Alzheimer's & Cognition

TOPLINE:

Higher triglyceride levels – a main energy source for the brain – are associated with lower risk for dementia that is not mediated by age, sex, or APOE epsilon-4 allele status, a large study of community-dwelling older adults suggests.

METHODOLOGY:

• The analysis included 18,294 participants, median age 75 years and median triglyceride level 106 mg/dL, from the Aspirin in Reducing Events in the Elderly (ASPREE) study, a placebo-controlled, randomized trial of daily low-dose aspirin in older people without dementia or history of cardiovascular disease (CVD) at recruitment.
• Researchers repeated their main analyses in a sub-cohort of 13,976 subjects with APOE epsilon-4 genetic data, and an external cohort of 68,200 participants, mean age 66.9 years and a median nonfasting triglyceride of 139 mg/dL, from the UK biobank, followed for a median of 12.5 years.
• The main outcome was incident dementia over 6.4 years and secondary outcomes included changes in composite cognitive function and domain-specific cognition.
• Researchers controlled for a number of potential confounders, including age, sex, race, smoking, alcohol consumption, education, family history of dementia, diabetes, hypertension, and statin use.

TAKEAWAY:

• Every doubling of baseline triglycerides was associated with an 18% lower risk of incident dementia across the entire study cohort (adjusted hazard ratio, 0.82) and in participants with genotypic data (aHR, 0.82) and a 17% lower risk in the external UK Biobank cohort (aHR, 0.83) (P ≤ .01 for all).
• In the entire cohort, the risk for dementia was 15% lower in those with triglyceride levels at 63-106 mg/dL (aHR, 0.85); 24% lower in those at 107-186 mg/dL (aHR, 0.76); and 36% lower for those with levels higher than 187 mg/dL (aHR, 0.64), compared with individuals with levels below 62 mg/dL (P for trend <.001).
• The direction and magnitude of the inverse association between triglycerides and dementia risk were not modified by age, sex, or risk factors related to triglycerides or dementia.
• In the entire study cohort, higher triglyceride levels were significantly associated with slower decline in global cognition (P = .02), composite cognition (P = .03), and a borderline significantly slower decline in episodic memory (P = .05).

IN PRACTICE:

“Triglyceride levels may serve as a useful predictor for dementia risk and cognitive decline in older populations,” the investigators write. Higher triglyceride levels may reflect better overall health and/or lifestyle behaviors that protect against dementia.

SOURCE:

The study was led by Zhen Zhou, of Monash University, Melbourne. It was published online in Neurology.

LIMITATIONS:

The study can’t establish a causal relationship between triglyceride levels and dementia or fully exclude reverse causality. As most ASPREE participants had normal to high-normal triglyceride levels, the results can’t be generalized to those with severe hypertriglyceridemia. The findings are unique to older people without CVD and may not be generalizable to other populations.

DISCLOSURES:

The study received support from the Royal Australian College of General Practitioners (RACGP)/HCF Research Foundation. Dr. Zhou reported receiving salary from the RACGP/HCF Research Foundation.

A version of this article first appeared on Medscape.com.

TOPLINE:

Higher triglyceride levels – a main energy source for the brain – are associated with lower risk for dementia that is not mediated by age, sex, or APOE epsilon-4 allele status, a large study of community-dwelling older adults suggests.

METHODOLOGY:

• The analysis included 18,294 participants, median age 75 years and median triglyceride level 106 mg/dL, from the Aspirin in Reducing Events in the Elderly (ASPREE) study, a placebo-controlled, randomized trial of daily low-dose aspirin in older people without dementia or history of cardiovascular disease (CVD) at recruitment.
• Researchers repeated their main analyses in a sub-cohort of 13,976 subjects with APOE epsilon-4 genetic data, and an external cohort of 68,200 participants, mean age 66.9 years and a median nonfasting triglyceride of 139 mg/dL, from the UK biobank, followed for a median of 12.5 years.
• The main outcome was incident dementia over 6.4 years and secondary outcomes included changes in composite cognitive function and domain-specific cognition.
• Researchers controlled for a number of potential confounders, including age, sex, race, smoking, alcohol consumption, education, family history of dementia, diabetes, hypertension, and statin use.

TAKEAWAY:

• Every doubling of baseline triglycerides was associated with an 18% lower risk of incident dementia across the entire study cohort (adjusted hazard ratio, 0.82) and in participants with genotypic data (aHR, 0.82) and a 17% lower risk in the external UK Biobank cohort (aHR, 0.83) (P ≤ .01 for all).
• In the entire cohort, the risk for dementia was 15% lower in those with triglyceride levels at 63-106 mg/dL (aHR, 0.85); 24% lower in those at 107-186 mg/dL (aHR, 0.76); and 36% lower for those with levels higher than 187 mg/dL (aHR, 0.64), compared with individuals with levels below 62 mg/dL (P for trend <.001).
• The direction and magnitude of the inverse association between triglycerides and dementia risk were not modified by age, sex, or risk factors related to triglycerides or dementia.
• In the entire study cohort, higher triglyceride levels were significantly associated with slower decline in global cognition (P = .02), composite cognition (P = .03), and a borderline significantly slower decline in episodic memory (P = .05).

IN PRACTICE:

“Triglyceride levels may serve as a useful predictor for dementia risk and cognitive decline in older populations,” the investigators write. Higher triglyceride levels may reflect better overall health and/or lifestyle behaviors that protect against dementia.

SOURCE:

The study was led by Zhen Zhou, of Monash University, Melbourne. It was published online in Neurology.

LIMITATIONS:

The study can’t establish a causal relationship between triglyceride levels and dementia or fully exclude reverse causality. As most ASPREE participants had normal to high-normal triglyceride levels, the results can’t be generalized to those with severe hypertriglyceridemia. The findings are unique to older people without CVD and may not be generalizable to other populations.

DISCLOSURES:

The study received support from the Royal Australian College of General Practitioners (RACGP)/HCF Research Foundation. Dr. Zhou reported receiving salary from the RACGP/HCF Research Foundation.

A version of this article first appeared on Medscape.com.

TOPLINE:

Higher triglyceride levels – a main energy source for the brain – are associated with lower risk for dementia that is not mediated by age, sex, or APOE epsilon-4 allele status, a large study of community-dwelling older adults suggests.

METHODOLOGY:

• The analysis included 18,294 participants, median age 75 years and median triglyceride level 106 mg/dL, from the Aspirin in Reducing Events in the Elderly (ASPREE) study, a placebo-controlled, randomized trial of daily low-dose aspirin in older people without dementia or history of cardiovascular disease (CVD) at recruitment.
• Researchers repeated their main analyses in a sub-cohort of 13,976 subjects with APOE epsilon-4 genetic data, and an external cohort of 68,200 participants, mean age 66.9 years and a median nonfasting triglyceride of 139 mg/dL, from the UK biobank, followed for a median of 12.5 years.
• The main outcome was incident dementia over 6.4 years and secondary outcomes included changes in composite cognitive function and domain-specific cognition.
• Researchers controlled for a number of potential confounders, including age, sex, race, smoking, alcohol consumption, education, family history of dementia, diabetes, hypertension, and statin use.

TAKEAWAY:

• Every doubling of baseline triglycerides was associated with an 18% lower risk of incident dementia across the entire study cohort (adjusted hazard ratio, 0.82) and in participants with genotypic data (aHR, 0.82) and a 17% lower risk in the external UK Biobank cohort (aHR, 0.83) (P ≤ .01 for all).
• In the entire cohort, the risk for dementia was 15% lower in those with triglyceride levels at 63-106 mg/dL (aHR, 0.85); 24% lower in those at 107-186 mg/dL (aHR, 0.76); and 36% lower for those with levels higher than 187 mg/dL (aHR, 0.64), compared with individuals with levels below 62 mg/dL (P for trend <.001).
• The direction and magnitude of the inverse association between triglycerides and dementia risk were not modified by age, sex, or risk factors related to triglycerides or dementia.
• In the entire study cohort, higher triglyceride levels were significantly associated with slower decline in global cognition (P = .02), composite cognition (P = .03), and a borderline significantly slower decline in episodic memory (P = .05).

IN PRACTICE:

“Triglyceride levels may serve as a useful predictor for dementia risk and cognitive decline in older populations,” the investigators write. Higher triglyceride levels may reflect better overall health and/or lifestyle behaviors that protect against dementia.

SOURCE:

The study was led by Zhen Zhou, of Monash University, Melbourne. It was published online in Neurology.

LIMITATIONS:

The study can’t establish a causal relationship between triglyceride levels and dementia or fully exclude reverse causality. As most ASPREE participants had normal to high-normal triglyceride levels, the results can’t be generalized to those with severe hypertriglyceridemia. The findings are unique to older people without CVD and may not be generalizable to other populations.

DISCLOSURES:

The study received support from the Royal Australian College of General Practitioners (RACGP)/HCF Research Foundation. Dr. Zhou reported receiving salary from the RACGP/HCF Research Foundation.

A version of this article first appeared on Medscape.com.

TOPLINE:

Detection rates of mild cognitive impairment (MCI) in primary care are extremely low, with only about 8% of expected cases diagnosed on average, a finding that points to an urgent need to improve early detection in primary care.

METHODOLOGY:

• Researchers estimated MCI detection rates among 226,756 primary care clinicians and 54,597 practices that had at least 25 patients enrolled in Medicare between 2017 and 2019. 
• They compared the expected number of MCI cases, based on a predictive model, to actual diagnosed cases as documented in claims and encounter data.
• They accounted for uncertainty in these estimates to determine whether detection rates are within the expected range or significantly higher or lower.

TAKEAWAY:

• More than 25% of clinicians and practices did not have a single patient with diagnosed MCI; the average detection rate was 0.01 for both clinicians and practices.
• The modeled expected MCI detection rate, however, was much higher (average 0.19 for clinicians and 0.20 for practices).
• Average detection rates for clinicians and practices was 0.08, with more than 99% of clinicians and practices underdiagnosing MCI; clinicians practicing geriatric medicine had higher detection rates than others.

IN PRACTICE:

The findings are “concerning not only because patients might not get identified for a disease-modifying AD treatment in time, but also because numerous causes of MCI – such as hypothyroidism and medication side effects – are reversible, and the condition itself can be stabilized by lifestyle modification interventions,” the authors write.

SOURCE:

The study was published online in the Journal of Prevention of Alzheimer’s Disease. The first author was Ying Liu, PhD, of the University of Southern California, Los Angeles.

LIMITATIONS:

The predictive model based on demographic information has only moderate accuracy. Expected prevalence of MCI was based on cognitive test scores, which is not the same as a true clinical diagnosis.

DISCLOSURES:

The study was partially funded by a contract from Genentech to the University of Southern California. Coauthors Soeren Mattke and Christopher Wallick have disclosed relationships with Genentech.

A version of this article appeared on Medscape.com.

TOPLINE:

Detection rates of mild cognitive impairment (MCI) in primary care are extremely low, with only about 8% of expected cases diagnosed on average, a finding that points to an urgent need to improve early detection in primary care.

METHODOLOGY:

• Researchers estimated MCI detection rates among 226,756 primary care clinicians and 54,597 practices that had at least 25 patients enrolled in Medicare between 2017 and 2019. 
• They compared the expected number of MCI cases, based on a predictive model, to actual diagnosed cases as documented in claims and encounter data.
• They accounted for uncertainty in these estimates to determine whether detection rates are within the expected range or significantly higher or lower.

TAKEAWAY:

• More than 25% of clinicians and practices did not have a single patient with diagnosed MCI; the average detection rate was 0.01 for both clinicians and practices.
• The modeled expected MCI detection rate, however, was much higher (average 0.19 for clinicians and 0.20 for practices).
• Average detection rates for clinicians and practices was 0.08, with more than 99% of clinicians and practices underdiagnosing MCI; clinicians practicing geriatric medicine had higher detection rates than others.

IN PRACTICE:

The findings are “concerning not only because patients might not get identified for a disease-modifying AD treatment in time, but also because numerous causes of MCI – such as hypothyroidism and medication side effects – are reversible, and the condition itself can be stabilized by lifestyle modification interventions,” the authors write.

SOURCE:

The study was published online in the Journal of Prevention of Alzheimer’s Disease. The first author was Ying Liu, PhD, of the University of Southern California, Los Angeles.

LIMITATIONS:

The predictive model based on demographic information has only moderate accuracy. Expected prevalence of MCI was based on cognitive test scores, which is not the same as a true clinical diagnosis.

DISCLOSURES:

The study was partially funded by a contract from Genentech to the University of Southern California. Coauthors Soeren Mattke and Christopher Wallick have disclosed relationships with Genentech.

A version of this article appeared on Medscape.com.

TOPLINE:

Detection rates of mild cognitive impairment (MCI) in primary care are extremely low, with only about 8% of expected cases diagnosed on average, a finding that points to an urgent need to improve early detection in primary care.

METHODOLOGY:

• Researchers estimated MCI detection rates among 226,756 primary care clinicians and 54,597 practices that had at least 25 patients enrolled in Medicare between 2017 and 2019. 
• They compared the expected number of MCI cases, based on a predictive model, to actual diagnosed cases as documented in claims and encounter data.
• They accounted for uncertainty in these estimates to determine whether detection rates are within the expected range or significantly higher or lower.

TAKEAWAY:

• More than 25% of clinicians and practices did not have a single patient with diagnosed MCI; the average detection rate was 0.01 for both clinicians and practices.
• The modeled expected MCI detection rate, however, was much higher (average 0.19 for clinicians and 0.20 for practices).
• Average detection rates for clinicians and practices was 0.08, with more than 99% of clinicians and practices underdiagnosing MCI; clinicians practicing geriatric medicine had higher detection rates than others.

IN PRACTICE:

The findings are “concerning not only because patients might not get identified for a disease-modifying AD treatment in time, but also because numerous causes of MCI – such as hypothyroidism and medication side effects – are reversible, and the condition itself can be stabilized by lifestyle modification interventions,” the authors write.

SOURCE:

The study was published online in the Journal of Prevention of Alzheimer’s Disease. The first author was Ying Liu, PhD, of the University of Southern California, Los Angeles.

LIMITATIONS:

The predictive model based on demographic information has only moderate accuracy. Expected prevalence of MCI was based on cognitive test scores, which is not the same as a true clinical diagnosis.

DISCLOSURES:

The study was partially funded by a contract from Genentech to the University of Southern California. Coauthors Soeren Mattke and Christopher Wallick have disclosed relationships with Genentech.

A version of this article appeared on Medscape.com.

Ultraprocessed foods (UPFs) make up nearly three-quarters of the entire U.S. food supply and about 60% of Americans’ daily caloric intake. A significant body of research has tied consumption of these foods – awash in added sugar, salt, fat, artificial colors, or preservatives – to cancer, diabetes, and heart disease.
 

Now, a growing number of studies also link them to poor brain health, including an increased risk of dementia, depression, and anxiety, and some experts are calling for public health policies aimed at reducing UPF consumption.

But what’s the science behind the link between UPFs and brain health and what does it mean for clinicians and their patients?
 

Under srutiny

A mainstay of diets in countries around the world, UPFs have come under increasing scrutiny because of their link to major diseases. The ingredients in UPFs add little or no nutritional value. Their primary function is to increase a product’s shelf life and palatability. Some recent evidence suggests these foods may be as addictive as tobacco. In addition, two pooled analysis studies using the Yale Food Addiction Scale showed that 14% of adults and 12% of children in the United States may have a UPF addiction.

The most widely used measure of what is, and what is not, a UPF was developed in 2009 by researchers in Brazil. The NOVA food classification system assigns food and beverages to one of four groups:

• Unprocessed and minimally processed foods, such as fruits, vegetables, milk, and meat.
• Processed culinary ingredients, including white sugar, butter, and oils derived from seeds, nuts, and fruits.
• Processed foods, such as tomato paste, bacon, canned tuna, and wine.
• Ultraprocessed foods, such as soda, ice cream, breakfast cereal, and prepackaged meals.

Those sounding the alarm about the potential harmful effects of UPFs are particularly concerned about their consumption by young people. The National Health and Nutrition Examination Survey showed that from 1999 to 2018, highly processed foods accounted for the majority of energy intake in those aged 2-19 years.

One of the most commonly used additives in UPFs, the artificial sweetener aspartame, garnered headlines this summer when the World Health Organization classified it as a likely carcinogen in humans. Aspartame is used in thousands of products, from soda to chewing gum to chewable vitamins.

The U.S. Food and Drug Administration strongly disagreed with the WHO’s position and is sticking by its recommended daily limit of 50 mg/kg of body weight – equivalent to 75 packets of the sweetener Equal – as safe for human consumption.

“Aspartame is one of the most studied food additives in the human food supply,” FDA officials said in a statement, adding that the agency found “significant shortcomings” in the studies the WHO used to justify the new classification. “FDA scientists do not have safety concerns when aspartame is used under the approved conditions.”

Increased attention to consumption of UPFs in general and aspartame particularly in recent years has yielded several studies pointing to the foods’ association with compromised brain health.
 

Link to depression, dementia

A recent report on UPF consumption and mental well-being among nearly 300,000 people across 70 countries showed that 53% of those who consumed UPFs several times a day were distressed or were struggling with their mental well-being, compared with 18% of those who rarely or never consumed UPFs.

Part of the Global Mind Project run by the nonprofit Sapien Labs in Arlington, Va., the report also showed that individuals with the highest rates of UPF consumption reported higher levels of confusion, slowed thinking, unwanted or obsessive thoughts, irritability, and feelings of sadness.

“There seems to be a much broader effect than just depression symptoms,” Tara Thiagarajan, PhD, founder and chief scientist of Sapien Labs and coauthor of the report, said in an interview.

The report, which has not been peer reviewed, comes on the heels of several other studies, including one from the Nurses Health Study II that showed that participants who consumed more than eight servings of UPFs daily had about a 50% higher depression risk, compared with those who consumed half that much.

“We found that UPFs in general, and artificial sweeteners and beverages in particular, were associated with increased risk,” said lead investigator Andrew T. Chan, MD, MPH, professor of medicine at Harvard Medical School and chief of the clinical and translational epidemiology unit, Massachusetts General Hospital, both in Boston.

“This was an interesting finding that correlates with data from animal studies that artificial sweeteners may trigger the transmission of particular signaling molecules in the brain that are important for mood,” he told this news organization.

Cognition may also be affected. An analysis of more than 72,000 people in the UK Biobank showed that those who consumed a high levels of UPFs were 50% more likely to develop dementia than those who consumed fewer processed foods. For every 10% increase in UPF consumption, the odds of developing any kind of dementia increased by 25%.

Another study of nearly 11,000 people showed that higher UPF consumption was associated with a significantly faster decline in executive and global cognitive function.
 

Epigenetic changes

While these and other studies suggest a link between UPF consumption and brain health, they are designed to demonstrate correlation. To date, no human study has proven that eating highly processed foods directly causes a decline in mental health or cognition.

Animal studies could provide that causal link. Earlier this year, researchers at Florida State University in Tallahassee reported learning and memory deficits in two groups of male mice that completed a maze test after being fed water mixed with aspartame for about 20% of their adult lives, compared with a group of mice that drank water only. Animals that ingested aspartame could finish the test, but it took them longer, and they needed help.

The amount of aspartame used in the study was just 7% and 15% of the FDA’s recommended maximum intake of aspartame (equivalent to two to four 8-ounce diet sodas daily).

Most intriguing was that offspring of the mice in the aspartame groups demonstrated the same levels of cognitive decline and anxiety as their fathers, even though they had never ingested the artificial sweetener. Researchers theorize that in addition to changes in brain gene expression, aspartame also caused epigenetic changes in germ cells.

“Epigenetic changes in germ cells due to environmental exposures are both good and bad,” lead investigator Pradeep G. Bhide, PhD, professor of developmental neuroscience and director of the Center for Brain Repair at FSU, told this news organization. “They are bad because the next generation is affected. But they’re good because as long as the exposure no longer occurs, 2 or 3 generations later, that’s gone.”

The mice, which lacked taste receptors for aspartame, were the same age and weight in all three groups. Because the only difference was exposure to the artificial sweetener, Dr. Bhide says it suggests a causal link.

“Extrapolation of data from well-controlled laboratory experiments in mice to humans is always risky,” Dr. Bhide said. “The extrapolations give us insights into what could happen rather than what will happen.”
 

Potential mechanisms

Although scientists can’t say for certain how UPFs affect brain health, there are several theories. UPFs may influence an inflammatory immune response, which has been linked to depression and dementia. Consumption of highly processed foods may also disrupt the gut microbiome, Dr. Chan said, which, in turn, may increase depression risk.

“This is an important potential mechanism linking ultraprocessed food to depression since there is emerging evidence that microbes in the gut have been linked with mood through their role in metabolizing and producing proteins that have activity in the brain,” he said.

In addition, with UPFs that contain aspartame, there could be a more direct link to brain function. In the gastrointestinal track, the sweetener is quickly broken down into methanol, aspartic acid, and phenylalanine. All three enter the bloodstream, cross the blood-brain barrier, and are neuroactive.

“Phenylalanine is a precursor for neurotransmitters in the brain, and aspartic acid activates the glutamate excitatory neurotransmitter receptor,” Dr. Bhide said. “The effects we’ve seen could be due to these metabolites that have a direct effect on the brain function.”
 

Time to act?

Some researchers are building a case for classifying UPFs as addictive substances. Others are calling for additional research on UPF safety that is conducted outside the food industry.

There has also been some discussion of placing warning labels on UPFs. However, there is disagreement about what information should be included and how consumers might interpret it. The question of which food products are UPFs and which are not also isn’t settled. The NOVA system may be widely used, but it still has its detractors who believe it misclassifies some healthy foods as ultraprocessed.

Dr. Chan and other experts say the research conducted thus far requires additional corroboration to inform appropriate public health interventions. That would likely take the form of a large, randomized trial with one group of participants eating a healthy diet and the other consuming large amounts of UPFs.

“This type of study is extremely challenging given the number of people that would have to be willing to participate and be willing to eat a very specific diet over a long period of time,” Dr. Chan said. “I am also not sure it would be ethical to assign people to such a diet, given what we already know about the potential health effects of UPFs.”

Dr. Thiagarajan and others have called on funding agencies to direct more grant monies toward studies of UPFs to better understand their effect on brain health.

“Given the magnitude of the problem and given that there is a fair bit of evidence that points to a potential causal link, then we damn well better put money into this and get to the bottom of it,” she said.

Others are looking to the FDA to increase the agency’s scrutiny of food additives. While some additives such as artificial sweeteners have a place in diets of people with diabetes or obesity, Dr. Bhide suggests it may be wise for healthy individuals to reduce their daily intake of UPFs.

“Our data raise this to a different level because of the transgenerational transmission, which has never been shown before,” he said. “We are saying that the FDA should look in preclinical models at germ cells and maybe transgenerational transmission before approving any food additive.”

A version of this article first appeared on Medscape.com.

Ultraprocessed foods (UPFs) make up nearly three-quarters of the entire U.S. food supply and about 60% of Americans’ daily caloric intake. A significant body of research has tied consumption of these foods – awash in added sugar, salt, fat, artificial colors, or preservatives – to cancer, diabetes, and heart disease.
 

Now, a growing number of studies also link them to poor brain health, including an increased risk of dementia, depression, and anxiety, and some experts are calling for public health policies aimed at reducing UPF consumption.

But what’s the science behind the link between UPFs and brain health and what does it mean for clinicians and their patients?
 

Under srutiny

A mainstay of diets in countries around the world, UPFs have come under increasing scrutiny because of their link to major diseases. The ingredients in UPFs add little or no nutritional value. Their primary function is to increase a product’s shelf life and palatability. Some recent evidence suggests these foods may be as addictive as tobacco. In addition, two pooled analysis studies using the Yale Food Addiction Scale showed that 14% of adults and 12% of children in the United States may have a UPF addiction.

The most widely used measure of what is, and what is not, a UPF was developed in 2009 by researchers in Brazil. The NOVA food classification system assigns food and beverages to one of four groups:

• Unprocessed and minimally processed foods, such as fruits, vegetables, milk, and meat.
• Processed culinary ingredients, including white sugar, butter, and oils derived from seeds, nuts, and fruits.
• Processed foods, such as tomato paste, bacon, canned tuna, and wine.
• Ultraprocessed foods, such as soda, ice cream, breakfast cereal, and prepackaged meals.

Those sounding the alarm about the potential harmful effects of UPFs are particularly concerned about their consumption by young people. The National Health and Nutrition Examination Survey showed that from 1999 to 2018, highly processed foods accounted for the majority of energy intake in those aged 2-19 years.

One of the most commonly used additives in UPFs, the artificial sweetener aspartame, garnered headlines this summer when the World Health Organization classified it as a likely carcinogen in humans. Aspartame is used in thousands of products, from soda to chewing gum to chewable vitamins.

The U.S. Food and Drug Administration strongly disagreed with the WHO’s position and is sticking by its recommended daily limit of 50 mg/kg of body weight – equivalent to 75 packets of the sweetener Equal – as safe for human consumption.

“Aspartame is one of the most studied food additives in the human food supply,” FDA officials said in a statement, adding that the agency found “significant shortcomings” in the studies the WHO used to justify the new classification. “FDA scientists do not have safety concerns when aspartame is used under the approved conditions.”

Increased attention to consumption of UPFs in general and aspartame particularly in recent years has yielded several studies pointing to the foods’ association with compromised brain health.
 

Link to depression, dementia

A recent report on UPF consumption and mental well-being among nearly 300,000 people across 70 countries showed that 53% of those who consumed UPFs several times a day were distressed or were struggling with their mental well-being, compared with 18% of those who rarely or never consumed UPFs.

Part of the Global Mind Project run by the nonprofit Sapien Labs in Arlington, Va., the report also showed that individuals with the highest rates of UPF consumption reported higher levels of confusion, slowed thinking, unwanted or obsessive thoughts, irritability, and feelings of sadness.

“There seems to be a much broader effect than just depression symptoms,” Tara Thiagarajan, PhD, founder and chief scientist of Sapien Labs and coauthor of the report, said in an interview.

The report, which has not been peer reviewed, comes on the heels of several other studies, including one from the Nurses Health Study II that showed that participants who consumed more than eight servings of UPFs daily had about a 50% higher depression risk, compared with those who consumed half that much.

“We found that UPFs in general, and artificial sweeteners and beverages in particular, were associated with increased risk,” said lead investigator Andrew T. Chan, MD, MPH, professor of medicine at Harvard Medical School and chief of the clinical and translational epidemiology unit, Massachusetts General Hospital, both in Boston.

“This was an interesting finding that correlates with data from animal studies that artificial sweeteners may trigger the transmission of particular signaling molecules in the brain that are important for mood,” he told this news organization.

Cognition may also be affected. An analysis of more than 72,000 people in the UK Biobank showed that those who consumed a high levels of UPFs were 50% more likely to develop dementia than those who consumed fewer processed foods. For every 10% increase in UPF consumption, the odds of developing any kind of dementia increased by 25%.

Another study of nearly 11,000 people showed that higher UPF consumption was associated with a significantly faster decline in executive and global cognitive function.
 

Epigenetic changes

While these and other studies suggest a link between UPF consumption and brain health, they are designed to demonstrate correlation. To date, no human study has proven that eating highly processed foods directly causes a decline in mental health or cognition.

Animal studies could provide that causal link. Earlier this year, researchers at Florida State University in Tallahassee reported learning and memory deficits in two groups of male mice that completed a maze test after being fed water mixed with aspartame for about 20% of their adult lives, compared with a group of mice that drank water only. Animals that ingested aspartame could finish the test, but it took them longer, and they needed help.

The amount of aspartame used in the study was just 7% and 15% of the FDA’s recommended maximum intake of aspartame (equivalent to two to four 8-ounce diet sodas daily).

Most intriguing was that offspring of the mice in the aspartame groups demonstrated the same levels of cognitive decline and anxiety as their fathers, even though they had never ingested the artificial sweetener. Researchers theorize that in addition to changes in brain gene expression, aspartame also caused epigenetic changes in germ cells.

“Epigenetic changes in germ cells due to environmental exposures are both good and bad,” lead investigator Pradeep G. Bhide, PhD, professor of developmental neuroscience and director of the Center for Brain Repair at FSU, told this news organization. “They are bad because the next generation is affected. But they’re good because as long as the exposure no longer occurs, 2 or 3 generations later, that’s gone.”

The mice, which lacked taste receptors for aspartame, were the same age and weight in all three groups. Because the only difference was exposure to the artificial sweetener, Dr. Bhide says it suggests a causal link.

“Extrapolation of data from well-controlled laboratory experiments in mice to humans is always risky,” Dr. Bhide said. “The extrapolations give us insights into what could happen rather than what will happen.”
 

Potential mechanisms

Although scientists can’t say for certain how UPFs affect brain health, there are several theories. UPFs may influence an inflammatory immune response, which has been linked to depression and dementia. Consumption of highly processed foods may also disrupt the gut microbiome, Dr. Chan said, which, in turn, may increase depression risk.

“This is an important potential mechanism linking ultraprocessed food to depression since there is emerging evidence that microbes in the gut have been linked with mood through their role in metabolizing and producing proteins that have activity in the brain,” he said.

In addition, with UPFs that contain aspartame, there could be a more direct link to brain function. In the gastrointestinal track, the sweetener is quickly broken down into methanol, aspartic acid, and phenylalanine. All three enter the bloodstream, cross the blood-brain barrier, and are neuroactive.

“Phenylalanine is a precursor for neurotransmitters in the brain, and aspartic acid activates the glutamate excitatory neurotransmitter receptor,” Dr. Bhide said. “The effects we’ve seen could be due to these metabolites that have a direct effect on the brain function.”
 

Time to act?

Some researchers are building a case for classifying UPFs as addictive substances. Others are calling for additional research on UPF safety that is conducted outside the food industry.

There has also been some discussion of placing warning labels on UPFs. However, there is disagreement about what information should be included and how consumers might interpret it. The question of which food products are UPFs and which are not also isn’t settled. The NOVA system may be widely used, but it still has its detractors who believe it misclassifies some healthy foods as ultraprocessed.

Dr. Chan and other experts say the research conducted thus far requires additional corroboration to inform appropriate public health interventions. That would likely take the form of a large, randomized trial with one group of participants eating a healthy diet and the other consuming large amounts of UPFs.

“This type of study is extremely challenging given the number of people that would have to be willing to participate and be willing to eat a very specific diet over a long period of time,” Dr. Chan said. “I am also not sure it would be ethical to assign people to such a diet, given what we already know about the potential health effects of UPFs.”

Dr. Thiagarajan and others have called on funding agencies to direct more grant monies toward studies of UPFs to better understand their effect on brain health.

“Given the magnitude of the problem and given that there is a fair bit of evidence that points to a potential causal link, then we damn well better put money into this and get to the bottom of it,” she said.

Others are looking to the FDA to increase the agency’s scrutiny of food additives. While some additives such as artificial sweeteners have a place in diets of people with diabetes or obesity, Dr. Bhide suggests it may be wise for healthy individuals to reduce their daily intake of UPFs.

“Our data raise this to a different level because of the transgenerational transmission, which has never been shown before,” he said. “We are saying that the FDA should look in preclinical models at germ cells and maybe transgenerational transmission before approving any food additive.”

A version of this article first appeared on Medscape.com.

Ultraprocessed foods (UPFs) make up nearly three-quarters of the entire U.S. food supply and about 60% of Americans’ daily caloric intake. A significant body of research has tied consumption of these foods – awash in added sugar, salt, fat, artificial colors, or preservatives – to cancer, diabetes, and heart disease.
 

Now, a growing number of studies also link them to poor brain health, including an increased risk of dementia, depression, and anxiety, and some experts are calling for public health policies aimed at reducing UPF consumption.

But what’s the science behind the link between UPFs and brain health and what does it mean for clinicians and their patients?
 

Under srutiny

A mainstay of diets in countries around the world, UPFs have come under increasing scrutiny because of their link to major diseases. The ingredients in UPFs add little or no nutritional value. Their primary function is to increase a product’s shelf life and palatability. Some recent evidence suggests these foods may be as addictive as tobacco. In addition, two pooled analysis studies using the Yale Food Addiction Scale showed that 14% of adults and 12% of children in the United States may have a UPF addiction.

The most widely used measure of what is, and what is not, a UPF was developed in 2009 by researchers in Brazil. The NOVA food classification system assigns food and beverages to one of four groups:

• Unprocessed and minimally processed foods, such as fruits, vegetables, milk, and meat.
• Processed culinary ingredients, including white sugar, butter, and oils derived from seeds, nuts, and fruits.
• Processed foods, such as tomato paste, bacon, canned tuna, and wine.
• Ultraprocessed foods, such as soda, ice cream, breakfast cereal, and prepackaged meals.

Those sounding the alarm about the potential harmful effects of UPFs are particularly concerned about their consumption by young people. The National Health and Nutrition Examination Survey showed that from 1999 to 2018, highly processed foods accounted for the majority of energy intake in those aged 2-19 years.

One of the most commonly used additives in UPFs, the artificial sweetener aspartame, garnered headlines this summer when the World Health Organization classified it as a likely carcinogen in humans. Aspartame is used in thousands of products, from soda to chewing gum to chewable vitamins.

The U.S. Food and Drug Administration strongly disagreed with the WHO’s position and is sticking by its recommended daily limit of 50 mg/kg of body weight – equivalent to 75 packets of the sweetener Equal – as safe for human consumption.

“Aspartame is one of the most studied food additives in the human food supply,” FDA officials said in a statement, adding that the agency found “significant shortcomings” in the studies the WHO used to justify the new classification. “FDA scientists do not have safety concerns when aspartame is used under the approved conditions.”

Increased attention to consumption of UPFs in general and aspartame particularly in recent years has yielded several studies pointing to the foods’ association with compromised brain health.
 

Link to depression, dementia

A recent report on UPF consumption and mental well-being among nearly 300,000 people across 70 countries showed that 53% of those who consumed UPFs several times a day were distressed or were struggling with their mental well-being, compared with 18% of those who rarely or never consumed UPFs.

Part of the Global Mind Project run by the nonprofit Sapien Labs in Arlington, Va., the report also showed that individuals with the highest rates of UPF consumption reported higher levels of confusion, slowed thinking, unwanted or obsessive thoughts, irritability, and feelings of sadness.

“There seems to be a much broader effect than just depression symptoms,” Tara Thiagarajan, PhD, founder and chief scientist of Sapien Labs and coauthor of the report, said in an interview.

The report, which has not been peer reviewed, comes on the heels of several other studies, including one from the Nurses Health Study II that showed that participants who consumed more than eight servings of UPFs daily had about a 50% higher depression risk, compared with those who consumed half that much.

“We found that UPFs in general, and artificial sweeteners and beverages in particular, were associated with increased risk,” said lead investigator Andrew T. Chan, MD, MPH, professor of medicine at Harvard Medical School and chief of the clinical and translational epidemiology unit, Massachusetts General Hospital, both in Boston.

“This was an interesting finding that correlates with data from animal studies that artificial sweeteners may trigger the transmission of particular signaling molecules in the brain that are important for mood,” he told this news organization.

Cognition may also be affected. An analysis of more than 72,000 people in the UK Biobank showed that those who consumed a high levels of UPFs were 50% more likely to develop dementia than those who consumed fewer processed foods. For every 10% increase in UPF consumption, the odds of developing any kind of dementia increased by 25%.

Another study of nearly 11,000 people showed that higher UPF consumption was associated with a significantly faster decline in executive and global cognitive function.
 

Epigenetic changes

While these and other studies suggest a link between UPF consumption and brain health, they are designed to demonstrate correlation. To date, no human study has proven that eating highly processed foods directly causes a decline in mental health or cognition.

Animal studies could provide that causal link. Earlier this year, researchers at Florida State University in Tallahassee reported learning and memory deficits in two groups of male mice that completed a maze test after being fed water mixed with aspartame for about 20% of their adult lives, compared with a group of mice that drank water only. Animals that ingested aspartame could finish the test, but it took them longer, and they needed help.

The amount of aspartame used in the study was just 7% and 15% of the FDA’s recommended maximum intake of aspartame (equivalent to two to four 8-ounce diet sodas daily).

Most intriguing was that offspring of the mice in the aspartame groups demonstrated the same levels of cognitive decline and anxiety as their fathers, even though they had never ingested the artificial sweetener. Researchers theorize that in addition to changes in brain gene expression, aspartame also caused epigenetic changes in germ cells.

“Epigenetic changes in germ cells due to environmental exposures are both good and bad,” lead investigator Pradeep G. Bhide, PhD, professor of developmental neuroscience and director of the Center for Brain Repair at FSU, told this news organization. “They are bad because the next generation is affected. But they’re good because as long as the exposure no longer occurs, 2 or 3 generations later, that’s gone.”

The mice, which lacked taste receptors for aspartame, were the same age and weight in all three groups. Because the only difference was exposure to the artificial sweetener, Dr. Bhide says it suggests a causal link.

“Extrapolation of data from well-controlled laboratory experiments in mice to humans is always risky,” Dr. Bhide said. “The extrapolations give us insights into what could happen rather than what will happen.”
 

Potential mechanisms

Although scientists can’t say for certain how UPFs affect brain health, there are several theories. UPFs may influence an inflammatory immune response, which has been linked to depression and dementia. Consumption of highly processed foods may also disrupt the gut microbiome, Dr. Chan said, which, in turn, may increase depression risk.

“This is an important potential mechanism linking ultraprocessed food to depression since there is emerging evidence that microbes in the gut have been linked with mood through their role in metabolizing and producing proteins that have activity in the brain,” he said.

In addition, with UPFs that contain aspartame, there could be a more direct link to brain function. In the gastrointestinal track, the sweetener is quickly broken down into methanol, aspartic acid, and phenylalanine. All three enter the bloodstream, cross the blood-brain barrier, and are neuroactive.

“Phenylalanine is a precursor for neurotransmitters in the brain, and aspartic acid activates the glutamate excitatory neurotransmitter receptor,” Dr. Bhide said. “The effects we’ve seen could be due to these metabolites that have a direct effect on the brain function.”
 

Time to act?

Some researchers are building a case for classifying UPFs as addictive substances. Others are calling for additional research on UPF safety that is conducted outside the food industry.

There has also been some discussion of placing warning labels on UPFs. However, there is disagreement about what information should be included and how consumers might interpret it. The question of which food products are UPFs and which are not also isn’t settled. The NOVA system may be widely used, but it still has its detractors who believe it misclassifies some healthy foods as ultraprocessed.

Dr. Chan and other experts say the research conducted thus far requires additional corroboration to inform appropriate public health interventions. That would likely take the form of a large, randomized trial with one group of participants eating a healthy diet and the other consuming large amounts of UPFs.

“This type of study is extremely challenging given the number of people that would have to be willing to participate and be willing to eat a very specific diet over a long period of time,” Dr. Chan said. “I am also not sure it would be ethical to assign people to such a diet, given what we already know about the potential health effects of UPFs.”

Dr. Thiagarajan and others have called on funding agencies to direct more grant monies toward studies of UPFs to better understand their effect on brain health.

“Given the magnitude of the problem and given that there is a fair bit of evidence that points to a potential causal link, then we damn well better put money into this and get to the bottom of it,” she said.

Others are looking to the FDA to increase the agency’s scrutiny of food additives. While some additives such as artificial sweeteners have a place in diets of people with diabetes or obesity, Dr. Bhide suggests it may be wise for healthy individuals to reduce their daily intake of UPFs.

“Our data raise this to a different level because of the transgenerational transmission, which has never been shown before,” he said. “We are saying that the FDA should look in preclinical models at germ cells and maybe transgenerational transmission before approving any food additive.”

A version of this article first appeared on Medscape.com.

T3D-959, an oral dual delta/gamma peroxisome proliferator-activated nuclear receptor (PPAR) agonist, has shown promise in a phase 2 randomized, placebo-controlled study of adults with mild to moderate Alzheimer’s disease (AD).

Topline results provide “clinical evidence of a modification of multiple AD pathologies associated with amyloid plaque burden,” said John Didsbury, PhD, chief executive officer of T3D Therapeutics Inc., the company developing the drug.

While the primary cognitive endpoints were not met in the overall study population, the data suggest that a “high plasma pTau-217/non–pTau-217 ratio, a marker of AD pathology, likely defines an AD population responsive to T3D-959 therapy,” Dr. Didsbury said.

He said it’s important to note that no PET imaging (amyloid/tau) or biomarkers were used as entry criteria and, in hindsight, some participants likely did not have AD, which likely played a role in the negative primary outcome.

The findings from the PIONEER study were presented at the annual Clinical Trials on Alzheimer’s Disease conference.
 

‘Surprised and shocked’

The PPAR family of proteins helps regulate blood sugar and triglyceride levels. The rationale for evaluating PPAR agonists in AD is based on the hypothesis that sporadic AD is fundamentally an age-related metabolic disease.

T3D-959 is the first PPAR delta-activating compound to be developed for the treatment of AD. Uniquely, this drug also activates PPAR gamma, which may provide potential additive or synergistic effects in regulating dysfunctional brain glucose energy and lipid metabolism in AD.

The PIONEER tested three doses of T3D-959 (15 mg, 30 mg, and 45 mg) vs. placebo in 250 adults with mild to moderate AD (Mini-Mental State Examination [MMSE] 14-26, Clinical Dementia Rating (CDR)-Global 0.5-2.0, and Sum of Boxes [CDR-SB] ≥ 3.0). T3D-959 or placebo was taken once daily for 24 weeks.

In the overall population, the primary endpoints – Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog11) and Clinical Global Impression of Change (CGIC) – were not met.

“Plain and simple, when we saw this data, we were surprised and shocked,” said Dr. Didsbury, and wondered, “How can placebo be doing so well on a 6-month AD trial?”

“We suspect the presence of non-AD subjects in the trial based on the lower-than-typical number of ApoE4 positive subjects, increased cognitive performance and learning effects observed, and only 45% of trial subjects having a low pTau-217 ratio, a biomarker indicating that they would have no AD pathology plasma,” he explained.

Plasma baseline pTau-217 ratio correlates with AD risk and severity and is a marker of AD pathology; in the subgroup with high pTau-217 ratio, the ADAS-Cog11 endpoint was met in the 30-mg T3D-959 group vs. the placebo group (–0.74 vs. 1.27; P = .112), “consistent with clinical benefit,” Dr. Didsbury noted.

The secondary endpoint of change in plasma amyloid-beta (Ab)42/40 ratio was also met in the 30-mg T3D-959 group – increasing at week 24 with T3D-959 vs. decreasing with placebo (P = .0206), with even greater improvement in the high pTau-217 ratio group. In this group, improvement of Ab42/40 ratio was nearly twofold greater than the overall group.

T3D-959 had a similar magnitude of effect on Ab42/40 as lecanemab (Leqembi) at 6 months, the researchers point out in their late-breaking abstract.

Biomarkers of all three AD diagnostic criteria (amyloid/tau/neurodegeneration) were improved, as well as markers of inflammation, insulin resistance, and dysfunctional lipid metabolism – results that demonstrate “peripheral targeted engagement,” Dr. Didsbury said.

“Along with the strong safety profile of T3D-959, the evidence supports a larger study evaluating T3D-959 30 mg/day in patients with mild to moderate AD and a baseline plasma p-Tau-217/non–pTau-217 ratio of ≥ 0.015,” the researchers conclude in their abstract.
 

Lessons learned

Commenting on the research for this article, Rebecca Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, noted that “the idea behind this treatment is that impaired glucose metabolism in the brain leads to toxic misfolded proteins, including amyloid and tau in people with Alzheimer’s disease.”

“The treatment focuses on improving regulation of glucose and lipid metabolism in the brain. This is one of more than 140 approaches that are being tested today to target the biological drivers and contributors to Alzheimer’s disease,” Dr. Edelmayer said.

Because biomarkers were not used to enroll participants, “there was a high population of people in the trial who did not have Alzheimer’s. This very likely contributed to the negative result,” she noted.

However, the results also suggest that those taking the drug who had a high pTau217 ratio – and are likely to have brain amyloid plaques – had less cognitive decline, she noted.

Lessons learned from this negative trial include “the proper dose to balance efficacy and safety, and how to screen participants for their next study,” Dr. Edelmayer said.

Funding for the study was provided by the National Institute on Aging/National Institutes of Health and the Alzheimer’s Association. Dr. Didsbury and Dr. Edelmayer report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

T3D-959, an oral dual delta/gamma peroxisome proliferator-activated nuclear receptor (PPAR) agonist, has shown promise in a phase 2 randomized, placebo-controlled study of adults with mild to moderate Alzheimer’s disease (AD).

Topline results provide “clinical evidence of a modification of multiple AD pathologies associated with amyloid plaque burden,” said John Didsbury, PhD, chief executive officer of T3D Therapeutics Inc., the company developing the drug.

While the primary cognitive endpoints were not met in the overall study population, the data suggest that a “high plasma pTau-217/non–pTau-217 ratio, a marker of AD pathology, likely defines an AD population responsive to T3D-959 therapy,” Dr. Didsbury said.

He said it’s important to note that no PET imaging (amyloid/tau) or biomarkers were used as entry criteria and, in hindsight, some participants likely did not have AD, which likely played a role in the negative primary outcome.

The findings from the PIONEER study were presented at the annual Clinical Trials on Alzheimer’s Disease conference.
 

‘Surprised and shocked’

The PPAR family of proteins helps regulate blood sugar and triglyceride levels. The rationale for evaluating PPAR agonists in AD is based on the hypothesis that sporadic AD is fundamentally an age-related metabolic disease.

T3D-959 is the first PPAR delta-activating compound to be developed for the treatment of AD. Uniquely, this drug also activates PPAR gamma, which may provide potential additive or synergistic effects in regulating dysfunctional brain glucose energy and lipid metabolism in AD.

The PIONEER tested three doses of T3D-959 (15 mg, 30 mg, and 45 mg) vs. placebo in 250 adults with mild to moderate AD (Mini-Mental State Examination [MMSE] 14-26, Clinical Dementia Rating (CDR)-Global 0.5-2.0, and Sum of Boxes [CDR-SB] ≥ 3.0). T3D-959 or placebo was taken once daily for 24 weeks.

In the overall population, the primary endpoints – Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog11) and Clinical Global Impression of Change (CGIC) – were not met.

“Plain and simple, when we saw this data, we were surprised and shocked,” said Dr. Didsbury, and wondered, “How can placebo be doing so well on a 6-month AD trial?”

“We suspect the presence of non-AD subjects in the trial based on the lower-than-typical number of ApoE4 positive subjects, increased cognitive performance and learning effects observed, and only 45% of trial subjects having a low pTau-217 ratio, a biomarker indicating that they would have no AD pathology plasma,” he explained.

Plasma baseline pTau-217 ratio correlates with AD risk and severity and is a marker of AD pathology; in the subgroup with high pTau-217 ratio, the ADAS-Cog11 endpoint was met in the 30-mg T3D-959 group vs. the placebo group (–0.74 vs. 1.27; P = .112), “consistent with clinical benefit,” Dr. Didsbury noted.

The secondary endpoint of change in plasma amyloid-beta (Ab)42/40 ratio was also met in the 30-mg T3D-959 group – increasing at week 24 with T3D-959 vs. decreasing with placebo (P = .0206), with even greater improvement in the high pTau-217 ratio group. In this group, improvement of Ab42/40 ratio was nearly twofold greater than the overall group.

T3D-959 had a similar magnitude of effect on Ab42/40 as lecanemab (Leqembi) at 6 months, the researchers point out in their late-breaking abstract.

Biomarkers of all three AD diagnostic criteria (amyloid/tau/neurodegeneration) were improved, as well as markers of inflammation, insulin resistance, and dysfunctional lipid metabolism – results that demonstrate “peripheral targeted engagement,” Dr. Didsbury said.

“Along with the strong safety profile of T3D-959, the evidence supports a larger study evaluating T3D-959 30 mg/day in patients with mild to moderate AD and a baseline plasma p-Tau-217/non–pTau-217 ratio of ≥ 0.015,” the researchers conclude in their abstract.
 

Lessons learned

Commenting on the research for this article, Rebecca Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, noted that “the idea behind this treatment is that impaired glucose metabolism in the brain leads to toxic misfolded proteins, including amyloid and tau in people with Alzheimer’s disease.”

“The treatment focuses on improving regulation of glucose and lipid metabolism in the brain. This is one of more than 140 approaches that are being tested today to target the biological drivers and contributors to Alzheimer’s disease,” Dr. Edelmayer said.

Because biomarkers were not used to enroll participants, “there was a high population of people in the trial who did not have Alzheimer’s. This very likely contributed to the negative result,” she noted.

However, the results also suggest that those taking the drug who had a high pTau217 ratio – and are likely to have brain amyloid plaques – had less cognitive decline, she noted.

Lessons learned from this negative trial include “the proper dose to balance efficacy and safety, and how to screen participants for their next study,” Dr. Edelmayer said.

Funding for the study was provided by the National Institute on Aging/National Institutes of Health and the Alzheimer’s Association. Dr. Didsbury and Dr. Edelmayer report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

T3D-959, an oral dual delta/gamma peroxisome proliferator-activated nuclear receptor (PPAR) agonist, has shown promise in a phase 2 randomized, placebo-controlled study of adults with mild to moderate Alzheimer’s disease (AD).

Topline results provide “clinical evidence of a modification of multiple AD pathologies associated with amyloid plaque burden,” said John Didsbury, PhD, chief executive officer of T3D Therapeutics Inc., the company developing the drug.

While the primary cognitive endpoints were not met in the overall study population, the data suggest that a “high plasma pTau-217/non–pTau-217 ratio, a marker of AD pathology, likely defines an AD population responsive to T3D-959 therapy,” Dr. Didsbury said.

He said it’s important to note that no PET imaging (amyloid/tau) or biomarkers were used as entry criteria and, in hindsight, some participants likely did not have AD, which likely played a role in the negative primary outcome.

The findings from the PIONEER study were presented at the annual Clinical Trials on Alzheimer’s Disease conference.
 

‘Surprised and shocked’

The PPAR family of proteins helps regulate blood sugar and triglyceride levels. The rationale for evaluating PPAR agonists in AD is based on the hypothesis that sporadic AD is fundamentally an age-related metabolic disease.

T3D-959 is the first PPAR delta-activating compound to be developed for the treatment of AD. Uniquely, this drug also activates PPAR gamma, which may provide potential additive or synergistic effects in regulating dysfunctional brain glucose energy and lipid metabolism in AD.

The PIONEER tested three doses of T3D-959 (15 mg, 30 mg, and 45 mg) vs. placebo in 250 adults with mild to moderate AD (Mini-Mental State Examination [MMSE] 14-26, Clinical Dementia Rating (CDR)-Global 0.5-2.0, and Sum of Boxes [CDR-SB] ≥ 3.0). T3D-959 or placebo was taken once daily for 24 weeks.

In the overall population, the primary endpoints – Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog11) and Clinical Global Impression of Change (CGIC) – were not met.

“Plain and simple, when we saw this data, we were surprised and shocked,” said Dr. Didsbury, and wondered, “How can placebo be doing so well on a 6-month AD trial?”

“We suspect the presence of non-AD subjects in the trial based on the lower-than-typical number of ApoE4 positive subjects, increased cognitive performance and learning effects observed, and only 45% of trial subjects having a low pTau-217 ratio, a biomarker indicating that they would have no AD pathology plasma,” he explained.

Plasma baseline pTau-217 ratio correlates with AD risk and severity and is a marker of AD pathology; in the subgroup with high pTau-217 ratio, the ADAS-Cog11 endpoint was met in the 30-mg T3D-959 group vs. the placebo group (–0.74 vs. 1.27; P = .112), “consistent with clinical benefit,” Dr. Didsbury noted.

The secondary endpoint of change in plasma amyloid-beta (Ab)42/40 ratio was also met in the 30-mg T3D-959 group – increasing at week 24 with T3D-959 vs. decreasing with placebo (P = .0206), with even greater improvement in the high pTau-217 ratio group. In this group, improvement of Ab42/40 ratio was nearly twofold greater than the overall group.

T3D-959 had a similar magnitude of effect on Ab42/40 as lecanemab (Leqembi) at 6 months, the researchers point out in their late-breaking abstract.

Biomarkers of all three AD diagnostic criteria (amyloid/tau/neurodegeneration) were improved, as well as markers of inflammation, insulin resistance, and dysfunctional lipid metabolism – results that demonstrate “peripheral targeted engagement,” Dr. Didsbury said.

“Along with the strong safety profile of T3D-959, the evidence supports a larger study evaluating T3D-959 30 mg/day in patients with mild to moderate AD and a baseline plasma p-Tau-217/non–pTau-217 ratio of ≥ 0.015,” the researchers conclude in their abstract.
 

Lessons learned

Commenting on the research for this article, Rebecca Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, noted that “the idea behind this treatment is that impaired glucose metabolism in the brain leads to toxic misfolded proteins, including amyloid and tau in people with Alzheimer’s disease.”

“The treatment focuses on improving regulation of glucose and lipid metabolism in the brain. This is one of more than 140 approaches that are being tested today to target the biological drivers and contributors to Alzheimer’s disease,” Dr. Edelmayer said.

Because biomarkers were not used to enroll participants, “there was a high population of people in the trial who did not have Alzheimer’s. This very likely contributed to the negative result,” she noted.

However, the results also suggest that those taking the drug who had a high pTau217 ratio – and are likely to have brain amyloid plaques – had less cognitive decline, she noted.

Lessons learned from this negative trial include “the proper dose to balance efficacy and safety, and how to screen participants for their next study,” Dr. Edelmayer said.

Funding for the study was provided by the National Institute on Aging/National Institutes of Health and the Alzheimer’s Association. Dr. Didsbury and Dr. Edelmayer report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

TOPLINE:

Challenging conventional wisdom, new research suggests that hitting the snooze button does not lead to cognitive impairment on waking and may actually provide cognitive benefits.

METHODOLOGY:

• Researchers did two studies to determine why intermittent morning alarms are used and how they affect sleep, cognition, cortisol, and mood.
• Study 1 was a survey of 1,732 healthy adults (mean age 34 years; 66% women) designed to elucidate the characteristics of people who snooze and why they choose to delay their waking in this way.
• Study 2 was a within-subject polysomnography study of 31 healthy habitual snoozers (mean age 27 years; 18 women) designed to explore the acute effects of snoozing on sleep architecture, sleepiness, cognitive ability, mood, and cortisol awakening response.

TAKEAWAY:

• Overall, 69% reported using the snooze button or setting multiple alarms at least sometimes, most often on workdays (71%), with an average snooze time per morning of 22 minutes.
• Sleep quality did not differ between snoozers and nonsnoozers, but snoozers were more likely to feel mentally drowsy on waking (odds ratio, 3.0; P < .001) and had slightly shorter sleep time on workdays (13 minutes).
• In the polysomnography study, compared with waking up abruptly, 30 minutes of snoozing in the morning improved or did not affect performance on standard cognitive tests completed directly on final awakening.
• Snoozing resulted in about 6 minutes of lost sleep, but it prevented awakening from slow-wave sleep and had no clear effects on the cortisol awakening response, morning sleepiness, mood, or overnight sleep architecture.

IN PRACTICE:

“The findings indicate that there is no reason to stop snoozing in the morning if you enjoy it, at least not for snooze times around 30 minutes. In fact, it may even help those with morning drowsiness to be slightly more awake once they get up,” corresponding author Tina Sundelin, PhD, of Stockholm University, said in a statement.

SOURCE:

The study was published online in the Journal of Sleep Research.

LIMITATIONS:

Study 1 focused on waking preferences in a convenience sample of adults. Study 2 included only habitual snoozers making it difficult to generalize the findings to people who don’t usually snooze. The study investigated only the effect of 30 minutes of snoozing on the studied parameters. It’s possible that shorter or longer snooze times have different cognitive effects.

DISCLOSURES:

Support for the study was provided by the Stress Research Institute, Stockholm University, and a grant from Vetenskapsrådet. The authors disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

Challenging conventional wisdom, new research suggests that hitting the snooze button does not lead to cognitive impairment on waking and may actually provide cognitive benefits.

METHODOLOGY:

• Researchers did two studies to determine why intermittent morning alarms are used and how they affect sleep, cognition, cortisol, and mood.
• Study 1 was a survey of 1,732 healthy adults (mean age 34 years; 66% women) designed to elucidate the characteristics of people who snooze and why they choose to delay their waking in this way.
• Study 2 was a within-subject polysomnography study of 31 healthy habitual snoozers (mean age 27 years; 18 women) designed to explore the acute effects of snoozing on sleep architecture, sleepiness, cognitive ability, mood, and cortisol awakening response.

TAKEAWAY:

• Overall, 69% reported using the snooze button or setting multiple alarms at least sometimes, most often on workdays (71%), with an average snooze time per morning of 22 minutes.
• Sleep quality did not differ between snoozers and nonsnoozers, but snoozers were more likely to feel mentally drowsy on waking (odds ratio, 3.0; P < .001) and had slightly shorter sleep time on workdays (13 minutes).
• In the polysomnography study, compared with waking up abruptly, 30 minutes of snoozing in the morning improved or did not affect performance on standard cognitive tests completed directly on final awakening.
• Snoozing resulted in about 6 minutes of lost sleep, but it prevented awakening from slow-wave sleep and had no clear effects on the cortisol awakening response, morning sleepiness, mood, or overnight sleep architecture.

IN PRACTICE:

“The findings indicate that there is no reason to stop snoozing in the morning if you enjoy it, at least not for snooze times around 30 minutes. In fact, it may even help those with morning drowsiness to be slightly more awake once they get up,” corresponding author Tina Sundelin, PhD, of Stockholm University, said in a statement.

SOURCE:

The study was published online in the Journal of Sleep Research.

LIMITATIONS:

Study 1 focused on waking preferences in a convenience sample of adults. Study 2 included only habitual snoozers making it difficult to generalize the findings to people who don’t usually snooze. The study investigated only the effect of 30 minutes of snoozing on the studied parameters. It’s possible that shorter or longer snooze times have different cognitive effects.

DISCLOSURES:

Support for the study was provided by the Stress Research Institute, Stockholm University, and a grant from Vetenskapsrådet. The authors disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

Challenging conventional wisdom, new research suggests that hitting the snooze button does not lead to cognitive impairment on waking and may actually provide cognitive benefits.

METHODOLOGY:

• Researchers did two studies to determine why intermittent morning alarms are used and how they affect sleep, cognition, cortisol, and mood.
• Study 1 was a survey of 1,732 healthy adults (mean age 34 years; 66% women) designed to elucidate the characteristics of people who snooze and why they choose to delay their waking in this way.
• Study 2 was a within-subject polysomnography study of 31 healthy habitual snoozers (mean age 27 years; 18 women) designed to explore the acute effects of snoozing on sleep architecture, sleepiness, cognitive ability, mood, and cortisol awakening response.

TAKEAWAY:

• Overall, 69% reported using the snooze button or setting multiple alarms at least sometimes, most often on workdays (71%), with an average snooze time per morning of 22 minutes.
• Sleep quality did not differ between snoozers and nonsnoozers, but snoozers were more likely to feel mentally drowsy on waking (odds ratio, 3.0; P < .001) and had slightly shorter sleep time on workdays (13 minutes).
• In the polysomnography study, compared with waking up abruptly, 30 minutes of snoozing in the morning improved or did not affect performance on standard cognitive tests completed directly on final awakening.
• Snoozing resulted in about 6 minutes of lost sleep, but it prevented awakening from slow-wave sleep and had no clear effects on the cortisol awakening response, morning sleepiness, mood, or overnight sleep architecture.

IN PRACTICE:

“The findings indicate that there is no reason to stop snoozing in the morning if you enjoy it, at least not for snooze times around 30 minutes. In fact, it may even help those with morning drowsiness to be slightly more awake once they get up,” corresponding author Tina Sundelin, PhD, of Stockholm University, said in a statement.

SOURCE:

The study was published online in the Journal of Sleep Research.

LIMITATIONS:

Study 1 focused on waking preferences in a convenience sample of adults. Study 2 included only habitual snoozers making it difficult to generalize the findings to people who don’t usually snooze. The study investigated only the effect of 30 minutes of snoozing on the studied parameters. It’s possible that shorter or longer snooze times have different cognitive effects.

DISCLOSURES:

Support for the study was provided by the Stress Research Institute, Stockholm University, and a grant from Vetenskapsrådet. The authors disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

PHILADELPHIA – Acute stress in peri- and postmenopausal women is associated with more depressive symptoms, while chronic stress showed greater association with memory and concentration problems, according to research presented at the annual meeting of the Menopause Society (formerly the North American Menopause Society).

“This work suggests that markers of hypothalamic-pituitary-axis activation that capture total cortisol secretion over multiple months, [such as] hair cortisol, strongly correlate with cognitive performance on attention and working memory tasks, whereas measures of more acute cortisol, [such as] salivary cortisol, may be more strongly associated with depression symptom severity and verbal learning,” Christina Metcalf, PhD, an assistant professor of psychiatry in the Colorado Center for Women’s Behavioral Health and Wellness at the University of Colorado at Denver, Aurora, told attendees. “Given the associations with chronic stress, there’s a lot of potential here to increase our knowledge about how women are doing and managing stress and life stressors during this life transition,” she said.

Measuring hair cortisol more feasible

The study was conducted remotely, with participants using video conferencing to communicate with the study personnel and then completing study procedures at home, including 2 days of cognitive testing with the California Verbal Learning Test – Third Edition and the n-back and continuous performance tasks. The participants also completed the Center for Epidemiologic Studies Depression Scale (CES-D).

Participants with higher levels of hair cortisol and salivary cortisol also had more severe depression symptoms (P < .001). Hair cortisol was also significantly associated with attention and working memory: Women with higher levels had fewer correct answers on the 0-back and 1-back trials (P < .01) and made more mistakes on the 2-back trial (P < .001). They also scored with less specificity on the continuous performance tasks (P = .022).

Although no association existed between hair cortisol levels and verbal learning or verbal memory (P > .05), participants with higher hair cortisol did score worse on the immediate recall trials (P = .034). Salivary cortisol levels, on the other hand, showed no association with memory recall trials, attention or working memory (P > .05).

Measuring cortisol from hair samples is more feasible than using saliva samples and may offer valuable insights regarding hypothalamic-pituitary-axis activity “to consider alongside the cognitive and mental health of late peri-/early postmenopausal women,” Dr. Metcalf told attendees. The next step is to find out whether the hypothalamic-pituitary-axis axis is a modifiable biomarker that can be used to improve executive function.

The study was limited by its small population, its cross-sectional design, and the lack of covariates in the current analyses.
 

Monitor symptoms in midlife

Hadine Joffe, MD, MSc, a professor of psychiatry and executive director of the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said the study findings were not surprising given how common the complaints of stress and depressive symptoms are.

“Mood changes are linked with acute, immediate cortisol levels at the same point in time, and cognitive symptoms were linked to more chronically elevated cortisol levels,” Dr. Joffe said in an interview. “Women and their providers should monitor for these challenging brain symptoms in midlife as they affect performance and quality of life and are linked with changes in the HPA axis as stress biomarkers.”

Because the study is small and has a cross-sectional design, it’s not possible to determine the direction of the associations or to make any inferences about causation, Dr. Joffe said.

“We cannot make the conclusion that stress is adversely affecting mood and cognitive performance given the design limitations. It is possible that mood and cognitive issues contributed to these stress markers,” Dr. Joffe said.“However, it is known that the experience of stress is linked with vulnerability to mood and cognitive symptoms, and also that mood and cognitive symptoms induce significant stress.”

The research was funded by the Menopause Society, Colorado University, the Ludeman Family Center for Women’s Health Research, the National Institute of Mental Health, and the National Institute of Aging. Dr. Metcalf had no disclosures. Dr. Joffe has received grant support from Merck, Pfizer and Sage, and has been a consultant or advisor for Bayer, Merck and Hello Therapeutics.

PHILADELPHIA – Acute stress in peri- and postmenopausal women is associated with more depressive symptoms, while chronic stress showed greater association with memory and concentration problems, according to research presented at the annual meeting of the Menopause Society (formerly the North American Menopause Society).

“This work suggests that markers of hypothalamic-pituitary-axis activation that capture total cortisol secretion over multiple months, [such as] hair cortisol, strongly correlate with cognitive performance on attention and working memory tasks, whereas measures of more acute cortisol, [such as] salivary cortisol, may be more strongly associated with depression symptom severity and verbal learning,” Christina Metcalf, PhD, an assistant professor of psychiatry in the Colorado Center for Women’s Behavioral Health and Wellness at the University of Colorado at Denver, Aurora, told attendees. “Given the associations with chronic stress, there’s a lot of potential here to increase our knowledge about how women are doing and managing stress and life stressors during this life transition,” she said.

Measuring hair cortisol more feasible

The study was conducted remotely, with participants using video conferencing to communicate with the study personnel and then completing study procedures at home, including 2 days of cognitive testing with the California Verbal Learning Test – Third Edition and the n-back and continuous performance tasks. The participants also completed the Center for Epidemiologic Studies Depression Scale (CES-D).

Participants with higher levels of hair cortisol and salivary cortisol also had more severe depression symptoms (P < .001). Hair cortisol was also significantly associated with attention and working memory: Women with higher levels had fewer correct answers on the 0-back and 1-back trials (P < .01) and made more mistakes on the 2-back trial (P < .001). They also scored with less specificity on the continuous performance tasks (P = .022).

Although no association existed between hair cortisol levels and verbal learning or verbal memory (P > .05), participants with higher hair cortisol did score worse on the immediate recall trials (P = .034). Salivary cortisol levels, on the other hand, showed no association with memory recall trials, attention or working memory (P > .05).

Measuring cortisol from hair samples is more feasible than using saliva samples and may offer valuable insights regarding hypothalamic-pituitary-axis activity “to consider alongside the cognitive and mental health of late peri-/early postmenopausal women,” Dr. Metcalf told attendees. The next step is to find out whether the hypothalamic-pituitary-axis axis is a modifiable biomarker that can be used to improve executive function.

The study was limited by its small population, its cross-sectional design, and the lack of covariates in the current analyses.
 

Monitor symptoms in midlife

Hadine Joffe, MD, MSc, a professor of psychiatry and executive director of the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said the study findings were not surprising given how common the complaints of stress and depressive symptoms are.

“Mood changes are linked with acute, immediate cortisol levels at the same point in time, and cognitive symptoms were linked to more chronically elevated cortisol levels,” Dr. Joffe said in an interview. “Women and their providers should monitor for these challenging brain symptoms in midlife as they affect performance and quality of life and are linked with changes in the HPA axis as stress biomarkers.”

Because the study is small and has a cross-sectional design, it’s not possible to determine the direction of the associations or to make any inferences about causation, Dr. Joffe said.

“We cannot make the conclusion that stress is adversely affecting mood and cognitive performance given the design limitations. It is possible that mood and cognitive issues contributed to these stress markers,” Dr. Joffe said.“However, it is known that the experience of stress is linked with vulnerability to mood and cognitive symptoms, and also that mood and cognitive symptoms induce significant stress.”

The research was funded by the Menopause Society, Colorado University, the Ludeman Family Center for Women’s Health Research, the National Institute of Mental Health, and the National Institute of Aging. Dr. Metcalf had no disclosures. Dr. Joffe has received grant support from Merck, Pfizer and Sage, and has been a consultant or advisor for Bayer, Merck and Hello Therapeutics.

PHILADELPHIA – Acute stress in peri- and postmenopausal women is associated with more depressive symptoms, while chronic stress showed greater association with memory and concentration problems, according to research presented at the annual meeting of the Menopause Society (formerly the North American Menopause Society).

“This work suggests that markers of hypothalamic-pituitary-axis activation that capture total cortisol secretion over multiple months, [such as] hair cortisol, strongly correlate with cognitive performance on attention and working memory tasks, whereas measures of more acute cortisol, [such as] salivary cortisol, may be more strongly associated with depression symptom severity and verbal learning,” Christina Metcalf, PhD, an assistant professor of psychiatry in the Colorado Center for Women’s Behavioral Health and Wellness at the University of Colorado at Denver, Aurora, told attendees. “Given the associations with chronic stress, there’s a lot of potential here to increase our knowledge about how women are doing and managing stress and life stressors during this life transition,” she said.

Measuring hair cortisol more feasible

The study was conducted remotely, with participants using video conferencing to communicate with the study personnel and then completing study procedures at home, including 2 days of cognitive testing with the California Verbal Learning Test – Third Edition and the n-back and continuous performance tasks. The participants also completed the Center for Epidemiologic Studies Depression Scale (CES-D).

Participants with higher levels of hair cortisol and salivary cortisol also had more severe depression symptoms (P < .001). Hair cortisol was also significantly associated with attention and working memory: Women with higher levels had fewer correct answers on the 0-back and 1-back trials (P < .01) and made more mistakes on the 2-back trial (P < .001). They also scored with less specificity on the continuous performance tasks (P = .022).

Although no association existed between hair cortisol levels and verbal learning or verbal memory (P > .05), participants with higher hair cortisol did score worse on the immediate recall trials (P = .034). Salivary cortisol levels, on the other hand, showed no association with memory recall trials, attention or working memory (P > .05).

Measuring cortisol from hair samples is more feasible than using saliva samples and may offer valuable insights regarding hypothalamic-pituitary-axis activity “to consider alongside the cognitive and mental health of late peri-/early postmenopausal women,” Dr. Metcalf told attendees. The next step is to find out whether the hypothalamic-pituitary-axis axis is a modifiable biomarker that can be used to improve executive function.

The study was limited by its small population, its cross-sectional design, and the lack of covariates in the current analyses.
 

Monitor symptoms in midlife

Hadine Joffe, MD, MSc, a professor of psychiatry and executive director of the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said the study findings were not surprising given how common the complaints of stress and depressive symptoms are.

“Mood changes are linked with acute, immediate cortisol levels at the same point in time, and cognitive symptoms were linked to more chronically elevated cortisol levels,” Dr. Joffe said in an interview. “Women and their providers should monitor for these challenging brain symptoms in midlife as they affect performance and quality of life and are linked with changes in the HPA axis as stress biomarkers.”

Because the study is small and has a cross-sectional design, it’s not possible to determine the direction of the associations or to make any inferences about causation, Dr. Joffe said.

“We cannot make the conclusion that stress is adversely affecting mood and cognitive performance given the design limitations. It is possible that mood and cognitive issues contributed to these stress markers,” Dr. Joffe said.“However, it is known that the experience of stress is linked with vulnerability to mood and cognitive symptoms, and also that mood and cognitive symptoms induce significant stress.”

The research was funded by the Menopause Society, Colorado University, the Ludeman Family Center for Women’s Health Research, the National Institute of Mental Health, and the National Institute of Aging. Dr. Metcalf had no disclosures. Dr. Joffe has received grant support from Merck, Pfizer and Sage, and has been a consultant or advisor for Bayer, Merck and Hello Therapeutics.

The enteric nervous system (ENS), which is regarded as our second brain, is the part of the autonomic nervous system that controls the digestive tract. Housed along the entire length of the digestive tract, it is made up of more than 100 million neurons. It plays a central role in controlling the regulation of gastrointestinal motility, absorption of nutrients, and control of the intestinal barrier that protects the body from external pathogens.

Braak’s hypothesis suggests that the digestive tract could be the starting point for Parkinson’s disease. The fact that nearly all patients with Parkinson’s disease experience digestive problems and have neuropathological lesions in intrinsic and extrinsic innervation of the gastrointestinal tract suggests that Parkinson’s disease also has a gastrointestinal component.

Besides the ascending pathway formulated by Braak, a descending etiology in which gastrointestinal symptoms are present in early stages when neurological signposts have not yet been noticed is supported by evidence from trials. These gastrointestinal symptoms then represent a risk factor. Links have also been described between a history of gastrointestinal symptoms and Alzheimer’s disease and cerebrovascular diseases (CVD), thus justifying studies on a larger scale.
 

Large combined study

The authors have conducted a combined case-control and cohort study using TriNetX, a national network of medical records based in the United States. They identified 24,624 patients with idiopathic Parkinson’s disease in the case-control analysis and compared them with control subjects without neurological disease. They also identified subjects with Alzheimer’s disease and CVD, to study previous gastrointestinal signs. Secondly, 18 cohorts with each exposure (various gastrointestinal symptoms, appendectomy, vagotomy) were compared with their negative controls (NC) for the development of Parkinson’s disease, Alzheimer’s disease, or CVD in 5 years.

Gastroparesis, dysphagia, and irritable bowel syndrome (IBS) without diarrhea or constipation were shown to have specific associations with Parkinson’s disease (vs. NC, Alzheimer’s disease, and CVD) in both case-controls (odds ratios all P < .0001) and cohort analyses (relative risks all P < .05). While functional dyspepsia, IBS with diarrhea, diarrhea, and fecal incontinence were not specific to Parkinson’s disease, IBS with constipation and intestinal pseudo-obstruction showed specificity to Parkinson’s disease in the case-control (OR, 4.11) and cohort (RR, 1.84) analyses. Appendectomy reduced the risk of Parkinson’s disease in the cohort study (RR, 0.48). Neither inflammatory bowel disease nor vagotomy was associated with Parkinson’s disease.
 

A ‘second brain’

This broad study attempted to explore the gut-brain axis by looking for associations between neurological diagnoses and prior gastrointestinal symptoms and later development of Parkinson’s disease. After adjustment to account for multiple comparisons and acknowledgment of the initial risk in patients with Alzheimer’s disease and CVD, only dysphagia, gastroparesis, IBS without diarrhea, and isolated constipation were significantly and specifically associated with Parkinson’s disease.

Numerous literature reviews mention that ENS lesions are responsible for gastrointestinal disorders observed in patients with Parkinson’s disease. Tests on gastrointestinal autopsy and biopsy specimens have established that alpha synuclein clusters, which are morphologically similar to Lewy bodies in the CNS, are seen in the vagus nerve and in the ENS in most subjects with Parkinson’s disease. However, these studies have not shown any loss of neurons in the ENS in Parkinson’s disease, and the presence of alpha synuclein deposits in the ENS is not sufficient in itself to explain these gastrointestinal disorders.

It therefore remains to be determined whether vagal nerve damage alone can explain gastrointestinal disorders or whether dysfunction of enteric neurons without neuronal loss is occurring. So, damage to the ENS from alpha synuclein deposits would be early and would precede damage to the CNS, thus affording evidence in support of Braak’s hypothesis, which relies on autopsy data that does not allow for longitudinal monitoring in a single individual.

Appendectomy appeared to be protective, leading to additional speculation about its role in the pathophysiology of Parkinson’s disease. Additional mechanistic studies are therefore needed to establish causality and confirm the gut-brain axis or the role of dysbiosis and of intestinal permeability problems.

In conclusion, this large, first-of-its-kind multicenter study conducted on a national scale shows that early gastrointestinal symptoms (dysphagia, gastroparesis, constipation, and IBS without diarrhea) are associated with an increased risk of Parkinson’s disease, as is suggested by Braak’s hypothesis. Subject to future longitudinal mechanistic studies, early detection of these gastrointestinal disorders could aid in identifying patients at risk of Parkinson’s, and it could then be assumed that disease-modifying treatments could, at this early stage, halt progression of the disease linked to toxic clusters of alpha synuclein.

This article was translated from JIM, which is part of the Medscape professional network.

A version of this article first appeared on Medscape.com.

The enteric nervous system (ENS), which is regarded as our second brain, is the part of the autonomic nervous system that controls the digestive tract. Housed along the entire length of the digestive tract, it is made up of more than 100 million neurons. It plays a central role in controlling the regulation of gastrointestinal motility, absorption of nutrients, and control of the intestinal barrier that protects the body from external pathogens.

Braak’s hypothesis suggests that the digestive tract could be the starting point for Parkinson’s disease. The fact that nearly all patients with Parkinson’s disease experience digestive problems and have neuropathological lesions in intrinsic and extrinsic innervation of the gastrointestinal tract suggests that Parkinson’s disease also has a gastrointestinal component.

Besides the ascending pathway formulated by Braak, a descending etiology in which gastrointestinal symptoms are present in early stages when neurological signposts have not yet been noticed is supported by evidence from trials. These gastrointestinal symptoms then represent a risk factor. Links have also been described between a history of gastrointestinal symptoms and Alzheimer’s disease and cerebrovascular diseases (CVD), thus justifying studies on a larger scale.
 

Large combined study

The authors have conducted a combined case-control and cohort study using TriNetX, a national network of medical records based in the United States. They identified 24,624 patients with idiopathic Parkinson’s disease in the case-control analysis and compared them with control subjects without neurological disease. They also identified subjects with Alzheimer’s disease and CVD, to study previous gastrointestinal signs. Secondly, 18 cohorts with each exposure (various gastrointestinal symptoms, appendectomy, vagotomy) were compared with their negative controls (NC) for the development of Parkinson’s disease, Alzheimer’s disease, or CVD in 5 years.

Gastroparesis, dysphagia, and irritable bowel syndrome (IBS) without diarrhea or constipation were shown to have specific associations with Parkinson’s disease (vs. NC, Alzheimer’s disease, and CVD) in both case-controls (odds ratios all P < .0001) and cohort analyses (relative risks all P < .05). While functional dyspepsia, IBS with diarrhea, diarrhea, and fecal incontinence were not specific to Parkinson’s disease, IBS with constipation and intestinal pseudo-obstruction showed specificity to Parkinson’s disease in the case-control (OR, 4.11) and cohort (RR, 1.84) analyses. Appendectomy reduced the risk of Parkinson’s disease in the cohort study (RR, 0.48). Neither inflammatory bowel disease nor vagotomy was associated with Parkinson’s disease.
 

A ‘second brain’

This broad study attempted to explore the gut-brain axis by looking for associations between neurological diagnoses and prior gastrointestinal symptoms and later development of Parkinson’s disease. After adjustment to account for multiple comparisons and acknowledgment of the initial risk in patients with Alzheimer’s disease and CVD, only dysphagia, gastroparesis, IBS without diarrhea, and isolated constipation were significantly and specifically associated with Parkinson’s disease.

Numerous literature reviews mention that ENS lesions are responsible for gastrointestinal disorders observed in patients with Parkinson’s disease. Tests on gastrointestinal autopsy and biopsy specimens have established that alpha synuclein clusters, which are morphologically similar to Lewy bodies in the CNS, are seen in the vagus nerve and in the ENS in most subjects with Parkinson’s disease. However, these studies have not shown any loss of neurons in the ENS in Parkinson’s disease, and the presence of alpha synuclein deposits in the ENS is not sufficient in itself to explain these gastrointestinal disorders.

It therefore remains to be determined whether vagal nerve damage alone can explain gastrointestinal disorders or whether dysfunction of enteric neurons without neuronal loss is occurring. So, damage to the ENS from alpha synuclein deposits would be early and would precede damage to the CNS, thus affording evidence in support of Braak’s hypothesis, which relies on autopsy data that does not allow for longitudinal monitoring in a single individual.

Appendectomy appeared to be protective, leading to additional speculation about its role in the pathophysiology of Parkinson’s disease. Additional mechanistic studies are therefore needed to establish causality and confirm the gut-brain axis or the role of dysbiosis and of intestinal permeability problems.

In conclusion, this large, first-of-its-kind multicenter study conducted on a national scale shows that early gastrointestinal symptoms (dysphagia, gastroparesis, constipation, and IBS without diarrhea) are associated with an increased risk of Parkinson’s disease, as is suggested by Braak’s hypothesis. Subject to future longitudinal mechanistic studies, early detection of these gastrointestinal disorders could aid in identifying patients at risk of Parkinson’s, and it could then be assumed that disease-modifying treatments could, at this early stage, halt progression of the disease linked to toxic clusters of alpha synuclein.

This article was translated from JIM, which is part of the Medscape professional network.

A version of this article first appeared on Medscape.com.

The enteric nervous system (ENS), which is regarded as our second brain, is the part of the autonomic nervous system that controls the digestive tract. Housed along the entire length of the digestive tract, it is made up of more than 100 million neurons. It plays a central role in controlling the regulation of gastrointestinal motility, absorption of nutrients, and control of the intestinal barrier that protects the body from external pathogens.

Braak’s hypothesis suggests that the digestive tract could be the starting point for Parkinson’s disease. The fact that nearly all patients with Parkinson’s disease experience digestive problems and have neuropathological lesions in intrinsic and extrinsic innervation of the gastrointestinal tract suggests that Parkinson’s disease also has a gastrointestinal component.

Besides the ascending pathway formulated by Braak, a descending etiology in which gastrointestinal symptoms are present in early stages when neurological signposts have not yet been noticed is supported by evidence from trials. These gastrointestinal symptoms then represent a risk factor. Links have also been described between a history of gastrointestinal symptoms and Alzheimer’s disease and cerebrovascular diseases (CVD), thus justifying studies on a larger scale.
 

Large combined study

The authors have conducted a combined case-control and cohort study using TriNetX, a national network of medical records based in the United States. They identified 24,624 patients with idiopathic Parkinson’s disease in the case-control analysis and compared them with control subjects without neurological disease. They also identified subjects with Alzheimer’s disease and CVD, to study previous gastrointestinal signs. Secondly, 18 cohorts with each exposure (various gastrointestinal symptoms, appendectomy, vagotomy) were compared with their negative controls (NC) for the development of Parkinson’s disease, Alzheimer’s disease, or CVD in 5 years.

Gastroparesis, dysphagia, and irritable bowel syndrome (IBS) without diarrhea or constipation were shown to have specific associations with Parkinson’s disease (vs. NC, Alzheimer’s disease, and CVD) in both case-controls (odds ratios all P < .0001) and cohort analyses (relative risks all P < .05). While functional dyspepsia, IBS with diarrhea, diarrhea, and fecal incontinence were not specific to Parkinson’s disease, IBS with constipation and intestinal pseudo-obstruction showed specificity to Parkinson’s disease in the case-control (OR, 4.11) and cohort (RR, 1.84) analyses. Appendectomy reduced the risk of Parkinson’s disease in the cohort study (RR, 0.48). Neither inflammatory bowel disease nor vagotomy was associated with Parkinson’s disease.
 

A ‘second brain’

This broad study attempted to explore the gut-brain axis by looking for associations between neurological diagnoses and prior gastrointestinal symptoms and later development of Parkinson’s disease. After adjustment to account for multiple comparisons and acknowledgment of the initial risk in patients with Alzheimer’s disease and CVD, only dysphagia, gastroparesis, IBS without diarrhea, and isolated constipation were significantly and specifically associated with Parkinson’s disease.

Numerous literature reviews mention that ENS lesions are responsible for gastrointestinal disorders observed in patients with Parkinson’s disease. Tests on gastrointestinal autopsy and biopsy specimens have established that alpha synuclein clusters, which are morphologically similar to Lewy bodies in the CNS, are seen in the vagus nerve and in the ENS in most subjects with Parkinson’s disease. However, these studies have not shown any loss of neurons in the ENS in Parkinson’s disease, and the presence of alpha synuclein deposits in the ENS is not sufficient in itself to explain these gastrointestinal disorders.

It therefore remains to be determined whether vagal nerve damage alone can explain gastrointestinal disorders or whether dysfunction of enteric neurons without neuronal loss is occurring. So, damage to the ENS from alpha synuclein deposits would be early and would precede damage to the CNS, thus affording evidence in support of Braak’s hypothesis, which relies on autopsy data that does not allow for longitudinal monitoring in a single individual.

Appendectomy appeared to be protective, leading to additional speculation about its role in the pathophysiology of Parkinson’s disease. Additional mechanistic studies are therefore needed to establish causality and confirm the gut-brain axis or the role of dysbiosis and of intestinal permeability problems.

In conclusion, this large, first-of-its-kind multicenter study conducted on a national scale shows that early gastrointestinal symptoms (dysphagia, gastroparesis, constipation, and IBS without diarrhea) are associated with an increased risk of Parkinson’s disease, as is suggested by Braak’s hypothesis. Subject to future longitudinal mechanistic studies, early detection of these gastrointestinal disorders could aid in identifying patients at risk of Parkinson’s, and it could then be assumed that disease-modifying treatments could, at this early stage, halt progression of the disease linked to toxic clusters of alpha synuclein.

This article was translated from JIM, which is part of the Medscape professional network.

A version of this article first appeared on Medscape.com.

Playing chess or other board games slows cognitive decline and improves quality of life in older patients, results of a new systematic review suggest.
 

“For patients who are elderly and suffer from social isolation and mild cognitive issues, I would definitely recommend board games,” study investigator Frederico Emanuele Pozzi, MD, a neurology resident at Fondazione IRCCS San Gerardo dei Tintori in Monza, Italy, told this news organization.

The findings were presented at the virtual XXVI World Congress of Neurology (WCN).

After searching the published literature, Dr. Pozzi and his colleagues selected 15 studies for the review. The studies assessed the impact of board games on older individuals at risk of or with cognitive impairment, or those with mild cognitive impairment (MCI) at any age.

The studies included different board games including chess, Mah-jongg, and Go, a two-player game popular in China, Japan, and Korea that involves moving board pieces to surround and capture as much territory as possible.

Most interventions lasted about an hour and were held once or twice per week for 3-4 months.
 

Which games are best?

Researchers found that board games improved cognitive function, as measured by improved scores on the Montreal Cognitive Assessment (P = .003) and Mini-Mental State Examination (P = .02).

Playing Go was linked with improved working memory, as measured by the Trail Making Test-A. Those who played Mah-jongg reported improved executive functioning and a temporary decrease in depressive symptoms. And chess players reported improved quality of life on the World Health Organization Quality of Life scale from playing chess (P < .00001).

In general, cognition improved across different populations. For example, some studies looked at unimpaired elderly while others looked at MCI, said Dr. Pozzi.

Playing board games in a social context appeared to be especially good at boosting brain power. One Japanese study included a control group that just did tai chi, a group that did Go alone on tablets, and another group that did Go in groups. Both Go groups improved cognitively, but participants who played together improved the most.

The results also seemed to suggest that Go and chess have different biological effects. “For example, Go increased [brain-derived neurotrophic factor] (BDNF) levels and metabolism in areas key for cognition like the middle temporal gyrus,” Dr. Pozzi said.

He noted that the methodology of the studies was generally “not bad,” although in some cases the analyses were per protocol and in others intention-to-treat. Outcomes varied across studies, there were a lot of dropouts, and some were not randomized, meaning reverse causality can’t be ruled out.

Dr. Pozzi has started a randomized controlled trial at a Go and chess club in Italy. He’s enrolling patients aged 60 and over with subjective cognitive decline or MCI and separating participants into a control group, a group that plays chess, another that plays Go, and another that plays both Go and chess.

In addition to the standard cognitive tests, and measures of depression and quality of life, Dr. Pozzi aims to assess cognitive reserve and is in the process of validating a questionnaire that will look at leisure activities and lifestyle.
 

Social and cognitive value

Commenting on the research for this news organization, Vladimir Hachinski, MD, a professor of clinical neurological sciences at Western University in London, Ont., said the results make sense.

Playing a board game involves concentration, strategy, and intermittent rewards – all of which are good for the brain and may involve the prefrontal cortex, he noted. Board games are also typically timed, which involves brain speed processing, and they have a winner and loser so emotions can run high, which also affects the brain, Dr. Hachinski added.

There may also be social value in playing a board game with someone else, added Dr. Hachinski.

“It’s encouraging that people can improve what they’re doing, and the longer they’re at it, the more of the brain they use,” he said. “There might be a long-term effect because players are building up networks.”

But Dr. Hachinski cautioned that playing a lot of chess does not necessarily make you a better thinker, just as learning to play one instrument doesn’t mean you can automatically play others.

“Learning one skill will translate only partially to another, and only if it’s related,” he said. “It increases cognition in the area you’re practicing in, but it doesn’t spread to other areas.”

Dr. Pozzi and Dr. Hachinski report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Playing chess or other board games slows cognitive decline and improves quality of life in older patients, results of a new systematic review suggest.
 

“For patients who are elderly and suffer from social isolation and mild cognitive issues, I would definitely recommend board games,” study investigator Frederico Emanuele Pozzi, MD, a neurology resident at Fondazione IRCCS San Gerardo dei Tintori in Monza, Italy, told this news organization.

The findings were presented at the virtual XXVI World Congress of Neurology (WCN).

After searching the published literature, Dr. Pozzi and his colleagues selected 15 studies for the review. The studies assessed the impact of board games on older individuals at risk of or with cognitive impairment, or those with mild cognitive impairment (MCI) at any age.

The studies included different board games including chess, Mah-jongg, and Go, a two-player game popular in China, Japan, and Korea that involves moving board pieces to surround and capture as much territory as possible.

Most interventions lasted about an hour and were held once or twice per week for 3-4 months.
 

Which games are best?

Researchers found that board games improved cognitive function, as measured by improved scores on the Montreal Cognitive Assessment (P = .003) and Mini-Mental State Examination (P = .02).

Playing Go was linked with improved working memory, as measured by the Trail Making Test-A. Those who played Mah-jongg reported improved executive functioning and a temporary decrease in depressive symptoms. And chess players reported improved quality of life on the World Health Organization Quality of Life scale from playing chess (P < .00001).

In general, cognition improved across different populations. For example, some studies looked at unimpaired elderly while others looked at MCI, said Dr. Pozzi.

Playing board games in a social context appeared to be especially good at boosting brain power. One Japanese study included a control group that just did tai chi, a group that did Go alone on tablets, and another group that did Go in groups. Both Go groups improved cognitively, but participants who played together improved the most.

The results also seemed to suggest that Go and chess have different biological effects. “For example, Go increased [brain-derived neurotrophic factor] (BDNF) levels and metabolism in areas key for cognition like the middle temporal gyrus,” Dr. Pozzi said.

He noted that the methodology of the studies was generally “not bad,” although in some cases the analyses were per protocol and in others intention-to-treat. Outcomes varied across studies, there were a lot of dropouts, and some were not randomized, meaning reverse causality can’t be ruled out.

Dr. Pozzi has started a randomized controlled trial at a Go and chess club in Italy. He’s enrolling patients aged 60 and over with subjective cognitive decline or MCI and separating participants into a control group, a group that plays chess, another that plays Go, and another that plays both Go and chess.

In addition to the standard cognitive tests, and measures of depression and quality of life, Dr. Pozzi aims to assess cognitive reserve and is in the process of validating a questionnaire that will look at leisure activities and lifestyle.
 

Social and cognitive value

Commenting on the research for this news organization, Vladimir Hachinski, MD, a professor of clinical neurological sciences at Western University in London, Ont., said the results make sense.

Playing a board game involves concentration, strategy, and intermittent rewards – all of which are good for the brain and may involve the prefrontal cortex, he noted. Board games are also typically timed, which involves brain speed processing, and they have a winner and loser so emotions can run high, which also affects the brain, Dr. Hachinski added.

There may also be social value in playing a board game with someone else, added Dr. Hachinski.

“It’s encouraging that people can improve what they’re doing, and the longer they’re at it, the more of the brain they use,” he said. “There might be a long-term effect because players are building up networks.”

But Dr. Hachinski cautioned that playing a lot of chess does not necessarily make you a better thinker, just as learning to play one instrument doesn’t mean you can automatically play others.

“Learning one skill will translate only partially to another, and only if it’s related,” he said. “It increases cognition in the area you’re practicing in, but it doesn’t spread to other areas.”

Dr. Pozzi and Dr. Hachinski report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Playing chess or other board games slows cognitive decline and improves quality of life in older patients, results of a new systematic review suggest.
 

“For patients who are elderly and suffer from social isolation and mild cognitive issues, I would definitely recommend board games,” study investigator Frederico Emanuele Pozzi, MD, a neurology resident at Fondazione IRCCS San Gerardo dei Tintori in Monza, Italy, told this news organization.

The findings were presented at the virtual XXVI World Congress of Neurology (WCN).

After searching the published literature, Dr. Pozzi and his colleagues selected 15 studies for the review. The studies assessed the impact of board games on older individuals at risk of or with cognitive impairment, or those with mild cognitive impairment (MCI) at any age.

The studies included different board games including chess, Mah-jongg, and Go, a two-player game popular in China, Japan, and Korea that involves moving board pieces to surround and capture as much territory as possible.

Most interventions lasted about an hour and were held once or twice per week for 3-4 months.
 

Which games are best?

Researchers found that board games improved cognitive function, as measured by improved scores on the Montreal Cognitive Assessment (P = .003) and Mini-Mental State Examination (P = .02).

Playing Go was linked with improved working memory, as measured by the Trail Making Test-A. Those who played Mah-jongg reported improved executive functioning and a temporary decrease in depressive symptoms. And chess players reported improved quality of life on the World Health Organization Quality of Life scale from playing chess (P < .00001).

In general, cognition improved across different populations. For example, some studies looked at unimpaired elderly while others looked at MCI, said Dr. Pozzi.

Playing board games in a social context appeared to be especially good at boosting brain power. One Japanese study included a control group that just did tai chi, a group that did Go alone on tablets, and another group that did Go in groups. Both Go groups improved cognitively, but participants who played together improved the most.

The results also seemed to suggest that Go and chess have different biological effects. “For example, Go increased [brain-derived neurotrophic factor] (BDNF) levels and metabolism in areas key for cognition like the middle temporal gyrus,” Dr. Pozzi said.

He noted that the methodology of the studies was generally “not bad,” although in some cases the analyses were per protocol and in others intention-to-treat. Outcomes varied across studies, there were a lot of dropouts, and some were not randomized, meaning reverse causality can’t be ruled out.

Dr. Pozzi has started a randomized controlled trial at a Go and chess club in Italy. He’s enrolling patients aged 60 and over with subjective cognitive decline or MCI and separating participants into a control group, a group that plays chess, another that plays Go, and another that plays both Go and chess.

In addition to the standard cognitive tests, and measures of depression and quality of life, Dr. Pozzi aims to assess cognitive reserve and is in the process of validating a questionnaire that will look at leisure activities and lifestyle.
 

Social and cognitive value

Commenting on the research for this news organization, Vladimir Hachinski, MD, a professor of clinical neurological sciences at Western University in London, Ont., said the results make sense.

Playing a board game involves concentration, strategy, and intermittent rewards – all of which are good for the brain and may involve the prefrontal cortex, he noted. Board games are also typically timed, which involves brain speed processing, and they have a winner and loser so emotions can run high, which also affects the brain, Dr. Hachinski added.

There may also be social value in playing a board game with someone else, added Dr. Hachinski.

“It’s encouraging that people can improve what they’re doing, and the longer they’re at it, the more of the brain they use,” he said. “There might be a long-term effect because players are building up networks.”

But Dr. Hachinski cautioned that playing a lot of chess does not necessarily make you a better thinker, just as learning to play one instrument doesn’t mean you can automatically play others.

“Learning one skill will translate only partially to another, and only if it’s related,” he said. “It increases cognition in the area you’re practicing in, but it doesn’t spread to other areas.”

Dr. Pozzi and Dr. Hachinski report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In 2014 neurologist Jeffrey L. Cummings, MD, startled the Alzheimer’s disease research world with a paper that laid bare the alarmingly high failure rate of Alzheimer’s disease therapies in development.

Publishing in the journal Alzheimer’s Research & Therapy, Dr. Cummings and his colleagues determined that 99.6% of all therapies tested between 2002 and 2012 had failed. Since downloaded some 75,000 times, Dr. Cumming’s “99% paper,” as it came to be nicknamed, led him to look more deeply and thoroughly at Alzheimer’s disease drugs in the pipeline, and describe them in a readable, user-friendly way.

Every year since 2016, Dr. Cummings, of the University of Nevada, Las Vegas, and his colleagues, have published an update of Alzheimer’s drugs in development that offers a concise, graphic, all-in-one overview. His “Alzheimer’s Drug Development Pipeline” report, in the journal Alzheimer’s & Dementia, classifies therapies by their targets, their mechanisms of action, and where they stand in the development process.

Heavy on color-coded visuals, this snapshot of Alzheimer’s disease therapies is widely consulted by industry, researchers, and clinicians. Over time this report – which first documented a crisis – has come to show something more optimistic: an increasingly crowded pipeline reflecting a broad array of treatment approaches. Dr. Cummings wants more people to know that Alzheimer’s disease drug research, which now includes the first two Food and Drug Administration–approved monoclonal antibodies against amyloid-beta, is not the bleak landscape that it was in recent memory.

Lately, with the help of a grant from the National Institute on Aging, Dr. Cummings and his group have been working to expand on their reports to build an even more user-friendly database that can be searched by people in all corners of the neurodegenerative disease world. Dr. Cummings says he plans for this public-facing database to be up and running by year end.

Neurology Reviews spoke with Dr. Cummings, who is a member of the publication’s Editorial Advisory Board, about the genesis of his influential drug-tracking effort, how it has evolved, and what has been learned from it over the years.
 

How did all this begin?

Already in 2014 there was a dialogue going on was about the high failure rate for Alzheimer’s drugs. And I thought: “there’s probably a number that can be assigned to that.” And when it turned out to be 99.6%, that generated a huge amount of interest. That’s when I realized what interests me also interests the world. And that I was uniquely positioned after that point to do something annually.

How do you create your annual report, and how do you classify the drugs in it when some might act on little-understood pathways or mechanisms?

We capture information available on clinicaltrials.gov. We are notified immediately of any new Alzheimer-related trials, and we automate everything that is possible to automate. But there is still some human curation required. Most of that is around mechanisms. If it’s a monoclonal antibody directed at amyloid-beta, that’s not difficult to categorize. But with the small molecules especially, it can be more complicated.

We often look to see how the sponsor describes the drug and what their perception of the primary target is. A resource of great importance to us is CADRO, Common Alzheimer’s and Related Dementias Disease Research Ontology, which describes about 20 mechanisms that a group of scientists sponsored by the National Institutes of Health and the Alzheimer’s Association have agreed on. Inflammation, epigenetics, and oxidation are just a few that most people know. CADRO is organized in a very specific way that allows us to go to the mechanism and relate it to the target. But we do try to be humble and acknowledge we probably make some errors in this.
 

Are you able to capture every Alzheimer’s drug in development globally?

If they’re on clinicaltrials.gov, they’re in our database. But we think there’s about 15% of drugs in the world that aren’t for some reason on clinicaltrials.gov – so we know we are comprehensive, but not quite exhaustive. I’m in kind of quandary about whether to search for that other 15%. But we do always acknowledge that we’re not 100% exhaustive.

Who are the report’s main readers?

Drug developers use it for investor discussions, and also to understand the competition and the landscape. The competition might be a drug with the same mechanism, and the landscape might be drugs coming into the Alzheimer’s disease world. So if someone is developing a PDE-5 inhibitor for mild dementia, for example, they can see that other people are working on a PDE-5 inhibitor for moderate dementia, and there’s no overlap. Investors use the report to make decisions about which horse in the race to bet on. And of course it’s used by academics and clinicians to learn which are the new drugs in the pipeline, which drugs have fallen out of the pipeline, how are biomarkers changing trials, what are the new outcomes.

It’s really become a community project. Investigators will email me and say “Jeff, we’re in phase 1, make sure it’s on your map.” Or, “you forgot our agent! We’re disappointed.” When that occurs it’s because they were not in a trial on the index date – the 1 day in our publication when everything we say in the paper is true. A trial initiated 1 day later won’t make the report for that year.
 

What about patients and families? Are they able to use the report as well?

One of the things we want to expand with the new database is its usefulness for patients. Among the new data display approaches that we have is a world map where you can go click on a dot near your home and find active trials. That’s something patients and families want to know, right? There’s 140 drugs in clinical trials, there must be one for me, how would I get to it? Soon we will have quite a good public portal so if you want to go in and see what new monoclonal antibodies are in phase 2, you can do that with drop-down menus. It’s a very easy to use site that anyone can explore.

Looking back at your last decade tracking drugs, what are some lessons learned and what are some of the more exciting drug categories to emerge?

My answer to this question is: Biologics rule. The main successes have been in biologics, in the monoclonal antibodies against amyloid, like the two FDA-approved agents lecanemab and aducanumab. But I think that the monoclonals, while I’m really happy to have them, are a first step. If you look back at tacrine, the first drug approved in 1993 for Alzheimer’s disease, it was a very difficult drug with lots of side effects. But then within 3 years we had donepezil, which was a very benign drug. I feel that a similar evolution is likely with regard to these antibodies. The first ones, we know, have big challenges, and you learn from those challenges and you just keep improving them. But you have to start somewhere, and you have to validate that target. Now I think that amyloid is validated.

What other approaches are interesting to you?

We have seen dramatic imaging results with marked reductions in neurofibrillary tangles from an antisense oligonucleotide aimed at tau protein. And there are two very active areas in the pipeline: inflammation and synaptic plasticity. Each has roughly 20 drugs apiece in development across all phases. And as you know, both synaptic plasticity and inflammation are represented across neurodegenerative conditions.

Your annual report has always focused on drugs to treat Alzheimer’s disease. Will the new database cover other types of dementia and neurodegenerative diseases?

That’s an obvious next step. I’m hoping that late this year we will have funding to expand the database into frontotemporal lobar degenerations, which will include all the tauopathies. And there’s also an overlap with TDP-43 diseases, so we’ll bring all of that in too. We have a new initiative on Parkinson’s disease and dementia with Lewy bodies that I hope will materialize by next year. My goal is that this will eventually become a neurodegenerative disease therapies database. The really interesting drugs right now are being tested in more than one neurodegenerative disease, and we should look at those more carefully. It will be more feasible to do that if they’re on the same data set.

What about other therapy classes?

We aim to be more serious about devices.

What will you call the database?

The Clinical Trial Observatory. We may start by calling it the Alzheimer’s Disease Clinical Trial Observatory. But the intention, obviously, is to go way beyond Alzheimer’s disease. The database is managed by a terrific team of data scientists at Cleveland Clinic, led by Feixiong Cheng, PhD.

The annual pipeline report is very much associated with you. Is the database going to be different?

Right now, I’m like the grandfather of this project. I won’t be around forever. This will have to pass on, and we’re already talking about succession. We’re thinking about how to make sure this community resource continues to be a community resource. Also, over all these years the annual report reflected my perspective. But with a database, many more people will be able to share their perspectives. I happen to think that “biologics rule,” but others might look at the data, see different scientific currents, and draw different conclusions. That will create a rich dialogue.

Do you think your reports have changed people’s perspectives on Alzheimer’s disease therapies? There’s a widely held idea that the field is exclusively focused on amyloid, or even dead-ended, but the papers seem to show something different.

We think this effort has helped, and will continue to help and foster investment and growth in treatments for our patients. It really does show how diverse the clinical trials landscape is now. People are surprised to learn of the number and diversity of approaches. Just last week I was presenting at the Center for Brain Health in Dallas and there was a doctor in the audience who was a caregiver to his wife with Alzheimer’s disease. He came up afterwards and said, “I had no idea there were so many drugs in clinical trials,” because there’s no way to find out if you don’t know about this resource.

Dr. Cummings discloses consulting for a range of companies working in Alzheimer’s therapies and diagnostics, including Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI. He has received several grants from the National Institute on Aging.

In 2014 neurologist Jeffrey L. Cummings, MD, startled the Alzheimer’s disease research world with a paper that laid bare the alarmingly high failure rate of Alzheimer’s disease therapies in development.

Publishing in the journal Alzheimer’s Research & Therapy, Dr. Cummings and his colleagues determined that 99.6% of all therapies tested between 2002 and 2012 had failed. Since downloaded some 75,000 times, Dr. Cumming’s “99% paper,” as it came to be nicknamed, led him to look more deeply and thoroughly at Alzheimer’s disease drugs in the pipeline, and describe them in a readable, user-friendly way.

Every year since 2016, Dr. Cummings, of the University of Nevada, Las Vegas, and his colleagues, have published an update of Alzheimer’s drugs in development that offers a concise, graphic, all-in-one overview. His “Alzheimer’s Drug Development Pipeline” report, in the journal Alzheimer’s & Dementia, classifies therapies by their targets, their mechanisms of action, and where they stand in the development process.

Heavy on color-coded visuals, this snapshot of Alzheimer’s disease therapies is widely consulted by industry, researchers, and clinicians. Over time this report – which first documented a crisis – has come to show something more optimistic: an increasingly crowded pipeline reflecting a broad array of treatment approaches. Dr. Cummings wants more people to know that Alzheimer’s disease drug research, which now includes the first two Food and Drug Administration–approved monoclonal antibodies against amyloid-beta, is not the bleak landscape that it was in recent memory.

Lately, with the help of a grant from the National Institute on Aging, Dr. Cummings and his group have been working to expand on their reports to build an even more user-friendly database that can be searched by people in all corners of the neurodegenerative disease world. Dr. Cummings says he plans for this public-facing database to be up and running by year end.

Neurology Reviews spoke with Dr. Cummings, who is a member of the publication’s Editorial Advisory Board, about the genesis of his influential drug-tracking effort, how it has evolved, and what has been learned from it over the years.
 

How did all this begin?

Already in 2014 there was a dialogue going on was about the high failure rate for Alzheimer’s drugs. And I thought: “there’s probably a number that can be assigned to that.” And when it turned out to be 99.6%, that generated a huge amount of interest. That’s when I realized what interests me also interests the world. And that I was uniquely positioned after that point to do something annually.

How do you create your annual report, and how do you classify the drugs in it when some might act on little-understood pathways or mechanisms?

We capture information available on clinicaltrials.gov. We are notified immediately of any new Alzheimer-related trials, and we automate everything that is possible to automate. But there is still some human curation required. Most of that is around mechanisms. If it’s a monoclonal antibody directed at amyloid-beta, that’s not difficult to categorize. But with the small molecules especially, it can be more complicated.

We often look to see how the sponsor describes the drug and what their perception of the primary target is. A resource of great importance to us is CADRO, Common Alzheimer’s and Related Dementias Disease Research Ontology, which describes about 20 mechanisms that a group of scientists sponsored by the National Institutes of Health and the Alzheimer’s Association have agreed on. Inflammation, epigenetics, and oxidation are just a few that most people know. CADRO is organized in a very specific way that allows us to go to the mechanism and relate it to the target. But we do try to be humble and acknowledge we probably make some errors in this.
 

Are you able to capture every Alzheimer’s drug in development globally?

If they’re on clinicaltrials.gov, they’re in our database. But we think there’s about 15% of drugs in the world that aren’t for some reason on clinicaltrials.gov – so we know we are comprehensive, but not quite exhaustive. I’m in kind of quandary about whether to search for that other 15%. But we do always acknowledge that we’re not 100% exhaustive.

Who are the report’s main readers?

Drug developers use it for investor discussions, and also to understand the competition and the landscape. The competition might be a drug with the same mechanism, and the landscape might be drugs coming into the Alzheimer’s disease world. So if someone is developing a PDE-5 inhibitor for mild dementia, for example, they can see that other people are working on a PDE-5 inhibitor for moderate dementia, and there’s no overlap. Investors use the report to make decisions about which horse in the race to bet on. And of course it’s used by academics and clinicians to learn which are the new drugs in the pipeline, which drugs have fallen out of the pipeline, how are biomarkers changing trials, what are the new outcomes.

It’s really become a community project. Investigators will email me and say “Jeff, we’re in phase 1, make sure it’s on your map.” Or, “you forgot our agent! We’re disappointed.” When that occurs it’s because they were not in a trial on the index date – the 1 day in our publication when everything we say in the paper is true. A trial initiated 1 day later won’t make the report for that year.
 

What about patients and families? Are they able to use the report as well?

One of the things we want to expand with the new database is its usefulness for patients. Among the new data display approaches that we have is a world map where you can go click on a dot near your home and find active trials. That’s something patients and families want to know, right? There’s 140 drugs in clinical trials, there must be one for me, how would I get to it? Soon we will have quite a good public portal so if you want to go in and see what new monoclonal antibodies are in phase 2, you can do that with drop-down menus. It’s a very easy to use site that anyone can explore.

Looking back at your last decade tracking drugs, what are some lessons learned and what are some of the more exciting drug categories to emerge?

My answer to this question is: Biologics rule. The main successes have been in biologics, in the monoclonal antibodies against amyloid, like the two FDA-approved agents lecanemab and aducanumab. But I think that the monoclonals, while I’m really happy to have them, are a first step. If you look back at tacrine, the first drug approved in 1993 for Alzheimer’s disease, it was a very difficult drug with lots of side effects. But then within 3 years we had donepezil, which was a very benign drug. I feel that a similar evolution is likely with regard to these antibodies. The first ones, we know, have big challenges, and you learn from those challenges and you just keep improving them. But you have to start somewhere, and you have to validate that target. Now I think that amyloid is validated.

What other approaches are interesting to you?

We have seen dramatic imaging results with marked reductions in neurofibrillary tangles from an antisense oligonucleotide aimed at tau protein. And there are two very active areas in the pipeline: inflammation and synaptic plasticity. Each has roughly 20 drugs apiece in development across all phases. And as you know, both synaptic plasticity and inflammation are represented across neurodegenerative conditions.

Your annual report has always focused on drugs to treat Alzheimer’s disease. Will the new database cover other types of dementia and neurodegenerative diseases?

That’s an obvious next step. I’m hoping that late this year we will have funding to expand the database into frontotemporal lobar degenerations, which will include all the tauopathies. And there’s also an overlap with TDP-43 diseases, so we’ll bring all of that in too. We have a new initiative on Parkinson’s disease and dementia with Lewy bodies that I hope will materialize by next year. My goal is that this will eventually become a neurodegenerative disease therapies database. The really interesting drugs right now are being tested in more than one neurodegenerative disease, and we should look at those more carefully. It will be more feasible to do that if they’re on the same data set.

What about other therapy classes?

We aim to be more serious about devices.

What will you call the database?

The Clinical Trial Observatory. We may start by calling it the Alzheimer’s Disease Clinical Trial Observatory. But the intention, obviously, is to go way beyond Alzheimer’s disease. The database is managed by a terrific team of data scientists at Cleveland Clinic, led by Feixiong Cheng, PhD.

The annual pipeline report is very much associated with you. Is the database going to be different?

Right now, I’m like the grandfather of this project. I won’t be around forever. This will have to pass on, and we’re already talking about succession. We’re thinking about how to make sure this community resource continues to be a community resource. Also, over all these years the annual report reflected my perspective. But with a database, many more people will be able to share their perspectives. I happen to think that “biologics rule,” but others might look at the data, see different scientific currents, and draw different conclusions. That will create a rich dialogue.

Do you think your reports have changed people’s perspectives on Alzheimer’s disease therapies? There’s a widely held idea that the field is exclusively focused on amyloid, or even dead-ended, but the papers seem to show something different.

We think this effort has helped, and will continue to help and foster investment and growth in treatments for our patients. It really does show how diverse the clinical trials landscape is now. People are surprised to learn of the number and diversity of approaches. Just last week I was presenting at the Center for Brain Health in Dallas and there was a doctor in the audience who was a caregiver to his wife with Alzheimer’s disease. He came up afterwards and said, “I had no idea there were so many drugs in clinical trials,” because there’s no way to find out if you don’t know about this resource.

Dr. Cummings discloses consulting for a range of companies working in Alzheimer’s therapies and diagnostics, including Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI. He has received several grants from the National Institute on Aging.

In 2014 neurologist Jeffrey L. Cummings, MD, startled the Alzheimer’s disease research world with a paper that laid bare the alarmingly high failure rate of Alzheimer’s disease therapies in development.

Publishing in the journal Alzheimer’s Research & Therapy, Dr. Cummings and his colleagues determined that 99.6% of all therapies tested between 2002 and 2012 had failed. Since downloaded some 75,000 times, Dr. Cumming’s “99% paper,” as it came to be nicknamed, led him to look more deeply and thoroughly at Alzheimer’s disease drugs in the pipeline, and describe them in a readable, user-friendly way.

Every year since 2016, Dr. Cummings, of the University of Nevada, Las Vegas, and his colleagues, have published an update of Alzheimer’s drugs in development that offers a concise, graphic, all-in-one overview. His “Alzheimer’s Drug Development Pipeline” report, in the journal Alzheimer’s & Dementia, classifies therapies by their targets, their mechanisms of action, and where they stand in the development process.

Heavy on color-coded visuals, this snapshot of Alzheimer’s disease therapies is widely consulted by industry, researchers, and clinicians. Over time this report – which first documented a crisis – has come to show something more optimistic: an increasingly crowded pipeline reflecting a broad array of treatment approaches. Dr. Cummings wants more people to know that Alzheimer’s disease drug research, which now includes the first two Food and Drug Administration–approved monoclonal antibodies against amyloid-beta, is not the bleak landscape that it was in recent memory.

Lately, with the help of a grant from the National Institute on Aging, Dr. Cummings and his group have been working to expand on their reports to build an even more user-friendly database that can be searched by people in all corners of the neurodegenerative disease world. Dr. Cummings says he plans for this public-facing database to be up and running by year end.

Neurology Reviews spoke with Dr. Cummings, who is a member of the publication’s Editorial Advisory Board, about the genesis of his influential drug-tracking effort, how it has evolved, and what has been learned from it over the years.
 

How did all this begin?

Already in 2014 there was a dialogue going on was about the high failure rate for Alzheimer’s drugs. And I thought: “there’s probably a number that can be assigned to that.” And when it turned out to be 99.6%, that generated a huge amount of interest. That’s when I realized what interests me also interests the world. And that I was uniquely positioned after that point to do something annually.

How do you create your annual report, and how do you classify the drugs in it when some might act on little-understood pathways or mechanisms?

We capture information available on clinicaltrials.gov. We are notified immediately of any new Alzheimer-related trials, and we automate everything that is possible to automate. But there is still some human curation required. Most of that is around mechanisms. If it’s a monoclonal antibody directed at amyloid-beta, that’s not difficult to categorize. But with the small molecules especially, it can be more complicated.

We often look to see how the sponsor describes the drug and what their perception of the primary target is. A resource of great importance to us is CADRO, Common Alzheimer’s and Related Dementias Disease Research Ontology, which describes about 20 mechanisms that a group of scientists sponsored by the National Institutes of Health and the Alzheimer’s Association have agreed on. Inflammation, epigenetics, and oxidation are just a few that most people know. CADRO is organized in a very specific way that allows us to go to the mechanism and relate it to the target. But we do try to be humble and acknowledge we probably make some errors in this.
 

Are you able to capture every Alzheimer’s drug in development globally?

If they’re on clinicaltrials.gov, they’re in our database. But we think there’s about 15% of drugs in the world that aren’t for some reason on clinicaltrials.gov – so we know we are comprehensive, but not quite exhaustive. I’m in kind of quandary about whether to search for that other 15%. But we do always acknowledge that we’re not 100% exhaustive.

Who are the report’s main readers?

Drug developers use it for investor discussions, and also to understand the competition and the landscape. The competition might be a drug with the same mechanism, and the landscape might be drugs coming into the Alzheimer’s disease world. So if someone is developing a PDE-5 inhibitor for mild dementia, for example, they can see that other people are working on a PDE-5 inhibitor for moderate dementia, and there’s no overlap. Investors use the report to make decisions about which horse in the race to bet on. And of course it’s used by academics and clinicians to learn which are the new drugs in the pipeline, which drugs have fallen out of the pipeline, how are biomarkers changing trials, what are the new outcomes.

It’s really become a community project. Investigators will email me and say “Jeff, we’re in phase 1, make sure it’s on your map.” Or, “you forgot our agent! We’re disappointed.” When that occurs it’s because they were not in a trial on the index date – the 1 day in our publication when everything we say in the paper is true. A trial initiated 1 day later won’t make the report for that year.
 

What about patients and families? Are they able to use the report as well?

One of the things we want to expand with the new database is its usefulness for patients. Among the new data display approaches that we have is a world map where you can go click on a dot near your home and find active trials. That’s something patients and families want to know, right? There’s 140 drugs in clinical trials, there must be one for me, how would I get to it? Soon we will have quite a good public portal so if you want to go in and see what new monoclonal antibodies are in phase 2, you can do that with drop-down menus. It’s a very easy to use site that anyone can explore.

Looking back at your last decade tracking drugs, what are some lessons learned and what are some of the more exciting drug categories to emerge?

My answer to this question is: Biologics rule. The main successes have been in biologics, in the monoclonal antibodies against amyloid, like the two FDA-approved agents lecanemab and aducanumab. But I think that the monoclonals, while I’m really happy to have them, are a first step. If you look back at tacrine, the first drug approved in 1993 for Alzheimer’s disease, it was a very difficult drug with lots of side effects. But then within 3 years we had donepezil, which was a very benign drug. I feel that a similar evolution is likely with regard to these antibodies. The first ones, we know, have big challenges, and you learn from those challenges and you just keep improving them. But you have to start somewhere, and you have to validate that target. Now I think that amyloid is validated.

What other approaches are interesting to you?

We have seen dramatic imaging results with marked reductions in neurofibrillary tangles from an antisense oligonucleotide aimed at tau protein. And there are two very active areas in the pipeline: inflammation and synaptic plasticity. Each has roughly 20 drugs apiece in development across all phases. And as you know, both synaptic plasticity and inflammation are represented across neurodegenerative conditions.

Your annual report has always focused on drugs to treat Alzheimer’s disease. Will the new database cover other types of dementia and neurodegenerative diseases?

That’s an obvious next step. I’m hoping that late this year we will have funding to expand the database into frontotemporal lobar degenerations, which will include all the tauopathies. And there’s also an overlap with TDP-43 diseases, so we’ll bring all of that in too. We have a new initiative on Parkinson’s disease and dementia with Lewy bodies that I hope will materialize by next year. My goal is that this will eventually become a neurodegenerative disease therapies database. The really interesting drugs right now are being tested in more than one neurodegenerative disease, and we should look at those more carefully. It will be more feasible to do that if they’re on the same data set.

What about other therapy classes?

We aim to be more serious about devices.

What will you call the database?

The Clinical Trial Observatory. We may start by calling it the Alzheimer’s Disease Clinical Trial Observatory. But the intention, obviously, is to go way beyond Alzheimer’s disease. The database is managed by a terrific team of data scientists at Cleveland Clinic, led by Feixiong Cheng, PhD.

The annual pipeline report is very much associated with you. Is the database going to be different?

Right now, I’m like the grandfather of this project. I won’t be around forever. This will have to pass on, and we’re already talking about succession. We’re thinking about how to make sure this community resource continues to be a community resource. Also, over all these years the annual report reflected my perspective. But with a database, many more people will be able to share their perspectives. I happen to think that “biologics rule,” but others might look at the data, see different scientific currents, and draw different conclusions. That will create a rich dialogue.

Do you think your reports have changed people’s perspectives on Alzheimer’s disease therapies? There’s a widely held idea that the field is exclusively focused on amyloid, or even dead-ended, but the papers seem to show something different.

We think this effort has helped, and will continue to help and foster investment and growth in treatments for our patients. It really does show how diverse the clinical trials landscape is now. People are surprised to learn of the number and diversity of approaches. Just last week I was presenting at the Center for Brain Health in Dallas and there was a doctor in the audience who was a caregiver to his wife with Alzheimer’s disease. He came up afterwards and said, “I had no idea there were so many drugs in clinical trials,” because there’s no way to find out if you don’t know about this resource.

Dr. Cummings discloses consulting for a range of companies working in Alzheimer’s therapies and diagnostics, including Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI. He has received several grants from the National Institute on Aging.

TOPLINE:

High and low levels of HDL cholesterol but not levels of LDL cholesterol are associated with an increased risk for dementia in older adults, a new study found.

METHODOLOGY:

• Electronic health record and survey data on 184,367 Kaiser Permanente Northern California participants (median age, 69.5 years) with no history of dementia were taken.
• Cholesterol levels were measured within 2 years of survey completion.

TAKEAWAY:

• There were 25,214 incident cases of dementia reported over an average follow-up of 8.77 years.
• Dementia risk was significantly higher in people with low HDL cholesterol (11-41 mg/dL; adjusted hazard ratio, 1.07; 95% confidence interval, 1.03-1.11) and high HDL cholesterol (> 65 mg/dL; aHR, 1.15; 95% CI, 1.11-1.20).
• The study demonstrates an association between low and high levels of “good” cholesterol but not a causal link.
• There was no significant association between LDL cholesterol and dementia risk.

IN PRACTICE:

“These results support the conclusion that some lipoproteins may be modifiable risk factors for dementia, even in late life,” the authors wrote.

SOURCE:

The study was conducted by Erin L. Ferguson, MPH, department of epidemiology & biostatistics, University of California, San Francisco, and was funded by the National Institutes of Health. It was published online in Neurology.

LIMITATIONS:

There were no adjustments for apo E status and confounding and selection bias.

DISCLOSURES:

The authors report no relevant disclosures.

A version of this article first appeared on Medscape.com.

TOPLINE:

High and low levels of HDL cholesterol but not levels of LDL cholesterol are associated with an increased risk for dementia in older adults, a new study found.

METHODOLOGY:

• Electronic health record and survey data on 184,367 Kaiser Permanente Northern California participants (median age, 69.5 years) with no history of dementia were taken.
• Cholesterol levels were measured within 2 years of survey completion.

TAKEAWAY:

• There were 25,214 incident cases of dementia reported over an average follow-up of 8.77 years.
• Dementia risk was significantly higher in people with low HDL cholesterol (11-41 mg/dL; adjusted hazard ratio, 1.07; 95% confidence interval, 1.03-1.11) and high HDL cholesterol (> 65 mg/dL; aHR, 1.15; 95% CI, 1.11-1.20).
• The study demonstrates an association between low and high levels of “good” cholesterol but not a causal link.
• There was no significant association between LDL cholesterol and dementia risk.

IN PRACTICE:

“These results support the conclusion that some lipoproteins may be modifiable risk factors for dementia, even in late life,” the authors wrote.

SOURCE:

The study was conducted by Erin L. Ferguson, MPH, department of epidemiology & biostatistics, University of California, San Francisco, and was funded by the National Institutes of Health. It was published online in Neurology.

LIMITATIONS:

There were no adjustments for apo E status and confounding and selection bias.

DISCLOSURES:

The authors report no relevant disclosures.

A version of this article first appeared on Medscape.com.

TOPLINE:

High and low levels of HDL cholesterol but not levels of LDL cholesterol are associated with an increased risk for dementia in older adults, a new study found.

METHODOLOGY:

• Electronic health record and survey data on 184,367 Kaiser Permanente Northern California participants (median age, 69.5 years) with no history of dementia were taken.
• Cholesterol levels were measured within 2 years of survey completion.

TAKEAWAY:

• There were 25,214 incident cases of dementia reported over an average follow-up of 8.77 years.
• Dementia risk was significantly higher in people with low HDL cholesterol (11-41 mg/dL; adjusted hazard ratio, 1.07; 95% confidence interval, 1.03-1.11) and high HDL cholesterol (> 65 mg/dL; aHR, 1.15; 95% CI, 1.11-1.20).
• The study demonstrates an association between low and high levels of “good” cholesterol but not a causal link.
• There was no significant association between LDL cholesterol and dementia risk.

IN PRACTICE:

“These results support the conclusion that some lipoproteins may be modifiable risk factors for dementia, even in late life,” the authors wrote.

SOURCE:

The study was conducted by Erin L. Ferguson, MPH, department of epidemiology & biostatistics, University of California, San Francisco, and was funded by the National Institutes of Health. It was published online in Neurology.

LIMITATIONS:

There were no adjustments for apo E status and confounding and selection bias.

DISCLOSURES:

The authors report no relevant disclosures.

A version of this article first appeared on Medscape.com.