 50%-60% of daily caloric intake, or a modified ketogenic-Mediterranean Diet with carbs comprising less than 10% of daily caloric intake.
BEAM’s primary outcome will be changes in the AD cerebrospinal fluid biomarkers beta-amyloid and tau. Secondary endpoints include cognitive assessments, brain ketone uptake on PET scanning, and insulin sensitivity.
Dr. Cunnane has no financial interest in the MCT emulsion, which was supplied by Abitec. He reported conference travel support from Abitec, Nisshin OilliO, and Pruvit. He also reported receiving research project funding from Nestlé and Bulletproof.
Dr. Swerdlow had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT AAIC 2017
Depression, PTSD double risk of dementia for older female veterans
LONDON – Women veterans with either depression or post-traumatic stress disorder face a doubling in their risk of dementia – and having both increases the risk even more, Dr. Kristine Yaffe reported at the Alzheimer’s Association International Conference.*
The risk ratios for incident dementia that Dr. Yaffe of the University of California, San Francisco, and her colleagues calculated from their analysis of a cohort of 149,000 older female veterans in the national Veterans Health Administration (VHA) database remained unchanged even when they adjusted for age, education, medical comorbidities, and other confounders.
Not only are older women veterans a growing group; they are frequently diagnosed with mental health disorders. In 2012, 45% of women veteran patients in the VHA had a mental health condition, Dr. Yaffe noted.
“Over 9% of all veterans in the U.S. are women, accounting for more than 2 million women veterans. And 30% of those are more than 55 years old. Additionally, the number of women utilizing the Veterans Healthcare Administration system has nearly doubled in the last decade.”
The study of the impact of depression and PTSD on incident dementia is the first of its kind, Dr. Yaffe noted. The cohort comprised women without dementia who had at least two VHA visits during 2005-2015. They were followed for a mean of 5 years. A diagnosis of depression or PTSD had to occur during a 2-year baseline period. Confounders considered in the analysis were demographics, medical comorbidities, and health habits, including alcohol and tobacco use. The primary outcome was time to incident dementia.
At baseline, the group was a mean of 67 years old. Most subjects (70%) were white. Hypertension was common (46%), as was diabetes (16%). About 6% had cardiovascular disease. Depression was present in 18% and PTSD in 4%.
When parsed by diagnosis, there were some significant between-group differences at baseline. Women with depression or PTSD were younger than those without (65 and 63 vs. 67 years). Women who had both disorders were the youngest group, at 62 years.
Hypertension was least common in women without depression or PTSD (41%), and most common among those with depression (65%). Diabetes was almost more common among women with depression than among those without (24% vs. 14%).
Dr. Yaffe created two regression analyses. Model 1 controlled for age, race, and education. Model 2 controlled for the factors in Model 1, plus diabetes, hypertension, and cardiovascular disease.
By the end of follow-up, 4% of the group had developed dementia. The presence of depression approximately doubled the risk of dementia (hazard ratio, 2.14), compared with women who had neither depression nor PTSD. This risk was virtually unchanged in both Model 1 and Model 2 (HRs, 2.12 and 2.00).
The risk associated with PTSD was quite similar, increasing the risk of dementia twofold (HR, 2.19). Again, this was similar after controlling for the confounders in both Model 1 (HR, 2.20) and Model 2 (HR, 2.16).
Women with both depression and PTSD had almost a tripling of risk for dementia (HR, 2.71). Adjustment for confounders did not significantly alter this risk, either in Model 1 (HR, 2.59) or Model 2 (HR, 2.42).
“A question that often comes up in these types of studies is, ‘Is this a reverse causation?’ ” Dr. Yaffe said. “In other words, are people with dementia somehow getting more depression? We conducted a lag-time analysis that allowed a 2-year lag time for dementia, and also adjusted for the number of clinic visits. The results were almost identical.”
“This consistent doubling of risk is quite high,” Dr. Yaffe said. “In our prior work with male veterans, we didn’t see this robust an association.”
The study was funded by the Department of Defense and the National Institutes of Health. Dr. Yaffe had no financial disclosures.
Correction, 8/7/17: An earlier version of this article misstated Dr. Kristine Yaffe's degree.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – Women veterans with either depression or post-traumatic stress disorder face a doubling in their risk of dementia – and having both increases the risk even more, Dr. Kristine Yaffe reported at the Alzheimer’s Association International Conference.*
The risk ratios for incident dementia that Dr. Yaffe of the University of California, San Francisco, and her colleagues calculated from their analysis of a cohort of 149,000 older female veterans in the national Veterans Health Administration (VHA) database remained unchanged even when they adjusted for age, education, medical comorbidities, and other confounders.
Not only are older women veterans a growing group; they are frequently diagnosed with mental health disorders. In 2012, 45% of women veteran patients in the VHA had a mental health condition, Dr. Yaffe noted.
“Over 9% of all veterans in the U.S. are women, accounting for more than 2 million women veterans. And 30% of those are more than 55 years old. Additionally, the number of women utilizing the Veterans Healthcare Administration system has nearly doubled in the last decade.”
The study of the impact of depression and PTSD on incident dementia is the first of its kind, Dr. Yaffe noted. The cohort comprised women without dementia who had at least two VHA visits during 2005-2015. They were followed for a mean of 5 years. A diagnosis of depression or PTSD had to occur during a 2-year baseline period. Confounders considered in the analysis were demographics, medical comorbidities, and health habits, including alcohol and tobacco use. The primary outcome was time to incident dementia.
At baseline, the group was a mean of 67 years old. Most subjects (70%) were white. Hypertension was common (46%), as was diabetes (16%). About 6% had cardiovascular disease. Depression was present in 18% and PTSD in 4%.
When parsed by diagnosis, there were some significant between-group differences at baseline. Women with depression or PTSD were younger than those without (65 and 63 vs. 67 years). Women who had both disorders were the youngest group, at 62 years.
Hypertension was least common in women without depression or PTSD (41%), and most common among those with depression (65%). Diabetes was almost more common among women with depression than among those without (24% vs. 14%).
Dr. Yaffe created two regression analyses. Model 1 controlled for age, race, and education. Model 2 controlled for the factors in Model 1, plus diabetes, hypertension, and cardiovascular disease.
By the end of follow-up, 4% of the group had developed dementia. The presence of depression approximately doubled the risk of dementia (hazard ratio, 2.14), compared with women who had neither depression nor PTSD. This risk was virtually unchanged in both Model 1 and Model 2 (HRs, 2.12 and 2.00).
The risk associated with PTSD was quite similar, increasing the risk of dementia twofold (HR, 2.19). Again, this was similar after controlling for the confounders in both Model 1 (HR, 2.20) and Model 2 (HR, 2.16).
Women with both depression and PTSD had almost a tripling of risk for dementia (HR, 2.71). Adjustment for confounders did not significantly alter this risk, either in Model 1 (HR, 2.59) or Model 2 (HR, 2.42).
“A question that often comes up in these types of studies is, ‘Is this a reverse causation?’ ” Dr. Yaffe said. “In other words, are people with dementia somehow getting more depression? We conducted a lag-time analysis that allowed a 2-year lag time for dementia, and also adjusted for the number of clinic visits. The results were almost identical.”
“This consistent doubling of risk is quite high,” Dr. Yaffe said. “In our prior work with male veterans, we didn’t see this robust an association.”
The study was funded by the Department of Defense and the National Institutes of Health. Dr. Yaffe had no financial disclosures.
Correction, 8/7/17: An earlier version of this article misstated Dr. Kristine Yaffe's degree.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – Women veterans with either depression or post-traumatic stress disorder face a doubling in their risk of dementia – and having both increases the risk even more, Dr. Kristine Yaffe reported at the Alzheimer’s Association International Conference.*
The risk ratios for incident dementia that Dr. Yaffe of the University of California, San Francisco, and her colleagues calculated from their analysis of a cohort of 149,000 older female veterans in the national Veterans Health Administration (VHA) database remained unchanged even when they adjusted for age, education, medical comorbidities, and other confounders.
Not only are older women veterans a growing group; they are frequently diagnosed with mental health disorders. In 2012, 45% of women veteran patients in the VHA had a mental health condition, Dr. Yaffe noted.
“Over 9% of all veterans in the U.S. are women, accounting for more than 2 million women veterans. And 30% of those are more than 55 years old. Additionally, the number of women utilizing the Veterans Healthcare Administration system has nearly doubled in the last decade.”
The study of the impact of depression and PTSD on incident dementia is the first of its kind, Dr. Yaffe noted. The cohort comprised women without dementia who had at least two VHA visits during 2005-2015. They were followed for a mean of 5 years. A diagnosis of depression or PTSD had to occur during a 2-year baseline period. Confounders considered in the analysis were demographics, medical comorbidities, and health habits, including alcohol and tobacco use. The primary outcome was time to incident dementia.
At baseline, the group was a mean of 67 years old. Most subjects (70%) were white. Hypertension was common (46%), as was diabetes (16%). About 6% had cardiovascular disease. Depression was present in 18% and PTSD in 4%.
When parsed by diagnosis, there were some significant between-group differences at baseline. Women with depression or PTSD were younger than those without (65 and 63 vs. 67 years). Women who had both disorders were the youngest group, at 62 years.
Hypertension was least common in women without depression or PTSD (41%), and most common among those with depression (65%). Diabetes was almost more common among women with depression than among those without (24% vs. 14%).
Dr. Yaffe created two regression analyses. Model 1 controlled for age, race, and education. Model 2 controlled for the factors in Model 1, plus diabetes, hypertension, and cardiovascular disease.
By the end of follow-up, 4% of the group had developed dementia. The presence of depression approximately doubled the risk of dementia (hazard ratio, 2.14), compared with women who had neither depression nor PTSD. This risk was virtually unchanged in both Model 1 and Model 2 (HRs, 2.12 and 2.00).
The risk associated with PTSD was quite similar, increasing the risk of dementia twofold (HR, 2.19). Again, this was similar after controlling for the confounders in both Model 1 (HR, 2.20) and Model 2 (HR, 2.16).
Women with both depression and PTSD had almost a tripling of risk for dementia (HR, 2.71). Adjustment for confounders did not significantly alter this risk, either in Model 1 (HR, 2.59) or Model 2 (HR, 2.42).
“A question that often comes up in these types of studies is, ‘Is this a reverse causation?’ ” Dr. Yaffe said. “In other words, are people with dementia somehow getting more depression? We conducted a lag-time analysis that allowed a 2-year lag time for dementia, and also adjusted for the number of clinic visits. The results were almost identical.”
“This consistent doubling of risk is quite high,” Dr. Yaffe said. “In our prior work with male veterans, we didn’t see this robust an association.”
The study was funded by the Department of Defense and the National Institutes of Health. Dr. Yaffe had no financial disclosures.
Correction, 8/7/17: An earlier version of this article misstated Dr. Kristine Yaffe's degree.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT AAIC 2017
Key clinical point:
Major finding: Depression or PTSD both doubled the risk of dementia; both conditions together increased the risk by almost 2.5 times.
Data source: The retrospective cohort study comprised 149,000 women in the national Veterans Health Administration database.
Disclosures: The Department of Defense and National Institutes of Health Funded the study. The presenter had no financial disclosures.
Modifiable risk factors account for most of the dementia risk imposed by low socioeconomic status
LONDON – Twelve modifiable risk factors appear to account for more than half of the variation in dementia risk associated with socioeconomic status.
When integrated into an 18-point risk score, dubbed the “Lifestyle for Brain Health” (LIBRA) index, they accurately predicted dementia risk in more than 6,300 subjects who were followed for 7 years: Dementia risk increased by 30% for every 1-point increase on the LIBRA score, Sebastian Koehler, PhD, said at the Alzheimer’s Association International Conference.
According to Public Health England, 52% of citizens choose dementia prevention as a top health priority, but almost the same number believe that “there is nothing anyone can do to reduce their risk of getting dementia.” The LIBRA score could be employed as a public health measure to counteract that misunderstanding, he said.
“We can reduce the gap in risk that’s related to low socioeconomic status by improving health in that group. But we know that public health measures and messages are taken up much better by those with higher socioeconomic status. We think the first step is to raise awareness among this group that there is something we can do about dementia risk. And then we can reach out to this vulnerable group and design measures and messages that speak to both their needs and their resources.”
The 12 risk and protective factors were originally identified by epidemiologist Kay Deckers of Maastricht University, who drew them from a large meta-analysis published in 2015 (Int J Geriatr Psychiatry. 2015 Mar;30[3]:234-46).
They are the following:
• Diabetes.
• Hypertension.
• High cholesterol.
• Smoking.
• Obesity.
• Physical inactivity.
• Depression.
• Coronary heart disease.
• Kidney disease.
• Diet.
• Alcohol.
• Mental activity.
Dr. Koehler and his colleagues used them to create the weighted LIBRA score, which computes an 18-point risk level ranging from –5.9 (lower risk) to 12.7 (higher risk). Among the factors that reduce dementia risk are high cognitive activity, healthy diet or Mediterranean diet, and low-moderate alcohol intake. The others all increased risk. Each of the factors was assigned a point value based on its percentage of risk reduction or increase. For example, high cognitive activity reduced risk by more than 3 points, but depression increased it by 2 points. The investigators then validated this score on 6,346 participants in the English Longitudinal Study of Ageing, who were followed for up to 7 years.
Dr. Koehler’s study, however, was not just a LIBRA validation study. He wanted to correlate these protective and endangering factors with each subject’s socioeconomic status, and determine how much of the risk difference generally accredited to wealth was related to the LIBRA factors.
After 7 years, about 9% of the study sample developed incident dementia. These subjects were significantly older than those who didn’t (77 vs. 64 years). They were more likely to have lower education attainment (58% vs. 37%), and more likely to be poor (44% vs. 29%).
On the LIBRA risk factors, the participants who developed dementia were significantly more likely to have heart disease, diabetes, hypercholesterolemia, hypertension, and depression, although not significantly more likely to be obese or to smoke.
On the LIBRA protective factors, they were significantly less likely to be low-moderate alcohol users (37% vs. 57%), to have high cognitive activity (17% vs. 45%), and significantly more likely to be physically inactive (59% vs. 24%).
Two survival curves compared the incidence of dementia related to wealth and LIBRA score. Subjects of low socioeconomic status experienced an increase in dementia risk very similar to those with high LIBRA scores. Dr. Koehler also conducted three analyses that examined the effects of wealth on dementia risk: the total effect of wealth, the direct effect of wealth, and what he called the “indirect wealth effect.” This examined the impact of wealth on LIBRA scores, followed by the effect of these scores on dementia risk.
This final model concluded that 56% of the risk imposed by low socioeconomic status was actually attributable to LIBRA scores. In other words, low socioeconomic status was directly tied to both increases in physical and mental risk factors, and decreases in physical and mental protective factors.
“Health inequalities influencing dementia risk exist because of socioeconomic differences between people,” Dr. Koehler said. “People with less wealth have a higher frequency of being exposed to risk factors for dementia that are potentially treatable.”
The LIBRA study is part of a larger dementia prevention study called Innovative, Midlife Intervention for Dementia Deterrence (In-MINDD). Dr. Koehler had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – Twelve modifiable risk factors appear to account for more than half of the variation in dementia risk associated with socioeconomic status.
When integrated into an 18-point risk score, dubbed the “Lifestyle for Brain Health” (LIBRA) index, they accurately predicted dementia risk in more than 6,300 subjects who were followed for 7 years: Dementia risk increased by 30% for every 1-point increase on the LIBRA score, Sebastian Koehler, PhD, said at the Alzheimer’s Association International Conference.
According to Public Health England, 52% of citizens choose dementia prevention as a top health priority, but almost the same number believe that “there is nothing anyone can do to reduce their risk of getting dementia.” The LIBRA score could be employed as a public health measure to counteract that misunderstanding, he said.
“We can reduce the gap in risk that’s related to low socioeconomic status by improving health in that group. But we know that public health measures and messages are taken up much better by those with higher socioeconomic status. We think the first step is to raise awareness among this group that there is something we can do about dementia risk. And then we can reach out to this vulnerable group and design measures and messages that speak to both their needs and their resources.”
The 12 risk and protective factors were originally identified by epidemiologist Kay Deckers of Maastricht University, who drew them from a large meta-analysis published in 2015 (Int J Geriatr Psychiatry. 2015 Mar;30[3]:234-46).
They are the following:
• Diabetes.
• Hypertension.
• High cholesterol.
• Smoking.
• Obesity.
• Physical inactivity.
• Depression.
• Coronary heart disease.
• Kidney disease.
• Diet.
• Alcohol.
• Mental activity.
Dr. Koehler and his colleagues used them to create the weighted LIBRA score, which computes an 18-point risk level ranging from –5.9 (lower risk) to 12.7 (higher risk). Among the factors that reduce dementia risk are high cognitive activity, healthy diet or Mediterranean diet, and low-moderate alcohol intake. The others all increased risk. Each of the factors was assigned a point value based on its percentage of risk reduction or increase. For example, high cognitive activity reduced risk by more than 3 points, but depression increased it by 2 points. The investigators then validated this score on 6,346 participants in the English Longitudinal Study of Ageing, who were followed for up to 7 years.
Dr. Koehler’s study, however, was not just a LIBRA validation study. He wanted to correlate these protective and endangering factors with each subject’s socioeconomic status, and determine how much of the risk difference generally accredited to wealth was related to the LIBRA factors.
After 7 years, about 9% of the study sample developed incident dementia. These subjects were significantly older than those who didn’t (77 vs. 64 years). They were more likely to have lower education attainment (58% vs. 37%), and more likely to be poor (44% vs. 29%).
On the LIBRA risk factors, the participants who developed dementia were significantly more likely to have heart disease, diabetes, hypercholesterolemia, hypertension, and depression, although not significantly more likely to be obese or to smoke.
On the LIBRA protective factors, they were significantly less likely to be low-moderate alcohol users (37% vs. 57%), to have high cognitive activity (17% vs. 45%), and significantly more likely to be physically inactive (59% vs. 24%).
Two survival curves compared the incidence of dementia related to wealth and LIBRA score. Subjects of low socioeconomic status experienced an increase in dementia risk very similar to those with high LIBRA scores. Dr. Koehler also conducted three analyses that examined the effects of wealth on dementia risk: the total effect of wealth, the direct effect of wealth, and what he called the “indirect wealth effect.” This examined the impact of wealth on LIBRA scores, followed by the effect of these scores on dementia risk.
This final model concluded that 56% of the risk imposed by low socioeconomic status was actually attributable to LIBRA scores. In other words, low socioeconomic status was directly tied to both increases in physical and mental risk factors, and decreases in physical and mental protective factors.
“Health inequalities influencing dementia risk exist because of socioeconomic differences between people,” Dr. Koehler said. “People with less wealth have a higher frequency of being exposed to risk factors for dementia that are potentially treatable.”
The LIBRA study is part of a larger dementia prevention study called Innovative, Midlife Intervention for Dementia Deterrence (In-MINDD). Dr. Koehler had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – Twelve modifiable risk factors appear to account for more than half of the variation in dementia risk associated with socioeconomic status.
When integrated into an 18-point risk score, dubbed the “Lifestyle for Brain Health” (LIBRA) index, they accurately predicted dementia risk in more than 6,300 subjects who were followed for 7 years: Dementia risk increased by 30% for every 1-point increase on the LIBRA score, Sebastian Koehler, PhD, said at the Alzheimer’s Association International Conference.
According to Public Health England, 52% of citizens choose dementia prevention as a top health priority, but almost the same number believe that “there is nothing anyone can do to reduce their risk of getting dementia.” The LIBRA score could be employed as a public health measure to counteract that misunderstanding, he said.
“We can reduce the gap in risk that’s related to low socioeconomic status by improving health in that group. But we know that public health measures and messages are taken up much better by those with higher socioeconomic status. We think the first step is to raise awareness among this group that there is something we can do about dementia risk. And then we can reach out to this vulnerable group and design measures and messages that speak to both their needs and their resources.”
The 12 risk and protective factors were originally identified by epidemiologist Kay Deckers of Maastricht University, who drew them from a large meta-analysis published in 2015 (Int J Geriatr Psychiatry. 2015 Mar;30[3]:234-46).
They are the following:
• Diabetes.
• Hypertension.
• High cholesterol.
• Smoking.
• Obesity.
• Physical inactivity.
• Depression.
• Coronary heart disease.
• Kidney disease.
• Diet.
• Alcohol.
• Mental activity.
Dr. Koehler and his colleagues used them to create the weighted LIBRA score, which computes an 18-point risk level ranging from –5.9 (lower risk) to 12.7 (higher risk). Among the factors that reduce dementia risk are high cognitive activity, healthy diet or Mediterranean diet, and low-moderate alcohol intake. The others all increased risk. Each of the factors was assigned a point value based on its percentage of risk reduction or increase. For example, high cognitive activity reduced risk by more than 3 points, but depression increased it by 2 points. The investigators then validated this score on 6,346 participants in the English Longitudinal Study of Ageing, who were followed for up to 7 years.
Dr. Koehler’s study, however, was not just a LIBRA validation study. He wanted to correlate these protective and endangering factors with each subject’s socioeconomic status, and determine how much of the risk difference generally accredited to wealth was related to the LIBRA factors.
After 7 years, about 9% of the study sample developed incident dementia. These subjects were significantly older than those who didn’t (77 vs. 64 years). They were more likely to have lower education attainment (58% vs. 37%), and more likely to be poor (44% vs. 29%).
On the LIBRA risk factors, the participants who developed dementia were significantly more likely to have heart disease, diabetes, hypercholesterolemia, hypertension, and depression, although not significantly more likely to be obese or to smoke.
On the LIBRA protective factors, they were significantly less likely to be low-moderate alcohol users (37% vs. 57%), to have high cognitive activity (17% vs. 45%), and significantly more likely to be physically inactive (59% vs. 24%).
Two survival curves compared the incidence of dementia related to wealth and LIBRA score. Subjects of low socioeconomic status experienced an increase in dementia risk very similar to those with high LIBRA scores. Dr. Koehler also conducted three analyses that examined the effects of wealth on dementia risk: the total effect of wealth, the direct effect of wealth, and what he called the “indirect wealth effect.” This examined the impact of wealth on LIBRA scores, followed by the effect of these scores on dementia risk.
This final model concluded that 56% of the risk imposed by low socioeconomic status was actually attributable to LIBRA scores. In other words, low socioeconomic status was directly tied to both increases in physical and mental risk factors, and decreases in physical and mental protective factors.
“Health inequalities influencing dementia risk exist because of socioeconomic differences between people,” Dr. Koehler said. “People with less wealth have a higher frequency of being exposed to risk factors for dementia that are potentially treatable.”
The LIBRA study is part of a larger dementia prevention study called Innovative, Midlife Intervention for Dementia Deterrence (In-MINDD). Dr. Koehler had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT AAIC 2017
Key clinical point:
Major finding: The factors accounted for 56% of the risk imposed by low SES.
Data source: The LIBRA validation study comprised more than 6,300 subjects.
Disclosures: The LIBRA study is part of a larger dementia prevention study called In-MINDD. Dr. Koehler had no financial disclosures.
Racial differences in dementia risk persist from midlife to oldest old
LONDON – The racial and ethnic patterns of dementia risk seen in older adults appear to hold steady even in the oldest old, with blacks about 30% more likely than are whites to develop the disorder even well into their 90s.
The magnitude of disparity remained consistent even after researchers controlled for traditional risk factors such as access to health care, cardiovascular risk, stroke, and education, Maria Corrada, ScD, said at the Alzheimer’s Association International Conference.
“These are the first estimates of dementia in a diverse cohort of subjects 90 years or older,” said Dr. Corrada, a professor of epidemiology at the University of California, Irvine. “The racial and ethnic differences in dementia incidence didn’t appear to be due to these factors that we have come to expect. These estimates can provide us with an important foundation for understanding the burden of racial disparities in the oldest old, which is the fastest-growing segment of our population in the U.S. and in many other countries.”
Most of the cohort (72%) was white; blacks comprised 16%, Latinos 4%, and Asians 7%. Not surprisingly, most were women (65%). The mean age at baseline was 93 years. Overall, 50% had at least a high school education, but that percentage was higher in whites (56%) and lower in blacks and Latinos (33% and 24%, respectively).
Midlife obesity was present in 42% overall, but this was significantly higher in blacks and Latinos (63%), and lower in whites and Asians (38% and 24%). Midlife hypertension was present in 38% overall. This was highest in blacks (63%), followed by Latinos (42%) and whites (35%). Only 7% of Asians had high blood pressure in midlife. About 40% of each group had experienced a late-life stroke, with the exception of Asians, with a stroke incidence of just 7%. Diabetes was present in 24% overall, in 20% of whites, and about a third of the other groups.
Over the follow-up period, dementia developed in 33% of subjects, at a mean age of 95 years, which did not vary among groups. The incidence of dementia was lowest in whites (32%) and Asians (31%). It was most frequent in blacks (39%), followed by Latinos (35%). The age-adjusted, 5-year incidence rate was 10% overall. It was lowest in Asians (9%) and whites (9.7%), followed by Latinos (10.6%); it was highest in blacks (12%).
Dr. Corrada then conducted a series of five multivariate regression analyses to examine the effect of various risk factors on dementia. The first three controlled for age alone; for age and education; and for age, education, and midlife risk factors of obesity, hypertension, and cholesterol levels. In every model, blacks were 30% more likely to develop dementia over the follow-up period than were whites. Model 4 controlled for age, education, and the late-life risk factors of stroke, depression, ischemic heart disease, heart failure, and heart attack. Model 5 controlled for age, education, and both the late- and midlife risk factors.
Again, no matter which model was used, blacks faced the same 30% increased risk, compared with whites. “The differences remained very consistent,” Dr. Corrada said. “The patterns of racial and ethnic disparity seen in younger elderly continued well after age 90.”
Dr. Corrada had no financial conflicts of interest.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – The racial and ethnic patterns of dementia risk seen in older adults appear to hold steady even in the oldest old, with blacks about 30% more likely than are whites to develop the disorder even well into their 90s.
The magnitude of disparity remained consistent even after researchers controlled for traditional risk factors such as access to health care, cardiovascular risk, stroke, and education, Maria Corrada, ScD, said at the Alzheimer’s Association International Conference.
“These are the first estimates of dementia in a diverse cohort of subjects 90 years or older,” said Dr. Corrada, a professor of epidemiology at the University of California, Irvine. “The racial and ethnic differences in dementia incidence didn’t appear to be due to these factors that we have come to expect. These estimates can provide us with an important foundation for understanding the burden of racial disparities in the oldest old, which is the fastest-growing segment of our population in the U.S. and in many other countries.”
Most of the cohort (72%) was white; blacks comprised 16%, Latinos 4%, and Asians 7%. Not surprisingly, most were women (65%). The mean age at baseline was 93 years. Overall, 50% had at least a high school education, but that percentage was higher in whites (56%) and lower in blacks and Latinos (33% and 24%, respectively).
Midlife obesity was present in 42% overall, but this was significantly higher in blacks and Latinos (63%), and lower in whites and Asians (38% and 24%). Midlife hypertension was present in 38% overall. This was highest in blacks (63%), followed by Latinos (42%) and whites (35%). Only 7% of Asians had high blood pressure in midlife. About 40% of each group had experienced a late-life stroke, with the exception of Asians, with a stroke incidence of just 7%. Diabetes was present in 24% overall, in 20% of whites, and about a third of the other groups.
Over the follow-up period, dementia developed in 33% of subjects, at a mean age of 95 years, which did not vary among groups. The incidence of dementia was lowest in whites (32%) and Asians (31%). It was most frequent in blacks (39%), followed by Latinos (35%). The age-adjusted, 5-year incidence rate was 10% overall. It was lowest in Asians (9%) and whites (9.7%), followed by Latinos (10.6%); it was highest in blacks (12%).
Dr. Corrada then conducted a series of five multivariate regression analyses to examine the effect of various risk factors on dementia. The first three controlled for age alone; for age and education; and for age, education, and midlife risk factors of obesity, hypertension, and cholesterol levels. In every model, blacks were 30% more likely to develop dementia over the follow-up period than were whites. Model 4 controlled for age, education, and the late-life risk factors of stroke, depression, ischemic heart disease, heart failure, and heart attack. Model 5 controlled for age, education, and both the late- and midlife risk factors.
Again, no matter which model was used, blacks faced the same 30% increased risk, compared with whites. “The differences remained very consistent,” Dr. Corrada said. “The patterns of racial and ethnic disparity seen in younger elderly continued well after age 90.”
Dr. Corrada had no financial conflicts of interest.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – The racial and ethnic patterns of dementia risk seen in older adults appear to hold steady even in the oldest old, with blacks about 30% more likely than are whites to develop the disorder even well into their 90s.
The magnitude of disparity remained consistent even after researchers controlled for traditional risk factors such as access to health care, cardiovascular risk, stroke, and education, Maria Corrada, ScD, said at the Alzheimer’s Association International Conference.
“These are the first estimates of dementia in a diverse cohort of subjects 90 years or older,” said Dr. Corrada, a professor of epidemiology at the University of California, Irvine. “The racial and ethnic differences in dementia incidence didn’t appear to be due to these factors that we have come to expect. These estimates can provide us with an important foundation for understanding the burden of racial disparities in the oldest old, which is the fastest-growing segment of our population in the U.S. and in many other countries.”
Most of the cohort (72%) was white; blacks comprised 16%, Latinos 4%, and Asians 7%. Not surprisingly, most were women (65%). The mean age at baseline was 93 years. Overall, 50% had at least a high school education, but that percentage was higher in whites (56%) and lower in blacks and Latinos (33% and 24%, respectively).
Midlife obesity was present in 42% overall, but this was significantly higher in blacks and Latinos (63%), and lower in whites and Asians (38% and 24%). Midlife hypertension was present in 38% overall. This was highest in blacks (63%), followed by Latinos (42%) and whites (35%). Only 7% of Asians had high blood pressure in midlife. About 40% of each group had experienced a late-life stroke, with the exception of Asians, with a stroke incidence of just 7%. Diabetes was present in 24% overall, in 20% of whites, and about a third of the other groups.
Over the follow-up period, dementia developed in 33% of subjects, at a mean age of 95 years, which did not vary among groups. The incidence of dementia was lowest in whites (32%) and Asians (31%). It was most frequent in blacks (39%), followed by Latinos (35%). The age-adjusted, 5-year incidence rate was 10% overall. It was lowest in Asians (9%) and whites (9.7%), followed by Latinos (10.6%); it was highest in blacks (12%).
Dr. Corrada then conducted a series of five multivariate regression analyses to examine the effect of various risk factors on dementia. The first three controlled for age alone; for age and education; and for age, education, and midlife risk factors of obesity, hypertension, and cholesterol levels. In every model, blacks were 30% more likely to develop dementia over the follow-up period than were whites. Model 4 controlled for age, education, and the late-life risk factors of stroke, depression, ischemic heart disease, heart failure, and heart attack. Model 5 controlled for age, education, and both the late- and midlife risk factors.
Again, no matter which model was used, blacks faced the same 30% increased risk, compared with whites. “The differences remained very consistent,” Dr. Corrada said. “The patterns of racial and ethnic disparity seen in younger elderly continued well after age 90.”
Dr. Corrada had no financial conflicts of interest.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT AAIC 2017
Key clinical point:
Major finding: Blacks were 30% more likely to develop dementia than were whites, even after researchers controlled for age, education, and mid- and late-life health–related risk factors.
Data source: The 5-year prospective study comprised more than 2,000 subjects aged 90 years and older.
Disclosures: The presenter had no financial disclosures.
Life-long risk reduction could cut late-life dementia by up to 35%
LONDON – As many as a third of dementia cases could be prevented worldwide if society could adopt a life course–focused approach of supporting brain health with mostly common-sense measures.
Improving childhood education, controlling blood pressure and cholesterol, keeping socially and intellectually active, exercising, and ceasing tobacco use are among the recommendations to reduce the incidence of dementia made by a worldwide panel of expert clinicians and researchers.
The findings are part of an exhaustive report commission by The Lancet and released at the Alzheimer’s Association International Conference. The report has concluded that nine lifestyle factors, most of which are modifiable from childhood though middle age, account for 35% of dementia that strikes elderly persons, Gillian Livingston, MD, said at the conference. The report was simultaneously published.
Being homozygous for the ApoE4 allele confers about an immutable 7% increased chance of developing Alzheimer’s disease. But two of the other factors identified in the Lancet report, low education in childhood and hearing loss at middle age, confer even higher individual risks of 8% and 9%. And when combined with other mid-life risks of hypertension and obesity, and late-life risks imposed by smoking, depression, inactivity, social isolation, and diabetes, these factors not only dwarf the potential impact of ApoE4, but offer a lifelong chance to forestall or even prevent dementia.
The findings, all gathered from an exhaustive literature review, bolster the notion that public health interventions could block the tsunami of dementia cases that threaten to overwhelm the world’s health care resources by 2050, Dr. Livingston said.
“While public health interventions won’t prevent or cure all potentially modifiable dementia, intervention for cardiovascular risk factors, mental health, and hearing may push back the onset in many people for years. Even if only some of this promise is realized, it could make a huge difference. We have, in fact, already seen that in some populations dementia is being delayed for years. If we could achieve an overall delay of onset by 5 years, we could cut the global prevalence by half.”
The Lancet commissioned the panel of global dementia experts to review the extant literature and construct a lifespan-focused risk model. In addition to examining risk and making recommendations to ameliorate it, the panel issued recommendations about treating cognition and psychiatric and behavioral problems; protecting dementia patients in both home and long-term care settings; supporting the family members who provide most of the care for dementia patients; and helping patients and families navigate end-of-life situations.
The literature review identified nine modifiable risk factors that account for 35% of dementia risk worldwide:
• Education in youth. Less education in childhood, which the commission identified as a lack of secondary schooling, increased the risk of dementia by 8%. Improving education at this age would remove this portion of the population attributable risk factor (PAF), Dr. Livingston said.
This finding represents an enormous opportunity for improvement: The decline in dementia incidence seen in some populations occurs mostly among the better-educated. “The mechanism of prevention here appears to be increasing brain resilience,” said Lon Schneider, MD, a member of the Lancet panel.
Tackling poor childhood education is a daunting task and requires commitment from both public and private sectors, the report noted, but its importance cannot be overstated.
• Hearing loss at mid-life. This emerged as the most powerful risk factor in the analysis, conferring an independent 9% increased risk of dementia, “a relatively new idea that has not been included in previous calculations of population attributable factors,” the commission wrote. The mechanism of increased risk isn’t clear, but may be a combination of neurodegeneration and social isolation imposed by being shut out of easy communication. It’s unclear whether hearing aids can mitigate the effects of hearing loss on dementia risk, the report noted.
• Hypertension, obesity, and diabetes. Respectively, these accounted for 2%, 1%, and 1% of the PAF. Obesity is linked to prediabetes and diabetes, which are in turn linked to insulin resistance, decreased brain amyloid clearance, high blood glucose, and inflammation – all risks for Alzheimer’s disease.
The report recommends that anyone aged 45-65 years who has hypertension should be actively treated for the disorder.
• Smoking. At 5%, smoking posted the third-highest PAF. The risk is probably mediated through smoking’s detrimental effects on cardiovascular health. But the report noted that tobacco smoke contains known neurotoxins as well.
Preventing the smoking/dementia connection is simple, Dr. Livingston said. “Simply stop smoking. If you’re smoking, just stop. Please.”
• Depression. Depression in late life imposed a 4% PAF. The evidence reviewed suggested that depression is not, in fact, linked to dementia when experienced at mid-life. But late-life depression may be a prodromal symptom of dementia and biologically linked to increased stress hormones, decreased neuronal growth factors, and decreased hippocampal volume. The commission noted animal models that suggest some antidepressants, including citalopram, decrease amyloid progression.
• Social isolation. Associated with a 2% PAF, social isolation may, like depression, be a prodromal symptom. But, the report said, there is growing evidence that it actually is an independent risk factor as well. It has been shown to also increase the risk of hypertension, cardiovascular disease, and depression, all dementia risk factors in their own right.
Longitudinal studies suggest that social activities and personal connections may prevent or delay dementia, although top-grade evidence is lacking. Still, maintaining a rich social network not only reduces the chance of isolation, but helps prevent depression as well.
• Physical inactivity. Sedentary lifestyle carried a 3% PAF for dementia. Older adults who maintain physical activity are more likely to remain cognitively intact. Physical exercise improves mood, reduces the risk of falls, and maintains normal physical function. The report cited a meta-analysis of 16 studies and almost 164,000 participants without dementia; it concluded that those in the highest level of activity had a 25% decreased risk of all-cause dementia and a 45% decreased risk of Alzheimer’s disease.
The strongest evidence for exercise’s benefit on cognition may be from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Patients with a high risk of dementia who completed the lifestyle modification program of healthy diet cognitive training, vascular risk factor management, and aerobic exercise showed a slowing of cognitive decline and improvements in executive function and processing speed.
Becoming aware of the risk factors is one thing, the report said. Doing something about them is another. In general, the first step is to “be ambitious” about prevention.
“Prevention is always better than treatment,” Dr. Livingston said in an interview. “We need to start thinking about dementia not as something that simply happens outside our control, but as something that we can have an effect on.”
The Lancet commissioned the report. Dr. Livingston did not have any financial declarations but many of the other authors reported multiple relationships with pharmaceutical companies.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – As many as a third of dementia cases could be prevented worldwide if society could adopt a life course–focused approach of supporting brain health with mostly common-sense measures.
Improving childhood education, controlling blood pressure and cholesterol, keeping socially and intellectually active, exercising, and ceasing tobacco use are among the recommendations to reduce the incidence of dementia made by a worldwide panel of expert clinicians and researchers.
The findings are part of an exhaustive report commission by The Lancet and released at the Alzheimer’s Association International Conference. The report has concluded that nine lifestyle factors, most of which are modifiable from childhood though middle age, account for 35% of dementia that strikes elderly persons, Gillian Livingston, MD, said at the conference. The report was simultaneously published.
Being homozygous for the ApoE4 allele confers about an immutable 7% increased chance of developing Alzheimer’s disease. But two of the other factors identified in the Lancet report, low education in childhood and hearing loss at middle age, confer even higher individual risks of 8% and 9%. And when combined with other mid-life risks of hypertension and obesity, and late-life risks imposed by smoking, depression, inactivity, social isolation, and diabetes, these factors not only dwarf the potential impact of ApoE4, but offer a lifelong chance to forestall or even prevent dementia.
The findings, all gathered from an exhaustive literature review, bolster the notion that public health interventions could block the tsunami of dementia cases that threaten to overwhelm the world’s health care resources by 2050, Dr. Livingston said.
“While public health interventions won’t prevent or cure all potentially modifiable dementia, intervention for cardiovascular risk factors, mental health, and hearing may push back the onset in many people for years. Even if only some of this promise is realized, it could make a huge difference. We have, in fact, already seen that in some populations dementia is being delayed for years. If we could achieve an overall delay of onset by 5 years, we could cut the global prevalence by half.”
The Lancet commissioned the panel of global dementia experts to review the extant literature and construct a lifespan-focused risk model. In addition to examining risk and making recommendations to ameliorate it, the panel issued recommendations about treating cognition and psychiatric and behavioral problems; protecting dementia patients in both home and long-term care settings; supporting the family members who provide most of the care for dementia patients; and helping patients and families navigate end-of-life situations.
The literature review identified nine modifiable risk factors that account for 35% of dementia risk worldwide:
• Education in youth. Less education in childhood, which the commission identified as a lack of secondary schooling, increased the risk of dementia by 8%. Improving education at this age would remove this portion of the population attributable risk factor (PAF), Dr. Livingston said.
This finding represents an enormous opportunity for improvement: The decline in dementia incidence seen in some populations occurs mostly among the better-educated. “The mechanism of prevention here appears to be increasing brain resilience,” said Lon Schneider, MD, a member of the Lancet panel.
Tackling poor childhood education is a daunting task and requires commitment from both public and private sectors, the report noted, but its importance cannot be overstated.
• Hearing loss at mid-life. This emerged as the most powerful risk factor in the analysis, conferring an independent 9% increased risk of dementia, “a relatively new idea that has not been included in previous calculations of population attributable factors,” the commission wrote. The mechanism of increased risk isn’t clear, but may be a combination of neurodegeneration and social isolation imposed by being shut out of easy communication. It’s unclear whether hearing aids can mitigate the effects of hearing loss on dementia risk, the report noted.
• Hypertension, obesity, and diabetes. Respectively, these accounted for 2%, 1%, and 1% of the PAF. Obesity is linked to prediabetes and diabetes, which are in turn linked to insulin resistance, decreased brain amyloid clearance, high blood glucose, and inflammation – all risks for Alzheimer’s disease.
The report recommends that anyone aged 45-65 years who has hypertension should be actively treated for the disorder.
• Smoking. At 5%, smoking posted the third-highest PAF. The risk is probably mediated through smoking’s detrimental effects on cardiovascular health. But the report noted that tobacco smoke contains known neurotoxins as well.
Preventing the smoking/dementia connection is simple, Dr. Livingston said. “Simply stop smoking. If you’re smoking, just stop. Please.”
• Depression. Depression in late life imposed a 4% PAF. The evidence reviewed suggested that depression is not, in fact, linked to dementia when experienced at mid-life. But late-life depression may be a prodromal symptom of dementia and biologically linked to increased stress hormones, decreased neuronal growth factors, and decreased hippocampal volume. The commission noted animal models that suggest some antidepressants, including citalopram, decrease amyloid progression.
• Social isolation. Associated with a 2% PAF, social isolation may, like depression, be a prodromal symptom. But, the report said, there is growing evidence that it actually is an independent risk factor as well. It has been shown to also increase the risk of hypertension, cardiovascular disease, and depression, all dementia risk factors in their own right.
Longitudinal studies suggest that social activities and personal connections may prevent or delay dementia, although top-grade evidence is lacking. Still, maintaining a rich social network not only reduces the chance of isolation, but helps prevent depression as well.
• Physical inactivity. Sedentary lifestyle carried a 3% PAF for dementia. Older adults who maintain physical activity are more likely to remain cognitively intact. Physical exercise improves mood, reduces the risk of falls, and maintains normal physical function. The report cited a meta-analysis of 16 studies and almost 164,000 participants without dementia; it concluded that those in the highest level of activity had a 25% decreased risk of all-cause dementia and a 45% decreased risk of Alzheimer’s disease.
The strongest evidence for exercise’s benefit on cognition may be from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Patients with a high risk of dementia who completed the lifestyle modification program of healthy diet cognitive training, vascular risk factor management, and aerobic exercise showed a slowing of cognitive decline and improvements in executive function and processing speed.
Becoming aware of the risk factors is one thing, the report said. Doing something about them is another. In general, the first step is to “be ambitious” about prevention.
“Prevention is always better than treatment,” Dr. Livingston said in an interview. “We need to start thinking about dementia not as something that simply happens outside our control, but as something that we can have an effect on.”
The Lancet commissioned the report. Dr. Livingston did not have any financial declarations but many of the other authors reported multiple relationships with pharmaceutical companies.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – As many as a third of dementia cases could be prevented worldwide if society could adopt a life course–focused approach of supporting brain health with mostly common-sense measures.
Improving childhood education, controlling blood pressure and cholesterol, keeping socially and intellectually active, exercising, and ceasing tobacco use are among the recommendations to reduce the incidence of dementia made by a worldwide panel of expert clinicians and researchers.
The findings are part of an exhaustive report commission by The Lancet and released at the Alzheimer’s Association International Conference. The report has concluded that nine lifestyle factors, most of which are modifiable from childhood though middle age, account for 35% of dementia that strikes elderly persons, Gillian Livingston, MD, said at the conference. The report was simultaneously published.
Being homozygous for the ApoE4 allele confers about an immutable 7% increased chance of developing Alzheimer’s disease. But two of the other factors identified in the Lancet report, low education in childhood and hearing loss at middle age, confer even higher individual risks of 8% and 9%. And when combined with other mid-life risks of hypertension and obesity, and late-life risks imposed by smoking, depression, inactivity, social isolation, and diabetes, these factors not only dwarf the potential impact of ApoE4, but offer a lifelong chance to forestall or even prevent dementia.
The findings, all gathered from an exhaustive literature review, bolster the notion that public health interventions could block the tsunami of dementia cases that threaten to overwhelm the world’s health care resources by 2050, Dr. Livingston said.
“While public health interventions won’t prevent or cure all potentially modifiable dementia, intervention for cardiovascular risk factors, mental health, and hearing may push back the onset in many people for years. Even if only some of this promise is realized, it could make a huge difference. We have, in fact, already seen that in some populations dementia is being delayed for years. If we could achieve an overall delay of onset by 5 years, we could cut the global prevalence by half.”
The Lancet commissioned the panel of global dementia experts to review the extant literature and construct a lifespan-focused risk model. In addition to examining risk and making recommendations to ameliorate it, the panel issued recommendations about treating cognition and psychiatric and behavioral problems; protecting dementia patients in both home and long-term care settings; supporting the family members who provide most of the care for dementia patients; and helping patients and families navigate end-of-life situations.
The literature review identified nine modifiable risk factors that account for 35% of dementia risk worldwide:
• Education in youth. Less education in childhood, which the commission identified as a lack of secondary schooling, increased the risk of dementia by 8%. Improving education at this age would remove this portion of the population attributable risk factor (PAF), Dr. Livingston said.
This finding represents an enormous opportunity for improvement: The decline in dementia incidence seen in some populations occurs mostly among the better-educated. “The mechanism of prevention here appears to be increasing brain resilience,” said Lon Schneider, MD, a member of the Lancet panel.
Tackling poor childhood education is a daunting task and requires commitment from both public and private sectors, the report noted, but its importance cannot be overstated.
• Hearing loss at mid-life. This emerged as the most powerful risk factor in the analysis, conferring an independent 9% increased risk of dementia, “a relatively new idea that has not been included in previous calculations of population attributable factors,” the commission wrote. The mechanism of increased risk isn’t clear, but may be a combination of neurodegeneration and social isolation imposed by being shut out of easy communication. It’s unclear whether hearing aids can mitigate the effects of hearing loss on dementia risk, the report noted.
• Hypertension, obesity, and diabetes. Respectively, these accounted for 2%, 1%, and 1% of the PAF. Obesity is linked to prediabetes and diabetes, which are in turn linked to insulin resistance, decreased brain amyloid clearance, high blood glucose, and inflammation – all risks for Alzheimer’s disease.
The report recommends that anyone aged 45-65 years who has hypertension should be actively treated for the disorder.
• Smoking. At 5%, smoking posted the third-highest PAF. The risk is probably mediated through smoking’s detrimental effects on cardiovascular health. But the report noted that tobacco smoke contains known neurotoxins as well.
Preventing the smoking/dementia connection is simple, Dr. Livingston said. “Simply stop smoking. If you’re smoking, just stop. Please.”
• Depression. Depression in late life imposed a 4% PAF. The evidence reviewed suggested that depression is not, in fact, linked to dementia when experienced at mid-life. But late-life depression may be a prodromal symptom of dementia and biologically linked to increased stress hormones, decreased neuronal growth factors, and decreased hippocampal volume. The commission noted animal models that suggest some antidepressants, including citalopram, decrease amyloid progression.
• Social isolation. Associated with a 2% PAF, social isolation may, like depression, be a prodromal symptom. But, the report said, there is growing evidence that it actually is an independent risk factor as well. It has been shown to also increase the risk of hypertension, cardiovascular disease, and depression, all dementia risk factors in their own right.
Longitudinal studies suggest that social activities and personal connections may prevent or delay dementia, although top-grade evidence is lacking. Still, maintaining a rich social network not only reduces the chance of isolation, but helps prevent depression as well.
• Physical inactivity. Sedentary lifestyle carried a 3% PAF for dementia. Older adults who maintain physical activity are more likely to remain cognitively intact. Physical exercise improves mood, reduces the risk of falls, and maintains normal physical function. The report cited a meta-analysis of 16 studies and almost 164,000 participants without dementia; it concluded that those in the highest level of activity had a 25% decreased risk of all-cause dementia and a 45% decreased risk of Alzheimer’s disease.
The strongest evidence for exercise’s benefit on cognition may be from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Patients with a high risk of dementia who completed the lifestyle modification program of healthy diet cognitive training, vascular risk factor management, and aerobic exercise showed a slowing of cognitive decline and improvements in executive function and processing speed.
Becoming aware of the risk factors is one thing, the report said. Doing something about them is another. In general, the first step is to “be ambitious” about prevention.
“Prevention is always better than treatment,” Dr. Livingston said in an interview. “We need to start thinking about dementia not as something that simply happens outside our control, but as something that we can have an effect on.”
The Lancet commissioned the report. Dr. Livingston did not have any financial declarations but many of the other authors reported multiple relationships with pharmaceutical companies.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT AAIC 2017
Amyloid PET imaging impacts diagnoses, management for those with MCI and dementia
LONDON – A study to prove the practical clinical utility of amyloid PET scanning appears to be doing just that: The knowledge of patients’ brain amyloid status changed clinical management for 68% of those who had the imaging done.
Interim results of the Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study far exceeded the 30% change rate that investigators hoped to see, Gil Rabinovici, MD, said at the Alzheimer’s Association International Conference. Not only did many patients receive a more suitable care plan, the scans actually changed diagnoses in three-quarters of those who tested positive, said Dr. Rabinovici of the University of California, San Francisco.
The U.S.-wide, open-label study is being conducted in Medicare beneficiaries who have been diagnosed with mild cognitive impairment (MCI) or dementia of uncertain cause. Its two goals are to show that amyloid PET imaging affects a patient’s care plan within 3 months of the scan and to show an impact on major medical outcomes 12 months later. In diagnostically uncertain cases, investigators theorized, amyloid PET imaging would lead to significant changes in patient management, which would then translate into improved medical outcomes.
At the meeting, Dr. Rabinovici discussed the preplanned interim analysis of 3-month care plan changes. After the scan was completed, physicians related the results to patients and recommended any appropriate management changes. At the 90-day post-scan visit, physicians documented how any changes had been implemented. Data on the 12-month outcomes have not been announced on any portion of the cohort.
The patients were a mean of 76 years old; 64% had a diagnosis of MCI and 36% a diagnosis of dementia. Alzheimer’s disease was the suspected etiology in 74% of the MCI group and in 80% of the dementia group. About one-third of MCI patients and two-thirds of dementia patients were taking Alzheimer’s medications at enrollment.
The scans were positive in 54% of the MCI patients and in 70% of dementia patients. In amyloid-positive patients, the rate of Alzheimer’s diagnosis increased from 78% to 85%. In amyloid-negative patients, the rate of Alzheimer’s diagnosis decreased from 73% to 14%.
More than two-thirds of patients in both groups experienced a change in management after the scans were read. Changes in Alzheimer’s drugs occurred in 48% of both groups, while changes in non-Alzheimer’s drugs occurred in 36% of the MCI group and 32% of the dementia group. In amyloid-positive patients, use of Alzheimer’s drugs increased from 51% to 84%. In amyloid-negative patients, the use of Alzheimer’s drugs decreased from 39% to 31%.
Patient counseling also changed in 24% of the MCI group and 16% of the dementia group.
Dr. Rabinovici was cautiously optimistic about the interim results. “The study has two aims, and Medicare has made it clear that we need to complete both before they will consider covering the scans. I hope they understand that these changes in management are incredibly important, but they also want to see that they result in improved outcomes. That will take a year from when we enroll our last patient.”
Although the study is designed to show change in clinical outcomes, it’s also changing something less tangible, but no less important: patients’ understanding of their situation.
“We may be looking at objective changes in management, but we are also seeing that patients really want to know what’s going on in their brain, what the cause of their cognitive impairment is. They don’t want to be told that it’s normal aging, because they know it isn’t. There is a real value to getting that diagnosis, even if it’s the bad news that there are amyloid plaques in the brain. It leads to a clear plan in terms of what drugs to use, the possibility of enrolling in clinical trials, and getting some clarity about what’s going on. A lot of times, the certainty is better than the uncertainty.”
As of June, IDEAS had recruited 12,484 patients and completed 11,712 amyloid PET scans. Dr. Rabinovici hopes the recruitment will be completed by late this year, or early 2018.
IDEAS is being funded by the Centers for Medicare & Medicaid Services, Avid Radiopharmaceuticals/Eli Lilly, GE Healthcare, Piramal Imaging, the Alzheimer’s Association, and the American College of Radiology. Dr. Rabinovici has received honoraria or consulting fees from Eisai, Genentech, Lundbeck, Merck, Putnam, and Roche.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – A study to prove the practical clinical utility of amyloid PET scanning appears to be doing just that: The knowledge of patients’ brain amyloid status changed clinical management for 68% of those who had the imaging done.
Interim results of the Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study far exceeded the 30% change rate that investigators hoped to see, Gil Rabinovici, MD, said at the Alzheimer’s Association International Conference. Not only did many patients receive a more suitable care plan, the scans actually changed diagnoses in three-quarters of those who tested positive, said Dr. Rabinovici of the University of California, San Francisco.
The U.S.-wide, open-label study is being conducted in Medicare beneficiaries who have been diagnosed with mild cognitive impairment (MCI) or dementia of uncertain cause. Its two goals are to show that amyloid PET imaging affects a patient’s care plan within 3 months of the scan and to show an impact on major medical outcomes 12 months later. In diagnostically uncertain cases, investigators theorized, amyloid PET imaging would lead to significant changes in patient management, which would then translate into improved medical outcomes.
At the meeting, Dr. Rabinovici discussed the preplanned interim analysis of 3-month care plan changes. After the scan was completed, physicians related the results to patients and recommended any appropriate management changes. At the 90-day post-scan visit, physicians documented how any changes had been implemented. Data on the 12-month outcomes have not been announced on any portion of the cohort.
The patients were a mean of 76 years old; 64% had a diagnosis of MCI and 36% a diagnosis of dementia. Alzheimer’s disease was the suspected etiology in 74% of the MCI group and in 80% of the dementia group. About one-third of MCI patients and two-thirds of dementia patients were taking Alzheimer’s medications at enrollment.
The scans were positive in 54% of the MCI patients and in 70% of dementia patients. In amyloid-positive patients, the rate of Alzheimer’s diagnosis increased from 78% to 85%. In amyloid-negative patients, the rate of Alzheimer’s diagnosis decreased from 73% to 14%.
More than two-thirds of patients in both groups experienced a change in management after the scans were read. Changes in Alzheimer’s drugs occurred in 48% of both groups, while changes in non-Alzheimer’s drugs occurred in 36% of the MCI group and 32% of the dementia group. In amyloid-positive patients, use of Alzheimer’s drugs increased from 51% to 84%. In amyloid-negative patients, the use of Alzheimer’s drugs decreased from 39% to 31%.
Patient counseling also changed in 24% of the MCI group and 16% of the dementia group.
Dr. Rabinovici was cautiously optimistic about the interim results. “The study has two aims, and Medicare has made it clear that we need to complete both before they will consider covering the scans. I hope they understand that these changes in management are incredibly important, but they also want to see that they result in improved outcomes. That will take a year from when we enroll our last patient.”
Although the study is designed to show change in clinical outcomes, it’s also changing something less tangible, but no less important: patients’ understanding of their situation.
“We may be looking at objective changes in management, but we are also seeing that patients really want to know what’s going on in their brain, what the cause of their cognitive impairment is. They don’t want to be told that it’s normal aging, because they know it isn’t. There is a real value to getting that diagnosis, even if it’s the bad news that there are amyloid plaques in the brain. It leads to a clear plan in terms of what drugs to use, the possibility of enrolling in clinical trials, and getting some clarity about what’s going on. A lot of times, the certainty is better than the uncertainty.”
As of June, IDEAS had recruited 12,484 patients and completed 11,712 amyloid PET scans. Dr. Rabinovici hopes the recruitment will be completed by late this year, or early 2018.
IDEAS is being funded by the Centers for Medicare & Medicaid Services, Avid Radiopharmaceuticals/Eli Lilly, GE Healthcare, Piramal Imaging, the Alzheimer’s Association, and the American College of Radiology. Dr. Rabinovici has received honoraria or consulting fees from Eisai, Genentech, Lundbeck, Merck, Putnam, and Roche.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – A study to prove the practical clinical utility of amyloid PET scanning appears to be doing just that: The knowledge of patients’ brain amyloid status changed clinical management for 68% of those who had the imaging done.
Interim results of the Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study far exceeded the 30% change rate that investigators hoped to see, Gil Rabinovici, MD, said at the Alzheimer’s Association International Conference. Not only did many patients receive a more suitable care plan, the scans actually changed diagnoses in three-quarters of those who tested positive, said Dr. Rabinovici of the University of California, San Francisco.
The U.S.-wide, open-label study is being conducted in Medicare beneficiaries who have been diagnosed with mild cognitive impairment (MCI) or dementia of uncertain cause. Its two goals are to show that amyloid PET imaging affects a patient’s care plan within 3 months of the scan and to show an impact on major medical outcomes 12 months later. In diagnostically uncertain cases, investigators theorized, amyloid PET imaging would lead to significant changes in patient management, which would then translate into improved medical outcomes.
At the meeting, Dr. Rabinovici discussed the preplanned interim analysis of 3-month care plan changes. After the scan was completed, physicians related the results to patients and recommended any appropriate management changes. At the 90-day post-scan visit, physicians documented how any changes had been implemented. Data on the 12-month outcomes have not been announced on any portion of the cohort.
The patients were a mean of 76 years old; 64% had a diagnosis of MCI and 36% a diagnosis of dementia. Alzheimer’s disease was the suspected etiology in 74% of the MCI group and in 80% of the dementia group. About one-third of MCI patients and two-thirds of dementia patients were taking Alzheimer’s medications at enrollment.
The scans were positive in 54% of the MCI patients and in 70% of dementia patients. In amyloid-positive patients, the rate of Alzheimer’s diagnosis increased from 78% to 85%. In amyloid-negative patients, the rate of Alzheimer’s diagnosis decreased from 73% to 14%.
More than two-thirds of patients in both groups experienced a change in management after the scans were read. Changes in Alzheimer’s drugs occurred in 48% of both groups, while changes in non-Alzheimer’s drugs occurred in 36% of the MCI group and 32% of the dementia group. In amyloid-positive patients, use of Alzheimer’s drugs increased from 51% to 84%. In amyloid-negative patients, the use of Alzheimer’s drugs decreased from 39% to 31%.
Patient counseling also changed in 24% of the MCI group and 16% of the dementia group.
Dr. Rabinovici was cautiously optimistic about the interim results. “The study has two aims, and Medicare has made it clear that we need to complete both before they will consider covering the scans. I hope they understand that these changes in management are incredibly important, but they also want to see that they result in improved outcomes. That will take a year from when we enroll our last patient.”
Although the study is designed to show change in clinical outcomes, it’s also changing something less tangible, but no less important: patients’ understanding of their situation.
“We may be looking at objective changes in management, but we are also seeing that patients really want to know what’s going on in their brain, what the cause of their cognitive impairment is. They don’t want to be told that it’s normal aging, because they know it isn’t. There is a real value to getting that diagnosis, even if it’s the bad news that there are amyloid plaques in the brain. It leads to a clear plan in terms of what drugs to use, the possibility of enrolling in clinical trials, and getting some clarity about what’s going on. A lot of times, the certainty is better than the uncertainty.”
As of June, IDEAS had recruited 12,484 patients and completed 11,712 amyloid PET scans. Dr. Rabinovici hopes the recruitment will be completed by late this year, or early 2018.
IDEAS is being funded by the Centers for Medicare & Medicaid Services, Avid Radiopharmaceuticals/Eli Lilly, GE Healthcare, Piramal Imaging, the Alzheimer’s Association, and the American College of Radiology. Dr. Rabinovici has received honoraria or consulting fees from Eisai, Genentech, Lundbeck, Merck, Putnam, and Roche.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT AAIC 2017
Key clinical point:
Major finding: Amyloid status changed clinical management in 68% of patients diagnosed with mild cognitive impairment or dementia.
Data source: An interim analysis of 4,000 out of 18,500 planned for enrollment in the IDEAS study.
Disclosures: IDEAS is being funded by the Centers for Medicare & Medicaid Services, Avid Radiopharmaceuticals/Eli Lilly, GE Healthcare, Piramal Imaging, the Alzheimer’s Association, and the American College of Radiology. Dr. Rabinovici has received honoraria or consulting fees from Eisai, Genentech, Lundbeck, Merck, Putnam, and Roche.
Hospitalizations may speed up cognitive decline in older adults
LONDON – Older adult patients who already had cognitive decline when they were admitted to a hospital often left with a significantly accelerated rate of decline, according to findings from a large longitudinal cohort study.
The study found up to a 62% acceleration of prehospital cognitive decline after any hospitalization. Urgent or emergency hospitalizations exacted the biggest toll on cognitive health, Bryan James, PhD, said at the Alzheimer’s Association International Conference.
Cognitive decline after hospitalization in older patients is a common occurrence but still poorly understood, he said. “Some data suggest this could actually be seen as a public health crisis since 40% of all hospitalized patients in the U.S. are older than 65, and the risk of past-hospitalization cognitive impairment rises with age.
“Given the risk to cognitive health, older patients, families, and physicians require information on when to admit to the hospital,” Dr. James said. “We wondered if those who decline rapidly after the hospital admission were already declining before. Our second question was whether elective hospital admissions are associated with the same negative cognitive outcomes as nonelective (emergent or urgent) admissions.”
To examine this, Dr. James and his colleagues used patient data from the Rush Memory and Aging Project, which provides each participant with an annual cognitive assessment consisting of 19 neuropsychological tests. They linked these data to each patient’s Medicare claims record, allowing them to assess cognitive function both before and after the index hospitalization.
The cohort comprised 930 patients who were followed for a mean of 5 years. Hospitalized patients were older (81 vs. 79 years). Most patients in both groups had at least one medical condition, such as hypertension, heart disease, diabetes, cancer, thyroid disease, head injury, or stroke. Cognition was already impaired in many of the hospitalized patients; 62% had mild cognitive impairment (MCI) and 35% had dementia. Among the nonhospitalized subjects, 49% had MCI and 24% had dementia.
Of the cohort, 66% experienced a hospitalization during follow-up. Most hospitalizations (57%) were either for urgent or emergency problems. The rest were elective admissions. The main outcome was change in global cognition – an averaged z-score of all 19 tests of working memory, episodic memory, semantic memory, visuospatial processing, and perceptual speed.
Elective admissions were mostly planned surgeries (94%), and unplanned surgeries occurred in 64% of the nonelective admissions. Most of the elective admissions (81%) involved anesthesia, compared with 32% of the nonelective admissions. About 40% of each group required a stay in the intensive care unit. Around 11% in each group had a critical illness – a stroke, hemorrhage, or brain trauma in about 6% of each group.
A multivariate analysis looked at the change in cognition during two time points: 2 years before the index hospitalization and up to 8 years after it. As could be expected of aged subjects in a memory study cohort, most patients experienced a decline in cognition over the study period. However, nonhospitalized patients continued on a smooth linear slope of decline. Hospitalized patients experienced a significant 62% increased rate of decline, even after controlling for age, education, comorbidities, depression, Activities of Daily Living disability, and physical activity.
Visuospatial processing was the only domain not significantly affected by a hospital admission. All of the memory domains, as well as perceptual speed, declined significantly faster after hospitalization than before.
The second analysis examined which type of admission was most dangerous for cognitive health. This controlled for even more potential confounding factors, including length of stay, surgery and anesthesia, Charlson comorbidity index, critical illness, brain injury, and number of hospitalizations during the follow-up period.
Urgent and emergency admissions drove virtually all of the increase in decline, Dr. James said, with a 60% increase in the rate of decline, compared with the prehospitalization rate. Patients who had elective admissions showed no variance from their baseline rate of decline, and, in fact, followed the same slope as nonhospitalized patients. Again, change was seen in the global score and in all the memory domains and perceptual speed. Only visuospatial processing was unaffected.
“It’s unclear why the urgent and emergent admissions drove this finding, even after we controlled for illness and injury severity and other factors,” Dr. James said. “Obviously, we need more research in this area.”
He had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – Older adult patients who already had cognitive decline when they were admitted to a hospital often left with a significantly accelerated rate of decline, according to findings from a large longitudinal cohort study.
The study found up to a 62% acceleration of prehospital cognitive decline after any hospitalization. Urgent or emergency hospitalizations exacted the biggest toll on cognitive health, Bryan James, PhD, said at the Alzheimer’s Association International Conference.
Cognitive decline after hospitalization in older patients is a common occurrence but still poorly understood, he said. “Some data suggest this could actually be seen as a public health crisis since 40% of all hospitalized patients in the U.S. are older than 65, and the risk of past-hospitalization cognitive impairment rises with age.
“Given the risk to cognitive health, older patients, families, and physicians require information on when to admit to the hospital,” Dr. James said. “We wondered if those who decline rapidly after the hospital admission were already declining before. Our second question was whether elective hospital admissions are associated with the same negative cognitive outcomes as nonelective (emergent or urgent) admissions.”
To examine this, Dr. James and his colleagues used patient data from the Rush Memory and Aging Project, which provides each participant with an annual cognitive assessment consisting of 19 neuropsychological tests. They linked these data to each patient’s Medicare claims record, allowing them to assess cognitive function both before and after the index hospitalization.
The cohort comprised 930 patients who were followed for a mean of 5 years. Hospitalized patients were older (81 vs. 79 years). Most patients in both groups had at least one medical condition, such as hypertension, heart disease, diabetes, cancer, thyroid disease, head injury, or stroke. Cognition was already impaired in many of the hospitalized patients; 62% had mild cognitive impairment (MCI) and 35% had dementia. Among the nonhospitalized subjects, 49% had MCI and 24% had dementia.
Of the cohort, 66% experienced a hospitalization during follow-up. Most hospitalizations (57%) were either for urgent or emergency problems. The rest were elective admissions. The main outcome was change in global cognition – an averaged z-score of all 19 tests of working memory, episodic memory, semantic memory, visuospatial processing, and perceptual speed.
Elective admissions were mostly planned surgeries (94%), and unplanned surgeries occurred in 64% of the nonelective admissions. Most of the elective admissions (81%) involved anesthesia, compared with 32% of the nonelective admissions. About 40% of each group required a stay in the intensive care unit. Around 11% in each group had a critical illness – a stroke, hemorrhage, or brain trauma in about 6% of each group.
A multivariate analysis looked at the change in cognition during two time points: 2 years before the index hospitalization and up to 8 years after it. As could be expected of aged subjects in a memory study cohort, most patients experienced a decline in cognition over the study period. However, nonhospitalized patients continued on a smooth linear slope of decline. Hospitalized patients experienced a significant 62% increased rate of decline, even after controlling for age, education, comorbidities, depression, Activities of Daily Living disability, and physical activity.
Visuospatial processing was the only domain not significantly affected by a hospital admission. All of the memory domains, as well as perceptual speed, declined significantly faster after hospitalization than before.
The second analysis examined which type of admission was most dangerous for cognitive health. This controlled for even more potential confounding factors, including length of stay, surgery and anesthesia, Charlson comorbidity index, critical illness, brain injury, and number of hospitalizations during the follow-up period.
Urgent and emergency admissions drove virtually all of the increase in decline, Dr. James said, with a 60% increase in the rate of decline, compared with the prehospitalization rate. Patients who had elective admissions showed no variance from their baseline rate of decline, and, in fact, followed the same slope as nonhospitalized patients. Again, change was seen in the global score and in all the memory domains and perceptual speed. Only visuospatial processing was unaffected.
“It’s unclear why the urgent and emergent admissions drove this finding, even after we controlled for illness and injury severity and other factors,” Dr. James said. “Obviously, we need more research in this area.”
He had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – Older adult patients who already had cognitive decline when they were admitted to a hospital often left with a significantly accelerated rate of decline, according to findings from a large longitudinal cohort study.
The study found up to a 62% acceleration of prehospital cognitive decline after any hospitalization. Urgent or emergency hospitalizations exacted the biggest toll on cognitive health, Bryan James, PhD, said at the Alzheimer’s Association International Conference.
Cognitive decline after hospitalization in older patients is a common occurrence but still poorly understood, he said. “Some data suggest this could actually be seen as a public health crisis since 40% of all hospitalized patients in the U.S. are older than 65, and the risk of past-hospitalization cognitive impairment rises with age.
“Given the risk to cognitive health, older patients, families, and physicians require information on when to admit to the hospital,” Dr. James said. “We wondered if those who decline rapidly after the hospital admission were already declining before. Our second question was whether elective hospital admissions are associated with the same negative cognitive outcomes as nonelective (emergent or urgent) admissions.”
To examine this, Dr. James and his colleagues used patient data from the Rush Memory and Aging Project, which provides each participant with an annual cognitive assessment consisting of 19 neuropsychological tests. They linked these data to each patient’s Medicare claims record, allowing them to assess cognitive function both before and after the index hospitalization.
The cohort comprised 930 patients who were followed for a mean of 5 years. Hospitalized patients were older (81 vs. 79 years). Most patients in both groups had at least one medical condition, such as hypertension, heart disease, diabetes, cancer, thyroid disease, head injury, or stroke. Cognition was already impaired in many of the hospitalized patients; 62% had mild cognitive impairment (MCI) and 35% had dementia. Among the nonhospitalized subjects, 49% had MCI and 24% had dementia.
Of the cohort, 66% experienced a hospitalization during follow-up. Most hospitalizations (57%) were either for urgent or emergency problems. The rest were elective admissions. The main outcome was change in global cognition – an averaged z-score of all 19 tests of working memory, episodic memory, semantic memory, visuospatial processing, and perceptual speed.
Elective admissions were mostly planned surgeries (94%), and unplanned surgeries occurred in 64% of the nonelective admissions. Most of the elective admissions (81%) involved anesthesia, compared with 32% of the nonelective admissions. About 40% of each group required a stay in the intensive care unit. Around 11% in each group had a critical illness – a stroke, hemorrhage, or brain trauma in about 6% of each group.
A multivariate analysis looked at the change in cognition during two time points: 2 years before the index hospitalization and up to 8 years after it. As could be expected of aged subjects in a memory study cohort, most patients experienced a decline in cognition over the study period. However, nonhospitalized patients continued on a smooth linear slope of decline. Hospitalized patients experienced a significant 62% increased rate of decline, even after controlling for age, education, comorbidities, depression, Activities of Daily Living disability, and physical activity.
Visuospatial processing was the only domain not significantly affected by a hospital admission. All of the memory domains, as well as perceptual speed, declined significantly faster after hospitalization than before.
The second analysis examined which type of admission was most dangerous for cognitive health. This controlled for even more potential confounding factors, including length of stay, surgery and anesthesia, Charlson comorbidity index, critical illness, brain injury, and number of hospitalizations during the follow-up period.
Urgent and emergency admissions drove virtually all of the increase in decline, Dr. James said, with a 60% increase in the rate of decline, compared with the prehospitalization rate. Patients who had elective admissions showed no variance from their baseline rate of decline, and, in fact, followed the same slope as nonhospitalized patients. Again, change was seen in the global score and in all the memory domains and perceptual speed. Only visuospatial processing was unaffected.
“It’s unclear why the urgent and emergent admissions drove this finding, even after we controlled for illness and injury severity and other factors,” Dr. James said. “Obviously, we need more research in this area.”
He had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT AAIC 2017
Key clinical point:
Major finding: Urgent or emergency admissions accelerated the rate of cognitive decline by 60%, compared with the prehospitalization rate. Elective admissions did not change the rate of cognitive decline.
Data source: The 930 patients were drawn from the Rush Memory and Aging Project.
Disclosures: The presenter had no financial disclosures.
Small brain infarcts’ cognitive impact equals that of large infarcts
LONDON – Small infarct-like brain lesions have long been ignored in both research and clinical settings, but an ongoing analysis of an observational cohort shows that they can be just as cognitively damaging as large infarcts. Having both is a serious one-two punch to thinking and memory.
At less than 3 mm, infarct-like lesions (ILL) may be tiny, but, over 20 years, they exerted exactly the same deleterious effect on cognition as lesions 3 mm or larger, Beverly Gwen Windham, MD, said at the Alzheimer’s Association International Conference.
When neuroradiologists began to look at brain infarcts several decades ago, they used then state-of-the-art 1.5 Tesla MRI. As infarct description and classification evolved, anything measuring smaller than 3 mm was classified as an infarct-like lesion and anything 3 mm or larger as a large infarct. There was some concern that readers would confuse the ILLs with perivascular spaces and flag these normal voids as pathological changes, Dr. Windham said. As a result, research studies have always excluded them. Since they’re usually associated with silent events, without any clinical signs or symptoms, they’ve been clinically disregarded as well, adding to the perception that they have little long-term impact.
However, in 2015, Dr. Windham and her team proved this perception incorrect, at least when it came to stroke and stroke mortality. Using the large Atherosclerosis Risk in Communities (ARIC) Study cohort, they showed that ILLs alone tripled the risk of both a stroke and stroke mortality. Patients who had both ILLs and large infarcts were nine times more likely to have a stroke and seven times more likely to die from a stroke than were patients who had no lesions.
Dr. Windham used the same ARIC cohort in the 20-year cognition study. Begun in 1987, ARIC enrolled 15,800 middle-aged adults who have been followed regularly with physical and neurocognitive testing. Its goals are largely to investigate the natural history and multiple risk factors of cardiovascular and cerebrovascular disease. In 1993, subjects who had not experienced a stroke also had a brain MRI to add more detail to the study. The investigators also have performed cognitive assessments of a large number of participants five times since 1993 on measures of delayed word recall, digit symbol substitution, and word fluency. The outcome was the change in the composite Z-score over time.
The cognition study comprised 1,881 who had brain MRI and the full five cognitive assessments over a 20-year period. The participants were stratified as having no infarcts (1,611), only ILLs (50) or large infarcts (185), or both lesions (35).
At baseline, these subjects had a mean age of 63 years, 17% had diabetes, and 48% had hypertension. About one-third were positive for an ApoE e4 allele. The mean white matter intensity score was 1.4.
“In general, everyone in the cohort had some decline in cognitive function as they got older,” Dr. Windham said. But, a striking observation was that those with ILLs only and those with large lesions only had virtually identical decline slopes over the 20-year follow-up. The change from baseline in global Z-score was 0.18 standard deviations for the ILL-only group and 0.24 standard deviations for the large infarct group. For those with both lesions, the change from baseline was 0.62.
“At the end of 20 years, those with no lesion burden declined 1.3 standard deviations from baseline, those with only ILLs declined 1.5 standard deviations, and those with large infarcts, 1.6 standard deviations,” Dr. Windham said. “But, subjects who had both lesions declined 2.5 standard deviations from baseline. This is equivalent to adding 27 years of aging. The effect of having both was nearly four times greater than [that of] having only large lesions, which, up until now, have been the only ones read on MRI in either clinical practice or in research. Overall, our findings confirm that the relationship of ILLs to cognition is very similar that of large infarcts.
“The presence of midlife ILLs appears to amplify the effect of large infarcts on cognition, and we hypothesize that this process may represent vascular disease at midlife. We may also be able to identify people at high risk of cognitive decline or even dementia at midlife. I also think that we need to be rethinking how we read MRIs. Stopping at the 3-mm threshold may be too conservative. We should be looking at other studies on the consequences of these small lesions,” she said.
Dr. Windham had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
Virtually every time researchers look for an effect of brain vascular health on cognition, they find it. Not only do these data reveal a surprisingly large effect of a previously ignored type of brain lesion on cognition, they also highlight that poor management of vascular risk factors in midlife may lead to dementia decades later. This suggests we need more research to understand the long-term impact of these small lesions on brain health and the development of Alzheimer’s disease.
Keith Fargo, PhD, is the Alzheimer’s Association’s director of scientific programs and outreach.
Virtually every time researchers look for an effect of brain vascular health on cognition, they find it. Not only do these data reveal a surprisingly large effect of a previously ignored type of brain lesion on cognition, they also highlight that poor management of vascular risk factors in midlife may lead to dementia decades later. This suggests we need more research to understand the long-term impact of these small lesions on brain health and the development of Alzheimer’s disease.
Keith Fargo, PhD, is the Alzheimer’s Association’s director of scientific programs and outreach.
Virtually every time researchers look for an effect of brain vascular health on cognition, they find it. Not only do these data reveal a surprisingly large effect of a previously ignored type of brain lesion on cognition, they also highlight that poor management of vascular risk factors in midlife may lead to dementia decades later. This suggests we need more research to understand the long-term impact of these small lesions on brain health and the development of Alzheimer’s disease.
Keith Fargo, PhD, is the Alzheimer’s Association’s director of scientific programs and outreach.
LONDON – Small infarct-like brain lesions have long been ignored in both research and clinical settings, but an ongoing analysis of an observational cohort shows that they can be just as cognitively damaging as large infarcts. Having both is a serious one-two punch to thinking and memory.
At less than 3 mm, infarct-like lesions (ILL) may be tiny, but, over 20 years, they exerted exactly the same deleterious effect on cognition as lesions 3 mm or larger, Beverly Gwen Windham, MD, said at the Alzheimer’s Association International Conference.
When neuroradiologists began to look at brain infarcts several decades ago, they used then state-of-the-art 1.5 Tesla MRI. As infarct description and classification evolved, anything measuring smaller than 3 mm was classified as an infarct-like lesion and anything 3 mm or larger as a large infarct. There was some concern that readers would confuse the ILLs with perivascular spaces and flag these normal voids as pathological changes, Dr. Windham said. As a result, research studies have always excluded them. Since they’re usually associated with silent events, without any clinical signs or symptoms, they’ve been clinically disregarded as well, adding to the perception that they have little long-term impact.
However, in 2015, Dr. Windham and her team proved this perception incorrect, at least when it came to stroke and stroke mortality. Using the large Atherosclerosis Risk in Communities (ARIC) Study cohort, they showed that ILLs alone tripled the risk of both a stroke and stroke mortality. Patients who had both ILLs and large infarcts were nine times more likely to have a stroke and seven times more likely to die from a stroke than were patients who had no lesions.
Dr. Windham used the same ARIC cohort in the 20-year cognition study. Begun in 1987, ARIC enrolled 15,800 middle-aged adults who have been followed regularly with physical and neurocognitive testing. Its goals are largely to investigate the natural history and multiple risk factors of cardiovascular and cerebrovascular disease. In 1993, subjects who had not experienced a stroke also had a brain MRI to add more detail to the study. The investigators also have performed cognitive assessments of a large number of participants five times since 1993 on measures of delayed word recall, digit symbol substitution, and word fluency. The outcome was the change in the composite Z-score over time.
The cognition study comprised 1,881 who had brain MRI and the full five cognitive assessments over a 20-year period. The participants were stratified as having no infarcts (1,611), only ILLs (50) or large infarcts (185), or both lesions (35).
At baseline, these subjects had a mean age of 63 years, 17% had diabetes, and 48% had hypertension. About one-third were positive for an ApoE e4 allele. The mean white matter intensity score was 1.4.
“In general, everyone in the cohort had some decline in cognitive function as they got older,” Dr. Windham said. But, a striking observation was that those with ILLs only and those with large lesions only had virtually identical decline slopes over the 20-year follow-up. The change from baseline in global Z-score was 0.18 standard deviations for the ILL-only group and 0.24 standard deviations for the large infarct group. For those with both lesions, the change from baseline was 0.62.
“At the end of 20 years, those with no lesion burden declined 1.3 standard deviations from baseline, those with only ILLs declined 1.5 standard deviations, and those with large infarcts, 1.6 standard deviations,” Dr. Windham said. “But, subjects who had both lesions declined 2.5 standard deviations from baseline. This is equivalent to adding 27 years of aging. The effect of having both was nearly four times greater than [that of] having only large lesions, which, up until now, have been the only ones read on MRI in either clinical practice or in research. Overall, our findings confirm that the relationship of ILLs to cognition is very similar that of large infarcts.
“The presence of midlife ILLs appears to amplify the effect of large infarcts on cognition, and we hypothesize that this process may represent vascular disease at midlife. We may also be able to identify people at high risk of cognitive decline or even dementia at midlife. I also think that we need to be rethinking how we read MRIs. Stopping at the 3-mm threshold may be too conservative. We should be looking at other studies on the consequences of these small lesions,” she said.
Dr. Windham had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – Small infarct-like brain lesions have long been ignored in both research and clinical settings, but an ongoing analysis of an observational cohort shows that they can be just as cognitively damaging as large infarcts. Having both is a serious one-two punch to thinking and memory.
At less than 3 mm, infarct-like lesions (ILL) may be tiny, but, over 20 years, they exerted exactly the same deleterious effect on cognition as lesions 3 mm or larger, Beverly Gwen Windham, MD, said at the Alzheimer’s Association International Conference.
When neuroradiologists began to look at brain infarcts several decades ago, they used then state-of-the-art 1.5 Tesla MRI. As infarct description and classification evolved, anything measuring smaller than 3 mm was classified as an infarct-like lesion and anything 3 mm or larger as a large infarct. There was some concern that readers would confuse the ILLs with perivascular spaces and flag these normal voids as pathological changes, Dr. Windham said. As a result, research studies have always excluded them. Since they’re usually associated with silent events, without any clinical signs or symptoms, they’ve been clinically disregarded as well, adding to the perception that they have little long-term impact.
However, in 2015, Dr. Windham and her team proved this perception incorrect, at least when it came to stroke and stroke mortality. Using the large Atherosclerosis Risk in Communities (ARIC) Study cohort, they showed that ILLs alone tripled the risk of both a stroke and stroke mortality. Patients who had both ILLs and large infarcts were nine times more likely to have a stroke and seven times more likely to die from a stroke than were patients who had no lesions.
Dr. Windham used the same ARIC cohort in the 20-year cognition study. Begun in 1987, ARIC enrolled 15,800 middle-aged adults who have been followed regularly with physical and neurocognitive testing. Its goals are largely to investigate the natural history and multiple risk factors of cardiovascular and cerebrovascular disease. In 1993, subjects who had not experienced a stroke also had a brain MRI to add more detail to the study. The investigators also have performed cognitive assessments of a large number of participants five times since 1993 on measures of delayed word recall, digit symbol substitution, and word fluency. The outcome was the change in the composite Z-score over time.
The cognition study comprised 1,881 who had brain MRI and the full five cognitive assessments over a 20-year period. The participants were stratified as having no infarcts (1,611), only ILLs (50) or large infarcts (185), or both lesions (35).
At baseline, these subjects had a mean age of 63 years, 17% had diabetes, and 48% had hypertension. About one-third were positive for an ApoE e4 allele. The mean white matter intensity score was 1.4.
“In general, everyone in the cohort had some decline in cognitive function as they got older,” Dr. Windham said. But, a striking observation was that those with ILLs only and those with large lesions only had virtually identical decline slopes over the 20-year follow-up. The change from baseline in global Z-score was 0.18 standard deviations for the ILL-only group and 0.24 standard deviations for the large infarct group. For those with both lesions, the change from baseline was 0.62.
“At the end of 20 years, those with no lesion burden declined 1.3 standard deviations from baseline, those with only ILLs declined 1.5 standard deviations, and those with large infarcts, 1.6 standard deviations,” Dr. Windham said. “But, subjects who had both lesions declined 2.5 standard deviations from baseline. This is equivalent to adding 27 years of aging. The effect of having both was nearly four times greater than [that of] having only large lesions, which, up until now, have been the only ones read on MRI in either clinical practice or in research. Overall, our findings confirm that the relationship of ILLs to cognition is very similar that of large infarcts.
“The presence of midlife ILLs appears to amplify the effect of large infarcts on cognition, and we hypothesize that this process may represent vascular disease at midlife. We may also be able to identify people at high risk of cognitive decline or even dementia at midlife. I also think that we need to be rethinking how we read MRIs. Stopping at the 3-mm threshold may be too conservative. We should be looking at other studies on the consequences of these small lesions,” she said.
Dr. Windham had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT AAIC 2017
Key clinical point:
Major finding: A composite cognitive measure showed a decline of 1.5 standard deviations from baseline in patients with only infarct-like lesions, 1.6 standard deviations in those with large infarcts, and 2.5 standard deviations in subjects who had both lesions.
Data source: The ARIC substudy comprised 1,881 subjects followed for 20 years.
Disclosures: Dr. Windham had no financial disclosures.
Stressful life events take greater cognitive toll on African Americans than whites
LONDON – African Americans not only report experiencing more stressful experiences across their lifespans than do whites, but they have more cognitive consequences from them as well, new research suggests.
In fact, the weight of these experiences affected cognition even more than traditional risk factors like genetic status and even age, Megan Zuelsdorff, PhD, said at the Alzheimer’s Association International Conference.
Racial disparities have long been evident in the development and progression of dementia, Dr. Zuelsdorff said. Socioeconomic factors are also important players in this scenario. Stress, likewise, has long been linked to poorer cognitive health. “But, there are still significant gaps in our knowledge of stress and cognition. The contribution of stress to well-established socioeconomic impacts on health is unclear, and the research focus here has always been on events happening in midlife and onward. But, it’s crucial to expand this window of time backward to include earlier years. If we look at a graph of cognitive function across the lifespan, the rate of decline doesn’t vary much. What we do see is that blacks, starting at midlife, are closer to the clinical threshold of cognitive impairment and may reach the threshold at an earlier age. What this said to me is that we needed to look at these earlier life factors that could bring someone to this state of lower cognitive function in midlife.”
Dr. Zuelsdorff and her colleagues analyzed data from the Wisconsin Registry for Alzheimer’s Prevention to examine this question. The observational study comprises 1,500 adults being followed for 15-20 years and is enriched for those with a family history of Alzheimer’s disease. The main goal of WRAP is to understand the biological, medical, environmental, and lifestyle factors that increase a person’s risk of developing Alzheimer’s disease.
Subjects have a study visit every 2-4 years that includes a full physical and cognitive workup. At one visit, Dr. Zuelsdorff said, they were asked to complete a questionnaire concerning 27 different stressful life events. These experiences were deeply disturbing and potentially life altering. They included childhood experiences, such as parental abuse, alcoholism, and flunking out of school, and adult experiences, such as combat experience, bankruptcy, or the death of a child. She then analyzed how the total number of stressful events in a person’s life changed that person’s risk of developing dementia.
Of the entire WRAP cohort, 1,314 completed the stress questionnaire and had sufficient cognitive data. These subjects were largely white (1,232). Only 82 were African American, a weakness of the study, Dr. Zuelsdorff noted, but a reflection of Wisconsin’s racial makeup.
They were similar in a number of important ways, including age (mean, 58 years), proportion of apolipoprotein E4 (APOE4) allele carriers (38%), and years of education (mean, 16). African Americans had higher body mass index (33.3 vs. 28.8 kg/m2), reported less physical activity, were more often current smokers (22% vs. 6%), and had a lower-quality education despite similar time in the classroom.
On average, African Americans reported a mean of 4.5 stressful life events – a significant, 60% increase over the 2.8 reported by whites. The experience of stressful events directly influenced a subject’s performance in the speed and flexibility domain of executive function and in working memory, Dr. Zuelsdorff said.
“We saw a substantial 13.5% attenuation of performance on speed and flexibility, but we also saw attenuation in working memory. That told us something else was going on – that it wasn’t just the accumulation of stressful events but that there was a differential vulnerability. The negative association between lifetime stressful events and the cognitive domains was much stronger in blacks than in whites.”
She then conducted a risk analysis to determine the impact of stress. “Stress was right at the top for blacks. It tended to be one of the most important predictors of cognitive function. The only other one that came out as significant was quality of education. The social environment in this sample was more important than the traditional risk factors of genetics and chronological age.”
The study barely scratches the surface of the stress/cognition conundrum, Dr. Zuelsdorff said. “We would like to look at the timing next and see if there is some critical window that is especially influencing to cognitive health. We then need to target both interventions and effect modifiers, such as social, community, and financial resources that might buffer the effects of this negative stress.”
She had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – African Americans not only report experiencing more stressful experiences across their lifespans than do whites, but they have more cognitive consequences from them as well, new research suggests.
In fact, the weight of these experiences affected cognition even more than traditional risk factors like genetic status and even age, Megan Zuelsdorff, PhD, said at the Alzheimer’s Association International Conference.
Racial disparities have long been evident in the development and progression of dementia, Dr. Zuelsdorff said. Socioeconomic factors are also important players in this scenario. Stress, likewise, has long been linked to poorer cognitive health. “But, there are still significant gaps in our knowledge of stress and cognition. The contribution of stress to well-established socioeconomic impacts on health is unclear, and the research focus here has always been on events happening in midlife and onward. But, it’s crucial to expand this window of time backward to include earlier years. If we look at a graph of cognitive function across the lifespan, the rate of decline doesn’t vary much. What we do see is that blacks, starting at midlife, are closer to the clinical threshold of cognitive impairment and may reach the threshold at an earlier age. What this said to me is that we needed to look at these earlier life factors that could bring someone to this state of lower cognitive function in midlife.”
Dr. Zuelsdorff and her colleagues analyzed data from the Wisconsin Registry for Alzheimer’s Prevention to examine this question. The observational study comprises 1,500 adults being followed for 15-20 years and is enriched for those with a family history of Alzheimer’s disease. The main goal of WRAP is to understand the biological, medical, environmental, and lifestyle factors that increase a person’s risk of developing Alzheimer’s disease.
Subjects have a study visit every 2-4 years that includes a full physical and cognitive workup. At one visit, Dr. Zuelsdorff said, they were asked to complete a questionnaire concerning 27 different stressful life events. These experiences were deeply disturbing and potentially life altering. They included childhood experiences, such as parental abuse, alcoholism, and flunking out of school, and adult experiences, such as combat experience, bankruptcy, or the death of a child. She then analyzed how the total number of stressful events in a person’s life changed that person’s risk of developing dementia.
Of the entire WRAP cohort, 1,314 completed the stress questionnaire and had sufficient cognitive data. These subjects were largely white (1,232). Only 82 were African American, a weakness of the study, Dr. Zuelsdorff noted, but a reflection of Wisconsin’s racial makeup.
They were similar in a number of important ways, including age (mean, 58 years), proportion of apolipoprotein E4 (APOE4) allele carriers (38%), and years of education (mean, 16). African Americans had higher body mass index (33.3 vs. 28.8 kg/m2), reported less physical activity, were more often current smokers (22% vs. 6%), and had a lower-quality education despite similar time in the classroom.
On average, African Americans reported a mean of 4.5 stressful life events – a significant, 60% increase over the 2.8 reported by whites. The experience of stressful events directly influenced a subject’s performance in the speed and flexibility domain of executive function and in working memory, Dr. Zuelsdorff said.
“We saw a substantial 13.5% attenuation of performance on speed and flexibility, but we also saw attenuation in working memory. That told us something else was going on – that it wasn’t just the accumulation of stressful events but that there was a differential vulnerability. The negative association between lifetime stressful events and the cognitive domains was much stronger in blacks than in whites.”
She then conducted a risk analysis to determine the impact of stress. “Stress was right at the top for blacks. It tended to be one of the most important predictors of cognitive function. The only other one that came out as significant was quality of education. The social environment in this sample was more important than the traditional risk factors of genetics and chronological age.”
The study barely scratches the surface of the stress/cognition conundrum, Dr. Zuelsdorff said. “We would like to look at the timing next and see if there is some critical window that is especially influencing to cognitive health. We then need to target both interventions and effect modifiers, such as social, community, and financial resources that might buffer the effects of this negative stress.”
She had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
LONDON – African Americans not only report experiencing more stressful experiences across their lifespans than do whites, but they have more cognitive consequences from them as well, new research suggests.
In fact, the weight of these experiences affected cognition even more than traditional risk factors like genetic status and even age, Megan Zuelsdorff, PhD, said at the Alzheimer’s Association International Conference.
Racial disparities have long been evident in the development and progression of dementia, Dr. Zuelsdorff said. Socioeconomic factors are also important players in this scenario. Stress, likewise, has long been linked to poorer cognitive health. “But, there are still significant gaps in our knowledge of stress and cognition. The contribution of stress to well-established socioeconomic impacts on health is unclear, and the research focus here has always been on events happening in midlife and onward. But, it’s crucial to expand this window of time backward to include earlier years. If we look at a graph of cognitive function across the lifespan, the rate of decline doesn’t vary much. What we do see is that blacks, starting at midlife, are closer to the clinical threshold of cognitive impairment and may reach the threshold at an earlier age. What this said to me is that we needed to look at these earlier life factors that could bring someone to this state of lower cognitive function in midlife.”
Dr. Zuelsdorff and her colleagues analyzed data from the Wisconsin Registry for Alzheimer’s Prevention to examine this question. The observational study comprises 1,500 adults being followed for 15-20 years and is enriched for those with a family history of Alzheimer’s disease. The main goal of WRAP is to understand the biological, medical, environmental, and lifestyle factors that increase a person’s risk of developing Alzheimer’s disease.
Subjects have a study visit every 2-4 years that includes a full physical and cognitive workup. At one visit, Dr. Zuelsdorff said, they were asked to complete a questionnaire concerning 27 different stressful life events. These experiences were deeply disturbing and potentially life altering. They included childhood experiences, such as parental abuse, alcoholism, and flunking out of school, and adult experiences, such as combat experience, bankruptcy, or the death of a child. She then analyzed how the total number of stressful events in a person’s life changed that person’s risk of developing dementia.
Of the entire WRAP cohort, 1,314 completed the stress questionnaire and had sufficient cognitive data. These subjects were largely white (1,232). Only 82 were African American, a weakness of the study, Dr. Zuelsdorff noted, but a reflection of Wisconsin’s racial makeup.
They were similar in a number of important ways, including age (mean, 58 years), proportion of apolipoprotein E4 (APOE4) allele carriers (38%), and years of education (mean, 16). African Americans had higher body mass index (33.3 vs. 28.8 kg/m2), reported less physical activity, were more often current smokers (22% vs. 6%), and had a lower-quality education despite similar time in the classroom.
On average, African Americans reported a mean of 4.5 stressful life events – a significant, 60% increase over the 2.8 reported by whites. The experience of stressful events directly influenced a subject’s performance in the speed and flexibility domain of executive function and in working memory, Dr. Zuelsdorff said.
“We saw a substantial 13.5% attenuation of performance on speed and flexibility, but we also saw attenuation in working memory. That told us something else was going on – that it wasn’t just the accumulation of stressful events but that there was a differential vulnerability. The negative association between lifetime stressful events and the cognitive domains was much stronger in blacks than in whites.”
She then conducted a risk analysis to determine the impact of stress. “Stress was right at the top for blacks. It tended to be one of the most important predictors of cognitive function. The only other one that came out as significant was quality of education. The social environment in this sample was more important than the traditional risk factors of genetics and chronological age.”
The study barely scratches the surface of the stress/cognition conundrum, Dr. Zuelsdorff said. “We would like to look at the timing next and see if there is some critical window that is especially influencing to cognitive health. We then need to target both interventions and effect modifiers, such as social, community, and financial resources that might buffer the effects of this negative stress.”
She had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT AAIC 2017
Key clinical point:
Major finding: African Americans reported 60% more stressful life events than whites, which were tied to a 13% decrease in the speed and flexibility domain of executive function.
Data source: The observational cohort study comprised 1,314 subjects.
Disclosures: Dr. Zuelsdorff had no financial disclosures.