Alzheimer's & Cognition

A work group convened by the Alzheimer’s Association has released revised biology-based criteria for the diagnosis and staging of Alzheimer’s disease, including a new biomarker classification system that incorporates fluid and imaging biomarkers as well as an updated disease staging system. 

“Plasma markers are here now, and it’s very important to incorporate them into the criteria for diagnosis,” said senior author Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer and medical affairs lead. 

The revised criteria are the first updates since 2018.

“Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine — including cancer, heart disease, and diabetes — and is becoming a unifying concept common to all neurodegenerative diseases,” lead author Clifford Jack Jr, MD, with Mayo Clinic, Rochester, Minnesota, said in a news release from the Alzheimer’s Association. 

“These updates to the diagnostic criteria are needed now because we know more about the underlying biology of Alzheimer’s and we are able to measure those changes,” Dr. Jack added. 

The 2024 revised criteria for diagnosis and staging of Alzheimer’s disease were published online in Alzheimer’s & Dementia. 
 

Core Biomarkers Defined

The revised criteria define Alzheimer’s disease as a biologic process that begins with the appearance of Alzheimer’s disease neuropathologic change (ADNPC) in the absence of symptoms. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms.

The work group organized Alzheimer’s disease biomarkers into three broad categories: (1) core biomarkers of ADNPC, (2) nonspecific biomarkers that are important in Alzheimer’s disease but are also involved in other brain diseases, and (3) biomarkers of diseases or conditions that commonly coexist with Alzheimer’s disease.

Core Alzheimer’s biomarkers are subdivided into Core 1 and Core 2. 

Core 1 biomarkers become abnormal early in the disease course and directly measure either amyloid plaques or phosphorylated tau (p-tau). They include amyloid PET; cerebrospinal fluid (CSF) amyloid beta 42/40 ratio, CSF p-tau181/amyloid beta 42 ratio, and CSF total (t)-tau/amyloid beta 42 ratio; and “accurate” plasma biomarkers, such as p-tau217. 

“An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of Alzheimer’s disease and to inform clinical decision making [sic] throughout the disease continuum,” the work group wrote. 

Core 2 biomarkers become abnormal later in the disease process and are more closely linked with the onset of symptoms. Core 2 biomarkers include tau PET and certain soluble tau fragments associated with tau proteinopathy (eg, MTBR-tau243) but also pT205 and nonphosphorylated mid-region tau fragments. 

Core 2 biomarkers, when combined with Core 1, may be used to stage biologic disease severity; abnormal Core 2 biomarkers “increase confidence that Alzheimer’s disease is contributing to symptoms,” the work group noted. 

The revised criteria give clinicians “the flexibility to use plasma or PET scans or CSF,” Dr. Carrillo said. “They will have several tools that they can choose from and offer this variety of tools to their patients. We need different tools for different individuals. There will be differences in coverage and access to these diagnostics.” 

The revised criteria also include an integrated biologic and clinical staging scheme that acknowledges the fact that common co-pathologies, cognitive reserve, and resistance may modify relationships between clinical and biologic Alzheimer’s disease stages. 
 

Formal Guidelines to Come 

The work group noted that currently, the clinical use of Alzheimer’s disease biomarkers is intended for the evaluation of symptomatic patients, not cognitively unimpaired individuals.

Disease-targeted therapies have not yet been approved for cognitively unimpaired individuals. For this reason, the work group currently recommends against diagnostic testing in cognitively unimpaired individuals outside the context of observational or therapeutic research studies. 

This recommendation would change in the future if disease-targeted therapies that are currently being evaluated in trials demonstrate a benefit in preventing cognitive decline and are approved for use in preclinical Alzheimer’s disease, they wrote. 

They emphasize that the revised criteria are not intended to provide step-by-step clinical practice guidelines for clinicians. Rather, they provide general principles to inform diagnosis and staging of Alzheimer’s disease that reflect current science.

“This is just the beginning,” said Dr. Carrillo. “This is a gathering of the evidence to date and putting it in one place so we can have a consensus and actually a way to test it and make it better as we add new science.”

This also serves as a “springboard” for the Alzheimer’s Association to create formal clinical guidelines. “That will come, hopefully, over the next 12 months. We’ll be working on it, and we hope to have that in 2025,” Dr. Carrillo said. 

The revised criteria also emphasize the role of the clinician. 

“The biologically based diagnosis of Alzheimer’s disease is meant to assist, rather than supplant, the clinical evaluation of individuals with cognitive impairment,” the work group wrote in a related commentary published online in Nature Medicine. 

Recent diagnostics and therapeutic developments “herald a virtuous cycle in which improvements in diagnostic methods enable more sophisticated treatment approaches, which in turn steer advances in diagnostic methods,” they continued. “An unchanging principle, however, is that effective treatment will always rely on the ability to diagnose and stage the biology driving the disease process.”

Funding for this research was provided by the National Institutes of Health, Alexander family professorship, GHR Foundation, Alzheimer’s Association, Veterans Administration, Life Molecular Imaging, Michael J. Fox Foundation for Parkinson’s Research, Avid Radiopharmaceuticals, Eli Lilly, Gates Foundation, Biogen, C2N Diagnostics, Eisai, Fujirebio, GE Healthcare, Roche, National Institute on Aging, Roche/Genentech, BrightFocus Foundation, Hoffmann-La Roche, Novo Nordisk, Toyama, National MS Society, Alzheimer Drug Discovery Foundation, and others. A complete list of donors and disclosures is included in the original article.

 A version of this article appeared on Medscape.com.

A work group convened by the Alzheimer’s Association has released revised biology-based criteria for the diagnosis and staging of Alzheimer’s disease, including a new biomarker classification system that incorporates fluid and imaging biomarkers as well as an updated disease staging system. 

“Plasma markers are here now, and it’s very important to incorporate them into the criteria for diagnosis,” said senior author Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer and medical affairs lead. 

The revised criteria are the first updates since 2018.

“Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine — including cancer, heart disease, and diabetes — and is becoming a unifying concept common to all neurodegenerative diseases,” lead author Clifford Jack Jr, MD, with Mayo Clinic, Rochester, Minnesota, said in a news release from the Alzheimer’s Association. 

“These updates to the diagnostic criteria are needed now because we know more about the underlying biology of Alzheimer’s and we are able to measure those changes,” Dr. Jack added. 

The 2024 revised criteria for diagnosis and staging of Alzheimer’s disease were published online in Alzheimer’s & Dementia. 
 

Core Biomarkers Defined

The revised criteria define Alzheimer’s disease as a biologic process that begins with the appearance of Alzheimer’s disease neuropathologic change (ADNPC) in the absence of symptoms. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms.

The work group organized Alzheimer’s disease biomarkers into three broad categories: (1) core biomarkers of ADNPC, (2) nonspecific biomarkers that are important in Alzheimer’s disease but are also involved in other brain diseases, and (3) biomarkers of diseases or conditions that commonly coexist with Alzheimer’s disease.

Core Alzheimer’s biomarkers are subdivided into Core 1 and Core 2. 

Core 1 biomarkers become abnormal early in the disease course and directly measure either amyloid plaques or phosphorylated tau (p-tau). They include amyloid PET; cerebrospinal fluid (CSF) amyloid beta 42/40 ratio, CSF p-tau181/amyloid beta 42 ratio, and CSF total (t)-tau/amyloid beta 42 ratio; and “accurate” plasma biomarkers, such as p-tau217. 

“An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of Alzheimer’s disease and to inform clinical decision making [sic] throughout the disease continuum,” the work group wrote. 

Core 2 biomarkers become abnormal later in the disease process and are more closely linked with the onset of symptoms. Core 2 biomarkers include tau PET and certain soluble tau fragments associated with tau proteinopathy (eg, MTBR-tau243) but also pT205 and nonphosphorylated mid-region tau fragments. 

Core 2 biomarkers, when combined with Core 1, may be used to stage biologic disease severity; abnormal Core 2 biomarkers “increase confidence that Alzheimer’s disease is contributing to symptoms,” the work group noted. 

The revised criteria give clinicians “the flexibility to use plasma or PET scans or CSF,” Dr. Carrillo said. “They will have several tools that they can choose from and offer this variety of tools to their patients. We need different tools for different individuals. There will be differences in coverage and access to these diagnostics.” 

The revised criteria also include an integrated biologic and clinical staging scheme that acknowledges the fact that common co-pathologies, cognitive reserve, and resistance may modify relationships between clinical and biologic Alzheimer’s disease stages. 
 

Formal Guidelines to Come 

The work group noted that currently, the clinical use of Alzheimer’s disease biomarkers is intended for the evaluation of symptomatic patients, not cognitively unimpaired individuals.

Disease-targeted therapies have not yet been approved for cognitively unimpaired individuals. For this reason, the work group currently recommends against diagnostic testing in cognitively unimpaired individuals outside the context of observational or therapeutic research studies. 

This recommendation would change in the future if disease-targeted therapies that are currently being evaluated in trials demonstrate a benefit in preventing cognitive decline and are approved for use in preclinical Alzheimer’s disease, they wrote. 

They emphasize that the revised criteria are not intended to provide step-by-step clinical practice guidelines for clinicians. Rather, they provide general principles to inform diagnosis and staging of Alzheimer’s disease that reflect current science.

“This is just the beginning,” said Dr. Carrillo. “This is a gathering of the evidence to date and putting it in one place so we can have a consensus and actually a way to test it and make it better as we add new science.”

This also serves as a “springboard” for the Alzheimer’s Association to create formal clinical guidelines. “That will come, hopefully, over the next 12 months. We’ll be working on it, and we hope to have that in 2025,” Dr. Carrillo said. 

The revised criteria also emphasize the role of the clinician. 

“The biologically based diagnosis of Alzheimer’s disease is meant to assist, rather than supplant, the clinical evaluation of individuals with cognitive impairment,” the work group wrote in a related commentary published online in Nature Medicine. 

Recent diagnostics and therapeutic developments “herald a virtuous cycle in which improvements in diagnostic methods enable more sophisticated treatment approaches, which in turn steer advances in diagnostic methods,” they continued. “An unchanging principle, however, is that effective treatment will always rely on the ability to diagnose and stage the biology driving the disease process.”

Funding for this research was provided by the National Institutes of Health, Alexander family professorship, GHR Foundation, Alzheimer’s Association, Veterans Administration, Life Molecular Imaging, Michael J. Fox Foundation for Parkinson’s Research, Avid Radiopharmaceuticals, Eli Lilly, Gates Foundation, Biogen, C2N Diagnostics, Eisai, Fujirebio, GE Healthcare, Roche, National Institute on Aging, Roche/Genentech, BrightFocus Foundation, Hoffmann-La Roche, Novo Nordisk, Toyama, National MS Society, Alzheimer Drug Discovery Foundation, and others. A complete list of donors and disclosures is included in the original article.

 A version of this article appeared on Medscape.com.

A work group convened by the Alzheimer’s Association has released revised biology-based criteria for the diagnosis and staging of Alzheimer’s disease, including a new biomarker classification system that incorporates fluid and imaging biomarkers as well as an updated disease staging system. 

“Plasma markers are here now, and it’s very important to incorporate them into the criteria for diagnosis,” said senior author Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer and medical affairs lead. 

The revised criteria are the first updates since 2018.

“Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine — including cancer, heart disease, and diabetes — and is becoming a unifying concept common to all neurodegenerative diseases,” lead author Clifford Jack Jr, MD, with Mayo Clinic, Rochester, Minnesota, said in a news release from the Alzheimer’s Association. 

“These updates to the diagnostic criteria are needed now because we know more about the underlying biology of Alzheimer’s and we are able to measure those changes,” Dr. Jack added. 

The 2024 revised criteria for diagnosis and staging of Alzheimer’s disease were published online in Alzheimer’s & Dementia. 
 

Core Biomarkers Defined

The revised criteria define Alzheimer’s disease as a biologic process that begins with the appearance of Alzheimer’s disease neuropathologic change (ADNPC) in the absence of symptoms. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms.

The work group organized Alzheimer’s disease biomarkers into three broad categories: (1) core biomarkers of ADNPC, (2) nonspecific biomarkers that are important in Alzheimer’s disease but are also involved in other brain diseases, and (3) biomarkers of diseases or conditions that commonly coexist with Alzheimer’s disease.

Core Alzheimer’s biomarkers are subdivided into Core 1 and Core 2. 

Core 1 biomarkers become abnormal early in the disease course and directly measure either amyloid plaques or phosphorylated tau (p-tau). They include amyloid PET; cerebrospinal fluid (CSF) amyloid beta 42/40 ratio, CSF p-tau181/amyloid beta 42 ratio, and CSF total (t)-tau/amyloid beta 42 ratio; and “accurate” plasma biomarkers, such as p-tau217. 

“An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of Alzheimer’s disease and to inform clinical decision making [sic] throughout the disease continuum,” the work group wrote. 

Core 2 biomarkers become abnormal later in the disease process and are more closely linked with the onset of symptoms. Core 2 biomarkers include tau PET and certain soluble tau fragments associated with tau proteinopathy (eg, MTBR-tau243) but also pT205 and nonphosphorylated mid-region tau fragments. 

Core 2 biomarkers, when combined with Core 1, may be used to stage biologic disease severity; abnormal Core 2 biomarkers “increase confidence that Alzheimer’s disease is contributing to symptoms,” the work group noted. 

The revised criteria give clinicians “the flexibility to use plasma or PET scans or CSF,” Dr. Carrillo said. “They will have several tools that they can choose from and offer this variety of tools to their patients. We need different tools for different individuals. There will be differences in coverage and access to these diagnostics.” 

The revised criteria also include an integrated biologic and clinical staging scheme that acknowledges the fact that common co-pathologies, cognitive reserve, and resistance may modify relationships between clinical and biologic Alzheimer’s disease stages. 
 

Formal Guidelines to Come 

The work group noted that currently, the clinical use of Alzheimer’s disease biomarkers is intended for the evaluation of symptomatic patients, not cognitively unimpaired individuals.

Disease-targeted therapies have not yet been approved for cognitively unimpaired individuals. For this reason, the work group currently recommends against diagnostic testing in cognitively unimpaired individuals outside the context of observational or therapeutic research studies. 

This recommendation would change in the future if disease-targeted therapies that are currently being evaluated in trials demonstrate a benefit in preventing cognitive decline and are approved for use in preclinical Alzheimer’s disease, they wrote. 

They emphasize that the revised criteria are not intended to provide step-by-step clinical practice guidelines for clinicians. Rather, they provide general principles to inform diagnosis and staging of Alzheimer’s disease that reflect current science.

“This is just the beginning,” said Dr. Carrillo. “This is a gathering of the evidence to date and putting it in one place so we can have a consensus and actually a way to test it and make it better as we add new science.”

This also serves as a “springboard” for the Alzheimer’s Association to create formal clinical guidelines. “That will come, hopefully, over the next 12 months. We’ll be working on it, and we hope to have that in 2025,” Dr. Carrillo said. 

The revised criteria also emphasize the role of the clinician. 

“The biologically based diagnosis of Alzheimer’s disease is meant to assist, rather than supplant, the clinical evaluation of individuals with cognitive impairment,” the work group wrote in a related commentary published online in Nature Medicine. 

Recent diagnostics and therapeutic developments “herald a virtuous cycle in which improvements in diagnostic methods enable more sophisticated treatment approaches, which in turn steer advances in diagnostic methods,” they continued. “An unchanging principle, however, is that effective treatment will always rely on the ability to diagnose and stage the biology driving the disease process.”

Funding for this research was provided by the National Institutes of Health, Alexander family professorship, GHR Foundation, Alzheimer’s Association, Veterans Administration, Life Molecular Imaging, Michael J. Fox Foundation for Parkinson’s Research, Avid Radiopharmaceuticals, Eli Lilly, Gates Foundation, Biogen, C2N Diagnostics, Eisai, Fujirebio, GE Healthcare, Roche, National Institute on Aging, Roche/Genentech, BrightFocus Foundation, Hoffmann-La Roche, Novo Nordisk, Toyama, National MS Society, Alzheimer Drug Discovery Foundation, and others. A complete list of donors and disclosures is included in the original article.

 A version of this article appeared on Medscape.com.

Certain medications that are used to treat benign prostatic hyperplasia (BPH) are associated with a reduced risk for dementia with Lewy bodies (DLB), the second most common neurodegenerative type of dementia after Alzheimer’s disease.

Investigators found older men taking alpha-1 blockers terazosin, doxazosin, or alfuzosin (Tz/Dz/Az) were 40% less likely to develop DLB than those taking tamsulosin and 37% less likely than men taking the 5-alpha reductase inhibitors (5ARI) finasteride and dutasteride.

“These results are exciting because right now there are no drugs to prevent or treat dementia with Lewy bodies,” study investigator Jacob E. Simmering, PhD, of the University of Iowa in Iowa City, said in a press release. “If we can determine that an existing drug can offer protection against this debilitating disease, that has the potential to greatly reduce its effects.”

The findings were published online in Neurology.
 

Increasing ATP Neuroprotective?

In recent years, investigators have speculated that improving metabolic activity in the brain may reduce the risk for Parkinson’s disease (PD). 

In previous studies, the use of Tz/Dz/Az resulted in the activation of phosphoglycerate kinase-1 (PKG1), which increases the availability of adenosine triphosphate (ATP).

There have been case reports of PD being linked to mutations affecting PGK1. Researchers speculate that increased ATP availability in neurons resulting from the activation of PKG1 allows cells to better adapt to aging and synuclein aggregation.

To investigate whether glycolysis-enhancing drugs might be neuroprotective in those with DLB, investigators conducted a retrospective cohort study using a commercial health insurance claims database and a Medicare supplemental health claims database to follow a sample of men aged > 40 years taking Tz, Dz, or Az (n = 126,313), tamsulosin (n = 437,035), or a 5ARI (n = 80,158) for BPH.

Tamsulosin and 5ARI medications do not activate PKG1, so investigators used them as comparators to Tz/Dz/Az. Participants were followed from the medication initiation date until the end of enrollment in the claims databases.

After following claimants for an average of 3 years, 195 participants developed DLB who were taking Tz, Dz, or Az, a rate of 5.21 cases per 10,000 people per year.

During the follow-up period, 1286 participants taking tamsulosin developed DLB, a rate of 10.8 per 10,000 people per year, and among those taking 5ARIs, 193 cases of DLB were reported, a rate of 7.8 per 10,000 people per year.

After matching the groups by age and other health conditions that may explain differences in rates of DLB, men taking Tz/Dz/Az had a 60% lower risk than those taking tamsulosin (P < .001) and a 37% lower risk for developing DLB than those taking the 5ARI medications (P = .012).

“This emerging evidence of a protective association across a spectrum of diseases suggests a broad neuroprotective effect for Tz/Dz/Az, consistent with our hypothesized mechanism that activation of PGK1 increases brain ATP and mitigates neurodegeneration,” the authors wrote.

Study limitations include excluding women from the study, so the findings cannot be generalized to women. Claims analyses were limited to administrative data that could have been incorrect, and the analyses did not include medication dosages.

No study funding or author disclosures were reported.

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

Certain medications that are used to treat benign prostatic hyperplasia (BPH) are associated with a reduced risk for dementia with Lewy bodies (DLB), the second most common neurodegenerative type of dementia after Alzheimer’s disease.

Investigators found older men taking alpha-1 blockers terazosin, doxazosin, or alfuzosin (Tz/Dz/Az) were 40% less likely to develop DLB than those taking tamsulosin and 37% less likely than men taking the 5-alpha reductase inhibitors (5ARI) finasteride and dutasteride.

“These results are exciting because right now there are no drugs to prevent or treat dementia with Lewy bodies,” study investigator Jacob E. Simmering, PhD, of the University of Iowa in Iowa City, said in a press release. “If we can determine that an existing drug can offer protection against this debilitating disease, that has the potential to greatly reduce its effects.”

The findings were published online in Neurology.
 

Increasing ATP Neuroprotective?

In recent years, investigators have speculated that improving metabolic activity in the brain may reduce the risk for Parkinson’s disease (PD). 

In previous studies, the use of Tz/Dz/Az resulted in the activation of phosphoglycerate kinase-1 (PKG1), which increases the availability of adenosine triphosphate (ATP).

There have been case reports of PD being linked to mutations affecting PGK1. Researchers speculate that increased ATP availability in neurons resulting from the activation of PKG1 allows cells to better adapt to aging and synuclein aggregation.

To investigate whether glycolysis-enhancing drugs might be neuroprotective in those with DLB, investigators conducted a retrospective cohort study using a commercial health insurance claims database and a Medicare supplemental health claims database to follow a sample of men aged > 40 years taking Tz, Dz, or Az (n = 126,313), tamsulosin (n = 437,035), or a 5ARI (n = 80,158) for BPH.

Tamsulosin and 5ARI medications do not activate PKG1, so investigators used them as comparators to Tz/Dz/Az. Participants were followed from the medication initiation date until the end of enrollment in the claims databases.

After following claimants for an average of 3 years, 195 participants developed DLB who were taking Tz, Dz, or Az, a rate of 5.21 cases per 10,000 people per year.

During the follow-up period, 1286 participants taking tamsulosin developed DLB, a rate of 10.8 per 10,000 people per year, and among those taking 5ARIs, 193 cases of DLB were reported, a rate of 7.8 per 10,000 people per year.

After matching the groups by age and other health conditions that may explain differences in rates of DLB, men taking Tz/Dz/Az had a 60% lower risk than those taking tamsulosin (P < .001) and a 37% lower risk for developing DLB than those taking the 5ARI medications (P = .012).

“This emerging evidence of a protective association across a spectrum of diseases suggests a broad neuroprotective effect for Tz/Dz/Az, consistent with our hypothesized mechanism that activation of PGK1 increases brain ATP and mitigates neurodegeneration,” the authors wrote.

Study limitations include excluding women from the study, so the findings cannot be generalized to women. Claims analyses were limited to administrative data that could have been incorrect, and the analyses did not include medication dosages.

No study funding or author disclosures were reported.

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

Certain medications that are used to treat benign prostatic hyperplasia (BPH) are associated with a reduced risk for dementia with Lewy bodies (DLB), the second most common neurodegenerative type of dementia after Alzheimer’s disease.

Investigators found older men taking alpha-1 blockers terazosin, doxazosin, or alfuzosin (Tz/Dz/Az) were 40% less likely to develop DLB than those taking tamsulosin and 37% less likely than men taking the 5-alpha reductase inhibitors (5ARI) finasteride and dutasteride.

“These results are exciting because right now there are no drugs to prevent or treat dementia with Lewy bodies,” study investigator Jacob E. Simmering, PhD, of the University of Iowa in Iowa City, said in a press release. “If we can determine that an existing drug can offer protection against this debilitating disease, that has the potential to greatly reduce its effects.”

The findings were published online in Neurology.
 

Increasing ATP Neuroprotective?

In recent years, investigators have speculated that improving metabolic activity in the brain may reduce the risk for Parkinson’s disease (PD). 

In previous studies, the use of Tz/Dz/Az resulted in the activation of phosphoglycerate kinase-1 (PKG1), which increases the availability of adenosine triphosphate (ATP).

There have been case reports of PD being linked to mutations affecting PGK1. Researchers speculate that increased ATP availability in neurons resulting from the activation of PKG1 allows cells to better adapt to aging and synuclein aggregation.

To investigate whether glycolysis-enhancing drugs might be neuroprotective in those with DLB, investigators conducted a retrospective cohort study using a commercial health insurance claims database and a Medicare supplemental health claims database to follow a sample of men aged > 40 years taking Tz, Dz, or Az (n = 126,313), tamsulosin (n = 437,035), or a 5ARI (n = 80,158) for BPH.

Tamsulosin and 5ARI medications do not activate PKG1, so investigators used them as comparators to Tz/Dz/Az. Participants were followed from the medication initiation date until the end of enrollment in the claims databases.

After following claimants for an average of 3 years, 195 participants developed DLB who were taking Tz, Dz, or Az, a rate of 5.21 cases per 10,000 people per year.

During the follow-up period, 1286 participants taking tamsulosin developed DLB, a rate of 10.8 per 10,000 people per year, and among those taking 5ARIs, 193 cases of DLB were reported, a rate of 7.8 per 10,000 people per year.

After matching the groups by age and other health conditions that may explain differences in rates of DLB, men taking Tz/Dz/Az had a 60% lower risk than those taking tamsulosin (P < .001) and a 37% lower risk for developing DLB than those taking the 5ARI medications (P = .012).

“This emerging evidence of a protective association across a spectrum of diseases suggests a broad neuroprotective effect for Tz/Dz/Az, consistent with our hypothesized mechanism that activation of PGK1 increases brain ATP and mitigates neurodegeneration,” the authors wrote.

Study limitations include excluding women from the study, so the findings cannot be generalized to women. Claims analyses were limited to administrative data that could have been incorrect, and the analyses did not include medication dosages.

No study funding or author disclosures were reported.

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

TOPLINE:

A new analysis showed that preeclampsia is associated with an increased risk for young-onset dementia.

METHODOLOGY:

• Researchers analyzed data from the French Conception study, a nationwide prospective cohort study of more than 1.9 million pregnancies.
• Mothers were followed for an average of 9 years.

TAKEAWAY:

• Nearly 3% of the mothers had preeclampsia, and 128 developed young-onset dementia.
• Preeclampsia was associated with a 2.65-fold increased risk for young-onset dementia after adjusting for obesity, diabetes, smoking, drug or alcohol addiction, and social deprivation.
• The risk was greater when preeclampsia occurred before 34 weeks of gestation (hazard ratio [HR], 4.15) or was superimposed on chronic hypertension (HR, 4.76).
• Prior research has found an association between preeclampsia and vascular dementia, but this analysis “is the first to show an increase in early-onset dementia risk,” the authors of the study wrote.

IN PRACTICE:

“Individuals who have had preeclampsia should be reassured that young-onset dementia remains a very rare condition. Their absolute risk increases only imperceptibly,” Stephen Tong, PhD, and Roxanne Hastie, PhD, both with the University of Melbourne, Melbourne, Australia, wrote in a related commentary about the findings.

“Individuals who have been affected by preeclampsia in a prior pregnancy might instead focus on reducing their risk of developing the many chronic health ailments that are far more common,” they added. “Although it is yet to be proven in clinical trials, it is plausible that after an episode of preeclampsia, adopting a healthy lifestyle may improve vascular health and reduce the risk of many serious cardiovascular conditions.”

SOURCE:

Valérie Olié, PhD, of the Santé Publique France in Saint-Maurice, France, was the corresponding author on the paper. The research letter was published online in JAMA Network Open.

LIMITATIONS:

The investigators relied on hospital records to identify cases of dementia, which may have led to underestimation of incidence of the disease.

DISCLOSURES:

The study was funded by the French Hypertension Society, the French Hypertension Research Foundation, and the French Cardiology Federation. A co-author disclosed personal fees from pharmaceutical companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

A new analysis showed that preeclampsia is associated with an increased risk for young-onset dementia.

METHODOLOGY:

• Researchers analyzed data from the French Conception study, a nationwide prospective cohort study of more than 1.9 million pregnancies.
• Mothers were followed for an average of 9 years.

TAKEAWAY:

• Nearly 3% of the mothers had preeclampsia, and 128 developed young-onset dementia.
• Preeclampsia was associated with a 2.65-fold increased risk for young-onset dementia after adjusting for obesity, diabetes, smoking, drug or alcohol addiction, and social deprivation.
• The risk was greater when preeclampsia occurred before 34 weeks of gestation (hazard ratio [HR], 4.15) or was superimposed on chronic hypertension (HR, 4.76).
• Prior research has found an association between preeclampsia and vascular dementia, but this analysis “is the first to show an increase in early-onset dementia risk,” the authors of the study wrote.

IN PRACTICE:

“Individuals who have had preeclampsia should be reassured that young-onset dementia remains a very rare condition. Their absolute risk increases only imperceptibly,” Stephen Tong, PhD, and Roxanne Hastie, PhD, both with the University of Melbourne, Melbourne, Australia, wrote in a related commentary about the findings.

“Individuals who have been affected by preeclampsia in a prior pregnancy might instead focus on reducing their risk of developing the many chronic health ailments that are far more common,” they added. “Although it is yet to be proven in clinical trials, it is plausible that after an episode of preeclampsia, adopting a healthy lifestyle may improve vascular health and reduce the risk of many serious cardiovascular conditions.”

SOURCE:

Valérie Olié, PhD, of the Santé Publique France in Saint-Maurice, France, was the corresponding author on the paper. The research letter was published online in JAMA Network Open.

LIMITATIONS:

The investigators relied on hospital records to identify cases of dementia, which may have led to underestimation of incidence of the disease.

DISCLOSURES:

The study was funded by the French Hypertension Society, the French Hypertension Research Foundation, and the French Cardiology Federation. A co-author disclosed personal fees from pharmaceutical companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

A new analysis showed that preeclampsia is associated with an increased risk for young-onset dementia.

METHODOLOGY:

• Researchers analyzed data from the French Conception study, a nationwide prospective cohort study of more than 1.9 million pregnancies.
• Mothers were followed for an average of 9 years.

TAKEAWAY:

• Nearly 3% of the mothers had preeclampsia, and 128 developed young-onset dementia.
• Preeclampsia was associated with a 2.65-fold increased risk for young-onset dementia after adjusting for obesity, diabetes, smoking, drug or alcohol addiction, and social deprivation.
• The risk was greater when preeclampsia occurred before 34 weeks of gestation (hazard ratio [HR], 4.15) or was superimposed on chronic hypertension (HR, 4.76).
• Prior research has found an association between preeclampsia and vascular dementia, but this analysis “is the first to show an increase in early-onset dementia risk,” the authors of the study wrote.

IN PRACTICE:

“Individuals who have had preeclampsia should be reassured that young-onset dementia remains a very rare condition. Their absolute risk increases only imperceptibly,” Stephen Tong, PhD, and Roxanne Hastie, PhD, both with the University of Melbourne, Melbourne, Australia, wrote in a related commentary about the findings.

“Individuals who have been affected by preeclampsia in a prior pregnancy might instead focus on reducing their risk of developing the many chronic health ailments that are far more common,” they added. “Although it is yet to be proven in clinical trials, it is plausible that after an episode of preeclampsia, adopting a healthy lifestyle may improve vascular health and reduce the risk of many serious cardiovascular conditions.”

SOURCE:

Valérie Olié, PhD, of the Santé Publique France in Saint-Maurice, France, was the corresponding author on the paper. The research letter was published online in JAMA Network Open.

LIMITATIONS:

The investigators relied on hospital records to identify cases of dementia, which may have led to underestimation of incidence of the disease.

DISCLOSURES:

The study was funded by the French Hypertension Society, the French Hypertension Research Foundation, and the French Cardiology Federation. A co-author disclosed personal fees from pharmaceutical companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

An algorithm using two well-known tests has shown strong accuracy (91%) in predicting whether an older driver can pass an on-road driving evaluation according to a new study published in the Journal of the American Medical Directors Association .

The Fit2Drive algorithm combines the Mini-Mental State Exam (MMSE), a 30-point dementia screening tool that has been found in several studies to have an association with driving ability, and the Trails B test, which gauges cognitive flexibility and set-shifting (task switching), considered to be measures of executive functioning.
 

Algorithm Available for Providers

The algorithm is clinically available and providers can fill in patients’ information and results of the two tests at the Fit2Drive website. Results may help physicians with often-difficult conversations with older patients about driving when they present with cognitive concerns.

Families report it is one of the most difficult conversations they have with a loved one and doctors are often asked to be part of the conversation. This is particularly difficult when, often, little objective information is available. In the past, a clinical rule of thumb has been that people diagnosed with Alzheimer’s disease or related dementias (ADRD) will usually be able to drive for 3 years after diagnosis.

“[T]he anger, tears, and frustration on the part of the individual patient and the lack of objective data to guide provider recommendations are the driving forces behind our effort to develop a highly accurate, evidence-based predictor of the ability to pass an on-road driving test,” the authors write. They added that the goal of the study was to identify the smallest number of cognitive test results that could predict likelihood of passing an on-road driver evaluation.

A number of tests were evaluated for the algorithm, but the combination of Trails B in seconds and MMSE using the highest scores of the serial 7s (counting back from 100 by 7s) or WORLD spelled backward accounted for the highest correlation with passing the on-road driving test, according to the authors, led by Ruth Tappen, EdD, FN, with the Christine E. Lynn College of Nursing at Florida Atlantic University, in Boca Raton.

A receiver operator characteristic (ROC) analysis was conducted on the linear combination of the two assessments.

“Because an ROC of 0.70 is considered to be the minimal requirement [for predictive value], 0.80 is considered good, and higher than 0.90 is excellent, these findings [with 91% area under the curve] suggest excellent accuracy using these two cognitive tests in this population,” the authors write.

For this analysis, researchers included 412 older drivers (179 men and 233 women) with an average age of 80. T he study was conducted at the Florida Atlantic University’s Memory Center and Clinical Research Unit. Participants included those who received a driving evaluation at the Memory Center and agreed to have their results included in the Driving Repository, and community-based older drivers who volunteered to participate.
 

Limitations of the Study

There were marginal differences between sexes on the measures, but they were not significant. The sample was composed of relatively well-educated people, primarily of European American ethnic origin, which is a consideration in generalizing the results.

Among other limitations are that physical and sensory factors, in addition to cognitive issues, may affect an individual’s ability to drive safely and are not included in the algorithm. Sensory disabilities, including reduced visual acuity caused by binocular field vision loss, contrast sensitivity, glare sensitivity, and other conditions, may affect driving ability as well as the ability to fully rotate the head and neck. Medical conditions affecting the cardiovascular, neurological, and orthopedic systems can also influence driving ability.

“Future studies should involve more diverse samples and a greater variety of driving challenges, including school zones and multilane highways, which are not included in the study,” the authors write.

The study received grant support from the State of Florida Department of Health and the Ed and Ethel Moore Alzheimer’s Disease Research Program.

An algorithm using two well-known tests has shown strong accuracy (91%) in predicting whether an older driver can pass an on-road driving evaluation according to a new study published in the Journal of the American Medical Directors Association .

The Fit2Drive algorithm combines the Mini-Mental State Exam (MMSE), a 30-point dementia screening tool that has been found in several studies to have an association with driving ability, and the Trails B test, which gauges cognitive flexibility and set-shifting (task switching), considered to be measures of executive functioning.
 

Algorithm Available for Providers

The algorithm is clinically available and providers can fill in patients’ information and results of the two tests at the Fit2Drive website. Results may help physicians with often-difficult conversations with older patients about driving when they present with cognitive concerns.

Families report it is one of the most difficult conversations they have with a loved one and doctors are often asked to be part of the conversation. This is particularly difficult when, often, little objective information is available. In the past, a clinical rule of thumb has been that people diagnosed with Alzheimer’s disease or related dementias (ADRD) will usually be able to drive for 3 years after diagnosis.

“[T]he anger, tears, and frustration on the part of the individual patient and the lack of objective data to guide provider recommendations are the driving forces behind our effort to develop a highly accurate, evidence-based predictor of the ability to pass an on-road driving test,” the authors write. They added that the goal of the study was to identify the smallest number of cognitive test results that could predict likelihood of passing an on-road driver evaluation.

A number of tests were evaluated for the algorithm, but the combination of Trails B in seconds and MMSE using the highest scores of the serial 7s (counting back from 100 by 7s) or WORLD spelled backward accounted for the highest correlation with passing the on-road driving test, according to the authors, led by Ruth Tappen, EdD, FN, with the Christine E. Lynn College of Nursing at Florida Atlantic University, in Boca Raton.

A receiver operator characteristic (ROC) analysis was conducted on the linear combination of the two assessments.

“Because an ROC of 0.70 is considered to be the minimal requirement [for predictive value], 0.80 is considered good, and higher than 0.90 is excellent, these findings [with 91% area under the curve] suggest excellent accuracy using these two cognitive tests in this population,” the authors write.

For this analysis, researchers included 412 older drivers (179 men and 233 women) with an average age of 80. T he study was conducted at the Florida Atlantic University’s Memory Center and Clinical Research Unit. Participants included those who received a driving evaluation at the Memory Center and agreed to have their results included in the Driving Repository, and community-based older drivers who volunteered to participate.
 

Limitations of the Study

There were marginal differences between sexes on the measures, but they were not significant. The sample was composed of relatively well-educated people, primarily of European American ethnic origin, which is a consideration in generalizing the results.

Among other limitations are that physical and sensory factors, in addition to cognitive issues, may affect an individual’s ability to drive safely and are not included in the algorithm. Sensory disabilities, including reduced visual acuity caused by binocular field vision loss, contrast sensitivity, glare sensitivity, and other conditions, may affect driving ability as well as the ability to fully rotate the head and neck. Medical conditions affecting the cardiovascular, neurological, and orthopedic systems can also influence driving ability.

“Future studies should involve more diverse samples and a greater variety of driving challenges, including school zones and multilane highways, which are not included in the study,” the authors write.

The study received grant support from the State of Florida Department of Health and the Ed and Ethel Moore Alzheimer’s Disease Research Program.

An algorithm using two well-known tests has shown strong accuracy (91%) in predicting whether an older driver can pass an on-road driving evaluation according to a new study published in the Journal of the American Medical Directors Association .

The Fit2Drive algorithm combines the Mini-Mental State Exam (MMSE), a 30-point dementia screening tool that has been found in several studies to have an association with driving ability, and the Trails B test, which gauges cognitive flexibility and set-shifting (task switching), considered to be measures of executive functioning.
 

Algorithm Available for Providers

The algorithm is clinically available and providers can fill in patients’ information and results of the two tests at the Fit2Drive website. Results may help physicians with often-difficult conversations with older patients about driving when they present with cognitive concerns.

Families report it is one of the most difficult conversations they have with a loved one and doctors are often asked to be part of the conversation. This is particularly difficult when, often, little objective information is available. In the past, a clinical rule of thumb has been that people diagnosed with Alzheimer’s disease or related dementias (ADRD) will usually be able to drive for 3 years after diagnosis.

“[T]he anger, tears, and frustration on the part of the individual patient and the lack of objective data to guide provider recommendations are the driving forces behind our effort to develop a highly accurate, evidence-based predictor of the ability to pass an on-road driving test,” the authors write. They added that the goal of the study was to identify the smallest number of cognitive test results that could predict likelihood of passing an on-road driver evaluation.

A number of tests were evaluated for the algorithm, but the combination of Trails B in seconds and MMSE using the highest scores of the serial 7s (counting back from 100 by 7s) or WORLD spelled backward accounted for the highest correlation with passing the on-road driving test, according to the authors, led by Ruth Tappen, EdD, FN, with the Christine E. Lynn College of Nursing at Florida Atlantic University, in Boca Raton.

A receiver operator characteristic (ROC) analysis was conducted on the linear combination of the two assessments.

“Because an ROC of 0.70 is considered to be the minimal requirement [for predictive value], 0.80 is considered good, and higher than 0.90 is excellent, these findings [with 91% area under the curve] suggest excellent accuracy using these two cognitive tests in this population,” the authors write.

For this analysis, researchers included 412 older drivers (179 men and 233 women) with an average age of 80. T he study was conducted at the Florida Atlantic University’s Memory Center and Clinical Research Unit. Participants included those who received a driving evaluation at the Memory Center and agreed to have their results included in the Driving Repository, and community-based older drivers who volunteered to participate.
 

Limitations of the Study

There were marginal differences between sexes on the measures, but they were not significant. The sample was composed of relatively well-educated people, primarily of European American ethnic origin, which is a consideration in generalizing the results.

Among other limitations are that physical and sensory factors, in addition to cognitive issues, may affect an individual’s ability to drive safely and are not included in the algorithm. Sensory disabilities, including reduced visual acuity caused by binocular field vision loss, contrast sensitivity, glare sensitivity, and other conditions, may affect driving ability as well as the ability to fully rotate the head and neck. Medical conditions affecting the cardiovascular, neurological, and orthopedic systems can also influence driving ability.

“Future studies should involve more diverse samples and a greater variety of driving challenges, including school zones and multilane highways, which are not included in the study,” the authors write.

The study received grant support from the State of Florida Department of Health and the Ed and Ethel Moore Alzheimer’s Disease Research Program.

In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.

A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”

Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.

New data suggest that repeated blast exposure may impair the brain’s waste clearance system, leading to biomarker changes indicative of preclinical Alzheimer’s disease 20 years earlier than typical. A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.

In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”

In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.

Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
 

What Is the Underlying Biology?

Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.

The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.

“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
 

Common Biomarker Signatures

A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.

“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.

The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.

The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.

For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).

High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.

The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).

In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
 

Is Impaired Clearance the Culprit?

Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.

“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”

Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”

A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.

The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.

In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”

It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.

The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”

Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.

In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.

And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.

The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
 

Veterans Especially Vulnerable

Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.

“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”

The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.

Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”

Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.

Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”

Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”

He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
 

Clinical Implications

For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.

But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”

The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.

Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.

Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”

Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”

Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”

Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.

The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
 

A version of this article appeared on Medscape.com.

In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.

A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”

Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.

New data suggest that repeated blast exposure may impair the brain’s waste clearance system, leading to biomarker changes indicative of preclinical Alzheimer’s disease 20 years earlier than typical. A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.

In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”

In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.

Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
 

What Is the Underlying Biology?

Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.

The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.

“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
 

Common Biomarker Signatures

A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.

“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.

The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.

The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.

For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).

High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.

The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).

In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
 

Is Impaired Clearance the Culprit?

Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.

“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”

Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”

A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.

The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.

In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”

It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.

The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”

Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.

In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.

And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.

The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
 

Veterans Especially Vulnerable

Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.

“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”

The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.

Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”

Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.

Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”

Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”

He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
 

Clinical Implications

For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.

But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”

The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.

Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.

Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”

Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”

Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”

Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.

The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
 

A version of this article appeared on Medscape.com.

In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.

A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”

Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.

New data suggest that repeated blast exposure may impair the brain’s waste clearance system, leading to biomarker changes indicative of preclinical Alzheimer’s disease 20 years earlier than typical. A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.

In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”

In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.

Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
 

What Is the Underlying Biology?

Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.

The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.

“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
 

Common Biomarker Signatures

A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.

“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.

The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.

The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.

For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).

High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.

The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).

In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
 

Is Impaired Clearance the Culprit?

Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.

“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”

Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”

A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.

The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.

In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”

It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.

The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”

Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.

In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.

And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.

The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
 

Veterans Especially Vulnerable

Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.

“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”

The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.

Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”

Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.

Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”

Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”

He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
 

Clinical Implications

For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.

But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”

The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.

Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.

Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”

Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”

Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”

Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.

The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Poor vision and contrast sensitivity at baseline increase the likelihood of incident dementia in older adults; a decline in contrast sensitivity over time also correlates with the risk of developing dementia.

METHODOLOGY:

• Researchers conducted a longitudinal study to analyze the association of visual function with the risk for dementia in 2159 men and women (mean age, 77.9 years; 54% women) included from the National Health and Aging Trends Study between 2021 and 2022.
• All participants were free from dementia at baseline and underwent visual assessment while wearing their usual glasses or contact lenses.
• Distance and near visual acuity were measured as the log minimum angle of resolution (logMAR) units where higher values indicated worse visual acuity; contrast sensitivity was measured as the log contrast sensitivity (logCS) units where lower values represented worse outcomes.
• Dementia status was determined by a medical diagnosis, a dementia score of 2 or more, or poor performance on cognitive testing.

TAKEAWAY:

• Over the 1-year follow-up period, 192 adults (6.6%) developed dementia.
• Worsening of distant and near vision by 0.1 logMAR increased the risk for dementia by 8% (P = .01) and 7% (P = .02), respectively.
• Each 0.1 logCS decline in baseline contrast sensitivity increased the risk for dementia by 9% (P = .003).
• A yearly decline in contrast sensitivity by 0.1 logCS increased the likelihood of dementia by 14% (P = .007).
• Changes in distant and near vision over time did not show a significant association with risk for dementia (P = .58 and P = .79, respectively).

IN PRACTICE:

“Visual function, especially contrast sensitivity, might be a risk factor for developing dementia,” the authors wrote. “Early vision screening may help identify adults at higher risk of dementia, allowing for timely interventions.”

SOURCE:

The study was led by Louay Almidani, MD, MSc, of the Wilmer Eye Institute at the Johns Hopkins University School of Medicine, in Baltimore, and was published online in the American Journal of Ophthalmology.

LIMITATIONS:

The study had a limited follow-up period of 1 year and may not have captured the long-term association between visual impairment and the risk for dementia. Moreover, the researchers did not consider other visual function measures such as depth perception and visual field, which might have affected the results.

DISCLOSURES:

The study did not have any funding source. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Poor vision and contrast sensitivity at baseline increase the likelihood of incident dementia in older adults; a decline in contrast sensitivity over time also correlates with the risk of developing dementia.

METHODOLOGY:

• Researchers conducted a longitudinal study to analyze the association of visual function with the risk for dementia in 2159 men and women (mean age, 77.9 years; 54% women) included from the National Health and Aging Trends Study between 2021 and 2022.
• All participants were free from dementia at baseline and underwent visual assessment while wearing their usual glasses or contact lenses.
• Distance and near visual acuity were measured as the log minimum angle of resolution (logMAR) units where higher values indicated worse visual acuity; contrast sensitivity was measured as the log contrast sensitivity (logCS) units where lower values represented worse outcomes.
• Dementia status was determined by a medical diagnosis, a dementia score of 2 or more, or poor performance on cognitive testing.

TAKEAWAY:

• Over the 1-year follow-up period, 192 adults (6.6%) developed dementia.
• Worsening of distant and near vision by 0.1 logMAR increased the risk for dementia by 8% (P = .01) and 7% (P = .02), respectively.
• Each 0.1 logCS decline in baseline contrast sensitivity increased the risk for dementia by 9% (P = .003).
• A yearly decline in contrast sensitivity by 0.1 logCS increased the likelihood of dementia by 14% (P = .007).
• Changes in distant and near vision over time did not show a significant association with risk for dementia (P = .58 and P = .79, respectively).

IN PRACTICE:

“Visual function, especially contrast sensitivity, might be a risk factor for developing dementia,” the authors wrote. “Early vision screening may help identify adults at higher risk of dementia, allowing for timely interventions.”

SOURCE:

The study was led by Louay Almidani, MD, MSc, of the Wilmer Eye Institute at the Johns Hopkins University School of Medicine, in Baltimore, and was published online in the American Journal of Ophthalmology.

LIMITATIONS:

The study had a limited follow-up period of 1 year and may not have captured the long-term association between visual impairment and the risk for dementia. Moreover, the researchers did not consider other visual function measures such as depth perception and visual field, which might have affected the results.

DISCLOSURES:

The study did not have any funding source. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Poor vision and contrast sensitivity at baseline increase the likelihood of incident dementia in older adults; a decline in contrast sensitivity over time also correlates with the risk of developing dementia.

METHODOLOGY:

• Researchers conducted a longitudinal study to analyze the association of visual function with the risk for dementia in 2159 men and women (mean age, 77.9 years; 54% women) included from the National Health and Aging Trends Study between 2021 and 2022.
• All participants were free from dementia at baseline and underwent visual assessment while wearing their usual glasses or contact lenses.
• Distance and near visual acuity were measured as the log minimum angle of resolution (logMAR) units where higher values indicated worse visual acuity; contrast sensitivity was measured as the log contrast sensitivity (logCS) units where lower values represented worse outcomes.
• Dementia status was determined by a medical diagnosis, a dementia score of 2 or more, or poor performance on cognitive testing.

TAKEAWAY:

• Over the 1-year follow-up period, 192 adults (6.6%) developed dementia.
• Worsening of distant and near vision by 0.1 logMAR increased the risk for dementia by 8% (P = .01) and 7% (P = .02), respectively.
• Each 0.1 logCS decline in baseline contrast sensitivity increased the risk for dementia by 9% (P = .003).
• A yearly decline in contrast sensitivity by 0.1 logCS increased the likelihood of dementia by 14% (P = .007).
• Changes in distant and near vision over time did not show a significant association with risk for dementia (P = .58 and P = .79, respectively).

IN PRACTICE:

“Visual function, especially contrast sensitivity, might be a risk factor for developing dementia,” the authors wrote. “Early vision screening may help identify adults at higher risk of dementia, allowing for timely interventions.”

SOURCE:

The study was led by Louay Almidani, MD, MSc, of the Wilmer Eye Institute at the Johns Hopkins University School of Medicine, in Baltimore, and was published online in the American Journal of Ophthalmology.

LIMITATIONS:

The study had a limited follow-up period of 1 year and may not have captured the long-term association between visual impairment and the risk for dementia. Moreover, the researchers did not consider other visual function measures such as depth perception and visual field, which might have affected the results.

DISCLOSURES:

The study did not have any funding source. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

An intensive lifestyle intervention significantly improved cognition and function in many patients with mild cognitive impairment (MCI) or early dementia due to Alzheimer’s disease, in what authors said is the first randomized controlled trial of intensive lifestyle modification for patients diagnosed with Alzheimer’s disease. Results could help physicians address patients at risk of Alzheimer’s disease who reject relevant testing because they believe nothing can forestall development of the disease, the authors added. The study was published online in Alzheimer’s Research & Therapy.

Although technology allows probable Alzheimer’s disease diagnosis years before clinical symptoms appear, wrote investigators led by Dean Ornish, MD, of the Preventive Medicine Research Institute in Sausalito, California, “many people do not want to know if they are likely to get Alzheimer’s disease if they do not believe they can do anything about it. If intensive lifestyle changes may cause improvement in cognition and function in MCI or early dementia due to Alzheimer’s disease, then it is reasonable to think that these lifestyle changes may also help to prevent MCI or early dementia due to Alzheimer’s disease.” As with cardiovascular disease, the authors added, preventing Alzheimer’s disease might require less intensive lifestyle modifications than treating it.
 

Study Methodology

Investigators randomized 26 patients with Montréal Cognitive Assessment scores of 18 or higher to an intensive intervention involving nutrition, exercise, and stress management techniques. To improve adherence, the protocol included participants’ spouses or caregivers.

Two patients, both in the treatment group, withdrew over logistical concerns.

After 20 weeks, treated patients exhibited statistically significant differences in several key measures versus a 25-patient usual-care control group. Scores that improved in the intervention group and worsened among controls included the following:

• Clinical Global Impression of Change (CGIC, P = .001)
• Clinical Dementia Rating-Global (CDR-Global, -0.04, P = .037)
• Clinical Dementia Rating Sum of Boxes (CDR-SB, +0.08, P = .032)
• Alzheimer’s Disease Assessment Scale (ADAS-Cog, -1.01, P = .053)

The validity of these changes in cognition and function, and possible biological mechanisms of improvement, were supported by statistically significant improvements in several clinically relevant biomarkers versus controls, the investigators wrote. These biomarkers included Abeta42/40 ratio, HbA1c, insulin, and glycoprotein acetylation. “This information may also help in predicting which patients are more likely to show improvements in cognition and function by making these intensive lifestyle changes,” the authors added.

In primary analysis, the degree of lifestyle changes required to stop progression of MCI ranged from 71.4% (ADAS-Cog) to 120.6% (CDR-SB). “This helps to explain why other studies of less intensive lifestyle interventions may not have been sufficient to stop deterioration or improve cognition and function,” the authors wrote. Moreover, they added, variable adherence might explain why in the intervention group, 10 patients improved their CGIC scores, while the rest held static or worsened.
 

Caveats

Alzheimer’s Association Vice President of Medical and Scientific Relations Heather M. Snyder, PhD, said, “This is an interesting paper in an important area of research and adds to the growing body of literature on how behavior or lifestyle may be related to cognitive decline. However, because this is a small phase 2 study, it is important for this or similar work to be done in larger, more diverse populations and over a longer duration of the intervention.” She was not involved with the study but was asked to comment.

Investigators chose the 20-week duration, they explained, because control-group patients likely would not refrain from trying the lifestyle intervention beyond that timeframe. Perhaps more importantly, challenges created by the COVID-19 pandemic required researchers to cut planned enrollment in half, eliminate planned MRI and amyloid PET scans, and reduce the number of cognition and function tests.

Such shortcomings limit what neurologists can glean and generalize from the study, said Dr. Snyder. “That said,” she added, “it does demonstrate the potential of an intensive behavior/lifestyle intervention, and the importance of this sort of research in Alzheimer’s and dementia.” Although the complexity of the interventions makes these studies challenging, she added, “it is important that we continue to advance larger, longer studies in more representative study populations to develop specific recommendations.”
 

Further Study

The Alzheimer’s Association’s U.S. POINTER study is the first large-scale study in the United States to explore the impact of comprehensive lifestyle changes on cognitive health. About 2000 older adults at risk for cognitive decline are participating, from diverse locations across the country. More than 25% of participants come from groups typically underrepresented in dementia research, said Dr. Snyder. Initial results are expected in summer 2025.

Future research also should explore reasons (beyond adherence) why some patients respond to lifestyle interventions better than others, and the potential synergy of lifestyle changes with drug therapies, wrote Dr. Ornish and colleagues.

“For now,” said Dr. Snyder, “there is an opportunity for providers to incorporate or expand messaging with their patients and families about the habits that they can incorporate into their daily lives. The Alzheimer’s Association offers 10 Healthy Habits for Your Brain — everyday actions that can make a difference for your brain health.”

Investigators received study funding from more than two dozen charitable foundations and other organizations. Dr. Snyder is a full-time employee of the Alzheimer’s Association and in this role, serves on the leadership team of the U.S. POINTER study. Her partner works for Abbott in an unrelated field. 

An intensive lifestyle intervention significantly improved cognition and function in many patients with mild cognitive impairment (MCI) or early dementia due to Alzheimer’s disease, in what authors said is the first randomized controlled trial of intensive lifestyle modification for patients diagnosed with Alzheimer’s disease. Results could help physicians address patients at risk of Alzheimer’s disease who reject relevant testing because they believe nothing can forestall development of the disease, the authors added. The study was published online in Alzheimer’s Research & Therapy.

Although technology allows probable Alzheimer’s disease diagnosis years before clinical symptoms appear, wrote investigators led by Dean Ornish, MD, of the Preventive Medicine Research Institute in Sausalito, California, “many people do not want to know if they are likely to get Alzheimer’s disease if they do not believe they can do anything about it. If intensive lifestyle changes may cause improvement in cognition and function in MCI or early dementia due to Alzheimer’s disease, then it is reasonable to think that these lifestyle changes may also help to prevent MCI or early dementia due to Alzheimer’s disease.” As with cardiovascular disease, the authors added, preventing Alzheimer’s disease might require less intensive lifestyle modifications than treating it.
 

Study Methodology

Investigators randomized 26 patients with Montréal Cognitive Assessment scores of 18 or higher to an intensive intervention involving nutrition, exercise, and stress management techniques. To improve adherence, the protocol included participants’ spouses or caregivers.

Two patients, both in the treatment group, withdrew over logistical concerns.

After 20 weeks, treated patients exhibited statistically significant differences in several key measures versus a 25-patient usual-care control group. Scores that improved in the intervention group and worsened among controls included the following:

• Clinical Global Impression of Change (CGIC, P = .001)
• Clinical Dementia Rating-Global (CDR-Global, -0.04, P = .037)
• Clinical Dementia Rating Sum of Boxes (CDR-SB, +0.08, P = .032)
• Alzheimer’s Disease Assessment Scale (ADAS-Cog, -1.01, P = .053)

The validity of these changes in cognition and function, and possible biological mechanisms of improvement, were supported by statistically significant improvements in several clinically relevant biomarkers versus controls, the investigators wrote. These biomarkers included Abeta42/40 ratio, HbA1c, insulin, and glycoprotein acetylation. “This information may also help in predicting which patients are more likely to show improvements in cognition and function by making these intensive lifestyle changes,” the authors added.

In primary analysis, the degree of lifestyle changes required to stop progression of MCI ranged from 71.4% (ADAS-Cog) to 120.6% (CDR-SB). “This helps to explain why other studies of less intensive lifestyle interventions may not have been sufficient to stop deterioration or improve cognition and function,” the authors wrote. Moreover, they added, variable adherence might explain why in the intervention group, 10 patients improved their CGIC scores, while the rest held static or worsened.
 

Caveats

Alzheimer’s Association Vice President of Medical and Scientific Relations Heather M. Snyder, PhD, said, “This is an interesting paper in an important area of research and adds to the growing body of literature on how behavior or lifestyle may be related to cognitive decline. However, because this is a small phase 2 study, it is important for this or similar work to be done in larger, more diverse populations and over a longer duration of the intervention.” She was not involved with the study but was asked to comment.

Investigators chose the 20-week duration, they explained, because control-group patients likely would not refrain from trying the lifestyle intervention beyond that timeframe. Perhaps more importantly, challenges created by the COVID-19 pandemic required researchers to cut planned enrollment in half, eliminate planned MRI and amyloid PET scans, and reduce the number of cognition and function tests.

Such shortcomings limit what neurologists can glean and generalize from the study, said Dr. Snyder. “That said,” she added, “it does demonstrate the potential of an intensive behavior/lifestyle intervention, and the importance of this sort of research in Alzheimer’s and dementia.” Although the complexity of the interventions makes these studies challenging, she added, “it is important that we continue to advance larger, longer studies in more representative study populations to develop specific recommendations.”
 

Further Study

The Alzheimer’s Association’s U.S. POINTER study is the first large-scale study in the United States to explore the impact of comprehensive lifestyle changes on cognitive health. About 2000 older adults at risk for cognitive decline are participating, from diverse locations across the country. More than 25% of participants come from groups typically underrepresented in dementia research, said Dr. Snyder. Initial results are expected in summer 2025.

Future research also should explore reasons (beyond adherence) why some patients respond to lifestyle interventions better than others, and the potential synergy of lifestyle changes with drug therapies, wrote Dr. Ornish and colleagues.

“For now,” said Dr. Snyder, “there is an opportunity for providers to incorporate or expand messaging with their patients and families about the habits that they can incorporate into their daily lives. The Alzheimer’s Association offers 10 Healthy Habits for Your Brain — everyday actions that can make a difference for your brain health.”

Investigators received study funding from more than two dozen charitable foundations and other organizations. Dr. Snyder is a full-time employee of the Alzheimer’s Association and in this role, serves on the leadership team of the U.S. POINTER study. Her partner works for Abbott in an unrelated field. 

An intensive lifestyle intervention significantly improved cognition and function in many patients with mild cognitive impairment (MCI) or early dementia due to Alzheimer’s disease, in what authors said is the first randomized controlled trial of intensive lifestyle modification for patients diagnosed with Alzheimer’s disease. Results could help physicians address patients at risk of Alzheimer’s disease who reject relevant testing because they believe nothing can forestall development of the disease, the authors added. The study was published online in Alzheimer’s Research & Therapy.

Although technology allows probable Alzheimer’s disease diagnosis years before clinical symptoms appear, wrote investigators led by Dean Ornish, MD, of the Preventive Medicine Research Institute in Sausalito, California, “many people do not want to know if they are likely to get Alzheimer’s disease if they do not believe they can do anything about it. If intensive lifestyle changes may cause improvement in cognition and function in MCI or early dementia due to Alzheimer’s disease, then it is reasonable to think that these lifestyle changes may also help to prevent MCI or early dementia due to Alzheimer’s disease.” As with cardiovascular disease, the authors added, preventing Alzheimer’s disease might require less intensive lifestyle modifications than treating it.
 

Study Methodology

Investigators randomized 26 patients with Montréal Cognitive Assessment scores of 18 or higher to an intensive intervention involving nutrition, exercise, and stress management techniques. To improve adherence, the protocol included participants’ spouses or caregivers.

Two patients, both in the treatment group, withdrew over logistical concerns.

After 20 weeks, treated patients exhibited statistically significant differences in several key measures versus a 25-patient usual-care control group. Scores that improved in the intervention group and worsened among controls included the following:

• Clinical Global Impression of Change (CGIC, P = .001)
• Clinical Dementia Rating-Global (CDR-Global, -0.04, P = .037)
• Clinical Dementia Rating Sum of Boxes (CDR-SB, +0.08, P = .032)
• Alzheimer’s Disease Assessment Scale (ADAS-Cog, -1.01, P = .053)

The validity of these changes in cognition and function, and possible biological mechanisms of improvement, were supported by statistically significant improvements in several clinically relevant biomarkers versus controls, the investigators wrote. These biomarkers included Abeta42/40 ratio, HbA1c, insulin, and glycoprotein acetylation. “This information may also help in predicting which patients are more likely to show improvements in cognition and function by making these intensive lifestyle changes,” the authors added.

In primary analysis, the degree of lifestyle changes required to stop progression of MCI ranged from 71.4% (ADAS-Cog) to 120.6% (CDR-SB). “This helps to explain why other studies of less intensive lifestyle interventions may not have been sufficient to stop deterioration or improve cognition and function,” the authors wrote. Moreover, they added, variable adherence might explain why in the intervention group, 10 patients improved their CGIC scores, while the rest held static or worsened.
 

Caveats

Alzheimer’s Association Vice President of Medical and Scientific Relations Heather M. Snyder, PhD, said, “This is an interesting paper in an important area of research and adds to the growing body of literature on how behavior or lifestyle may be related to cognitive decline. However, because this is a small phase 2 study, it is important for this or similar work to be done in larger, more diverse populations and over a longer duration of the intervention.” She was not involved with the study but was asked to comment.

Investigators chose the 20-week duration, they explained, because control-group patients likely would not refrain from trying the lifestyle intervention beyond that timeframe. Perhaps more importantly, challenges created by the COVID-19 pandemic required researchers to cut planned enrollment in half, eliminate planned MRI and amyloid PET scans, and reduce the number of cognition and function tests.

Such shortcomings limit what neurologists can glean and generalize from the study, said Dr. Snyder. “That said,” she added, “it does demonstrate the potential of an intensive behavior/lifestyle intervention, and the importance of this sort of research in Alzheimer’s and dementia.” Although the complexity of the interventions makes these studies challenging, she added, “it is important that we continue to advance larger, longer studies in more representative study populations to develop specific recommendations.”
 

Further Study

The Alzheimer’s Association’s U.S. POINTER study is the first large-scale study in the United States to explore the impact of comprehensive lifestyle changes on cognitive health. About 2000 older adults at risk for cognitive decline are participating, from diverse locations across the country. More than 25% of participants come from groups typically underrepresented in dementia research, said Dr. Snyder. Initial results are expected in summer 2025.

Future research also should explore reasons (beyond adherence) why some patients respond to lifestyle interventions better than others, and the potential synergy of lifestyle changes with drug therapies, wrote Dr. Ornish and colleagues.

“For now,” said Dr. Snyder, “there is an opportunity for providers to incorporate or expand messaging with their patients and families about the habits that they can incorporate into their daily lives. The Alzheimer’s Association offers 10 Healthy Habits for Your Brain — everyday actions that can make a difference for your brain health.”

Investigators received study funding from more than two dozen charitable foundations and other organizations. Dr. Snyder is a full-time employee of the Alzheimer’s Association and in this role, serves on the leadership team of the U.S. POINTER study. Her partner works for Abbott in an unrelated field. 

After 26 years in practice, there are still things about the brain that amaze me, often that I first notice on myself.

Filtering (I guess “selective attention” sounds better) is one of them. We don’t notice it, but it’s definitely there.

Working at a jigsaw puzzle, I find myself looking for a specific piece, say, a white tab with a dark background and yellow stripe in the center. There may be several hundred pieces spread around me at the table, but the brain quickly starts filtering them out. In a fraction of a second I only notice ones with a white tab, then mentally those are broken down by the other characteristics. If it looks promising, I’ll look back at the space I’m trying to fit it in, mentally rotate the piece (another tricky thing if you think about it) and, if that seems to match, will pick up the piece to try. If it doesn’t fit the process repeats.

Block_Allan_M_AZ_web.JPG

It’s a remarkable ability to see a relationship between two separate objects that isn’t always apparent.

But it’s not just sight. Although I’ve always loved music, it wasn’t until my own kids were in a band that I found the ability to break it down, removing the other instruments. It brings a remarkable clarity to suddenly hearing my daughter on the marimba, or son on the flute. Even with 70 other instrument playing around them.

You can try it yourself, listening to Keith Moon’s amazing drums on The Who’s “5:15.” Or in Bob Seger’s “Fire Lake.” Take out Seger and the instruments and you suddenly realize it’s the Eagles doing the background singing.

In Carly Simon’s “You’re So Vain,” a song you generally don’t attribute to the Rolling Stones, a little bit of focus will reveal Mick Jagger’s distinctive voice in the background chorus of “Don’t you, don’t you, don’t you?”

The ability isn’t something we created. It was there from our ancestors in the trees and caves. They used this ability to identify friend from foe, find the right path home, and pick out what was edible from what was poisonous. Like with so many other things, and without realizing it, our brains have retooled it for the world we now face, even if it’s just to find our car in the parking lot.

Sodium, calcium, potassium, and other ions flow in and out of nerve cells, an electrical impulse propagates though a network, matching incoming sounds and images to ones previously stored. That’s all it is, but the results are remarkable.

We take the everyday for granted, but should stop and think how amazing it really is.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

After 26 years in practice, there are still things about the brain that amaze me, often that I first notice on myself.

Filtering (I guess “selective attention” sounds better) is one of them. We don’t notice it, but it’s definitely there.

Working at a jigsaw puzzle, I find myself looking for a specific piece, say, a white tab with a dark background and yellow stripe in the center. There may be several hundred pieces spread around me at the table, but the brain quickly starts filtering them out. In a fraction of a second I only notice ones with a white tab, then mentally those are broken down by the other characteristics. If it looks promising, I’ll look back at the space I’m trying to fit it in, mentally rotate the piece (another tricky thing if you think about it) and, if that seems to match, will pick up the piece to try. If it doesn’t fit the process repeats.

Block_Allan_M_AZ_web.JPG

It’s a remarkable ability to see a relationship between two separate objects that isn’t always apparent.

But it’s not just sight. Although I’ve always loved music, it wasn’t until my own kids were in a band that I found the ability to break it down, removing the other instruments. It brings a remarkable clarity to suddenly hearing my daughter on the marimba, or son on the flute. Even with 70 other instrument playing around them.

You can try it yourself, listening to Keith Moon’s amazing drums on The Who’s “5:15.” Or in Bob Seger’s “Fire Lake.” Take out Seger and the instruments and you suddenly realize it’s the Eagles doing the background singing.

In Carly Simon’s “You’re So Vain,” a song you generally don’t attribute to the Rolling Stones, a little bit of focus will reveal Mick Jagger’s distinctive voice in the background chorus of “Don’t you, don’t you, don’t you?”

The ability isn’t something we created. It was there from our ancestors in the trees and caves. They used this ability to identify friend from foe, find the right path home, and pick out what was edible from what was poisonous. Like with so many other things, and without realizing it, our brains have retooled it for the world we now face, even if it’s just to find our car in the parking lot.

Sodium, calcium, potassium, and other ions flow in and out of nerve cells, an electrical impulse propagates though a network, matching incoming sounds and images to ones previously stored. That’s all it is, but the results are remarkable.

We take the everyday for granted, but should stop and think how amazing it really is.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

After 26 years in practice, there are still things about the brain that amaze me, often that I first notice on myself.

Filtering (I guess “selective attention” sounds better) is one of them. We don’t notice it, but it’s definitely there.

Working at a jigsaw puzzle, I find myself looking for a specific piece, say, a white tab with a dark background and yellow stripe in the center. There may be several hundred pieces spread around me at the table, but the brain quickly starts filtering them out. In a fraction of a second I only notice ones with a white tab, then mentally those are broken down by the other characteristics. If it looks promising, I’ll look back at the space I’m trying to fit it in, mentally rotate the piece (another tricky thing if you think about it) and, if that seems to match, will pick up the piece to try. If it doesn’t fit the process repeats.

Block_Allan_M_AZ_web.JPG

It’s a remarkable ability to see a relationship between two separate objects that isn’t always apparent.

But it’s not just sight. Although I’ve always loved music, it wasn’t until my own kids were in a band that I found the ability to break it down, removing the other instruments. It brings a remarkable clarity to suddenly hearing my daughter on the marimba, or son on the flute. Even with 70 other instrument playing around them.

You can try it yourself, listening to Keith Moon’s amazing drums on The Who’s “5:15.” Or in Bob Seger’s “Fire Lake.” Take out Seger and the instruments and you suddenly realize it’s the Eagles doing the background singing.

In Carly Simon’s “You’re So Vain,” a song you generally don’t attribute to the Rolling Stones, a little bit of focus will reveal Mick Jagger’s distinctive voice in the background chorus of “Don’t you, don’t you, don’t you?”

The ability isn’t something we created. It was there from our ancestors in the trees and caves. They used this ability to identify friend from foe, find the right path home, and pick out what was edible from what was poisonous. Like with so many other things, and without realizing it, our brains have retooled it for the world we now face, even if it’s just to find our car in the parking lot.

Sodium, calcium, potassium, and other ions flow in and out of nerve cells, an electrical impulse propagates though a network, matching incoming sounds and images to ones previously stored. That’s all it is, but the results are remarkable.

We take the everyday for granted, but should stop and think how amazing it really is.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

Novel, noninvasive testing is able to predict dementia onset with 80% accuracy up to 9 years before clinical diagnosis.

The results suggest resting-state functional MRI (rs-fMRI) could be used to identify a neural network signature of dementia risk early in the pathological course of the disease, an important advance as disease-modifying drugs such as those targeting amyloid beta are now becoming available.

“The brain has been changing for a long time before people get symptoms of dementia, and if we’re very precise about how we do it, we can actually, in principle, detect those changes, which could be really exciting,” study investigator Charles R. Marshall, PhD, professor of clinical neurology, Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, England, told this news organization.

“This could become a platform for screening people for risk status in the future, and it could one day make all the difference in terms of being able to prevent dementia,” he added.

The findings were published online in Nature Mental Health.

The rs-fMRI measures fluctuations in blood oxygen level–dependent signals across the brain, which reflect functional connectivity.

Brain regions commonly implicated in altered functional connectivity in Alzheimer’s disease (AD) are within the default-mode network (DMN). This is the group of regions “connecting with each other and communicating with each other when someone is just lying in an MRI scanner doing nothing, which is how it came to be called the default-mode network,” explained Dr. Marshall.

The DMN encompasses the medial prefrontal cortex, posterior cingulate cortex or precuneus, and bilateral inferior parietal cortices, as well as supplementary brain regions including the medial temporal lobes and temporal poles.

This network is believed to be selectively vulnerable to AD neuropathology. “Something about that network starts to be disrupted in the very earliest stages of Alzheimer’s disease,” said Dr. Marshall.

While this has been known for some time, “what we’ve not been able to do before is build a precise enough model of how the network is connected to be able to tell whether individual participants were going to get dementia or not,” he added.

The investigators used data from the UK Biobank, a large-scale biomedical database and research resource containing genetic and health information from about a half a million UK volunteer participants.

The analysis included 103 individuals with dementia (22 with prevalent dementia and 81 later diagnosed with dementia over a median of 3.7 years) and 1030 matched participants without dementia. All participants had MRI imaging between 2006 and 2010.

The total sample had a mean age of 70.4 years at the time of MRI data acquisition. For each participant, researchers extracted relevant data from 10 predefined regions of interest in the brain, which together defined their DMN. This included two midline regions and four regions in each hemisphere.
 

Greater Predictive Power

Researchers built a model using an approach related to how brain regions communicate with each other. “The model sort of incorporates what we know about how the changes that you see on a functional MRI scan relate to changes in the firing of brain cells, in a very precise way,” said Dr. Marshall.

The researchers then used a machine learning approach to develop a model for effective connectivity, which describes the causal influence of one brain region over another. “We trained a machine learning tool to recognize what a dementia-like pattern of connectivity looks like,” said Dr. Marshall.

Investigators controlled for potential confounders, including age, sex, handedness, in-scanner head motion, and geographical location of data acquisition.

The model was able to determine the difference in brain connectivity patterns between those who would go on to develop dementia and those who would not, with an accuracy of 82% up to 9 years before an official diagnosis was made.

When the researchers trained a model to use brain connections to predict time to diagnosis, the predicted time to diagnosis and actual time to diagnosis were within about 2 years.

This effective connectivity approach has much more predictive power than memory test scores or brain structural measures, said Dr. Marshall. “We looked at brain volumes and they performed very poorly, only just better than tossing a coin, and the same with cognitive test scores, which were only just better than chance.”

As for markers of amyloid beta and tau in the brain, these are “very useful diagnostically” but only when someone has symptoms, said Dr. Marshall. He noted people live for years with these proteins without developing dementia symptoms.

“We wouldn’t necessarily want to expose somebody who has a brain full of amyloid but was not going to get symptoms for the next 20 years to a treatment, but if we knew that person was highly likely to develop symptoms of dementia in the next 5 years, then we probably would,” he said.

Dr. Marshall believes the predictive power of all these diagnostic tools could be boosted if they were used together.
 

Potential for Early Detection, Treatment

Researchers examined a number of modifiable dementia risk factors, including hearing loss, depression, hypertension, and physical inactivity. They found self-reported social isolation was the only variable that showed a significant association with effective connectivity, meaning those who are socially isolated were more likely to have a “dementia-like” pattern of DMN effective connectivity. This finding suggests social isolation is a cause, rather than a consequence, of dementia.

The study also revealed associations between DMN effective connectivity and AD polygenic risk score, derived from meta-analysis of multiple external genome-wide association study sources.

A predictive tool that uses rs-fMRI could also help select participants at a high risk for dementia to investigate potential treatments. “There’s good reason to think that if we could go in earlier with, for example, anti-amyloid treatments, they’re more likely to be effective,” said Dr. Marshall.

The new test might eventually have value as a population screening tool, something akin to colon cancer screening, he added. “We don’t send everyone for a colonoscopy; you do a kind of pre-screening test at home, and if that’s positive, then you get called in for a colonoscopy.”

The researchers looked at all-cause dementia and not just AD because dementia subtype diagnoses in the UK Biobank “are not at all reliable,” said Dr. Marshall.

Study limitations included the fact that UK Biobank participants are healthier and less socioeconomically deprived than the general population and are predominantly White. Another study limitation was that labeling of cases and controls depended on clinician coding rather than on standardized diagnostic criteria.
 

Kudos, Caveats

In a release from the Science Media Center, a nonprofit organization promoting voices and views of the scientific community, Sebastian Walsh, National Institute for Health and Care Research doctoral fellow in Public Health Medicine, University of Cambridge, Cambridge, England, said the results are “potentially exciting,” and he praised the way the team conducted the study.

However, he noted some caveats, including the small sample size, with only about 100 people with dementia, and the relatively short time between the brain scan and diagnosis (an average of 3.7 years).

Dr. Walsh emphasized the importance of replicating the findings “in bigger samples with a much longer delay between scan and onset of cognitive symptoms.”

He also noted the average age of study participants was 70 years, whereas the average age at which individuals in the United Kingdom develop dementia is mid to late 80s, “so we need to see these results repeated for more diverse and older samples.”

He also noted that MRI scans are expensive, and the approach used in the study needs “a high-quality scan which requires people to keep their head still.”

Also commenting, Andrew Doig, PhD, professor, Division of Neuroscience, the University of Manchester, Manchester, England, said the MRI connectivity method used in the study might form part of a broader diagnostic approach.

“Dementia is a complex condition, and it is unlikely that we will ever find one simple test that can accurately diagnose it,” Dr. Doig noted. “Within a few years, however, there is good reason to believe that we will be routinely testing for dementia in middle-aged people, using a combination of methods, such as a blood test, followed by imaging.”

“The MRI connectivity method described here could form part of this diagnostic platform. We will then have an excellent understanding of which people are likely to benefit most from the new generation of dementia drugs,” he said.

Dr. Marshall and Dr. Walsh reported no relevant disclosures. Dr. Doig reported that he is a founder, shareholder, and consultant for PharmaKure Ltd, which is developing new diagnostics for neurodegenerative diseases using blood biomarkers.

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

Novel, noninvasive testing is able to predict dementia onset with 80% accuracy up to 9 years before clinical diagnosis.

The results suggest resting-state functional MRI (rs-fMRI) could be used to identify a neural network signature of dementia risk early in the pathological course of the disease, an important advance as disease-modifying drugs such as those targeting amyloid beta are now becoming available.

“The brain has been changing for a long time before people get symptoms of dementia, and if we’re very precise about how we do it, we can actually, in principle, detect those changes, which could be really exciting,” study investigator Charles R. Marshall, PhD, professor of clinical neurology, Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, England, told this news organization.

“This could become a platform for screening people for risk status in the future, and it could one day make all the difference in terms of being able to prevent dementia,” he added.

The findings were published online in Nature Mental Health.

The rs-fMRI measures fluctuations in blood oxygen level–dependent signals across the brain, which reflect functional connectivity.

Brain regions commonly implicated in altered functional connectivity in Alzheimer’s disease (AD) are within the default-mode network (DMN). This is the group of regions “connecting with each other and communicating with each other when someone is just lying in an MRI scanner doing nothing, which is how it came to be called the default-mode network,” explained Dr. Marshall.

The DMN encompasses the medial prefrontal cortex, posterior cingulate cortex or precuneus, and bilateral inferior parietal cortices, as well as supplementary brain regions including the medial temporal lobes and temporal poles.

This network is believed to be selectively vulnerable to AD neuropathology. “Something about that network starts to be disrupted in the very earliest stages of Alzheimer’s disease,” said Dr. Marshall.

While this has been known for some time, “what we’ve not been able to do before is build a precise enough model of how the network is connected to be able to tell whether individual participants were going to get dementia or not,” he added.

The investigators used data from the UK Biobank, a large-scale biomedical database and research resource containing genetic and health information from about a half a million UK volunteer participants.

The analysis included 103 individuals with dementia (22 with prevalent dementia and 81 later diagnosed with dementia over a median of 3.7 years) and 1030 matched participants without dementia. All participants had MRI imaging between 2006 and 2010.

The total sample had a mean age of 70.4 years at the time of MRI data acquisition. For each participant, researchers extracted relevant data from 10 predefined regions of interest in the brain, which together defined their DMN. This included two midline regions and four regions in each hemisphere.
 

Greater Predictive Power

Researchers built a model using an approach related to how brain regions communicate with each other. “The model sort of incorporates what we know about how the changes that you see on a functional MRI scan relate to changes in the firing of brain cells, in a very precise way,” said Dr. Marshall.

The researchers then used a machine learning approach to develop a model for effective connectivity, which describes the causal influence of one brain region over another. “We trained a machine learning tool to recognize what a dementia-like pattern of connectivity looks like,” said Dr. Marshall.

Investigators controlled for potential confounders, including age, sex, handedness, in-scanner head motion, and geographical location of data acquisition.

The model was able to determine the difference in brain connectivity patterns between those who would go on to develop dementia and those who would not, with an accuracy of 82% up to 9 years before an official diagnosis was made.

When the researchers trained a model to use brain connections to predict time to diagnosis, the predicted time to diagnosis and actual time to diagnosis were within about 2 years.

This effective connectivity approach has much more predictive power than memory test scores or brain structural measures, said Dr. Marshall. “We looked at brain volumes and they performed very poorly, only just better than tossing a coin, and the same with cognitive test scores, which were only just better than chance.”

As for markers of amyloid beta and tau in the brain, these are “very useful diagnostically” but only when someone has symptoms, said Dr. Marshall. He noted people live for years with these proteins without developing dementia symptoms.

“We wouldn’t necessarily want to expose somebody who has a brain full of amyloid but was not going to get symptoms for the next 20 years to a treatment, but if we knew that person was highly likely to develop symptoms of dementia in the next 5 years, then we probably would,” he said.

Dr. Marshall believes the predictive power of all these diagnostic tools could be boosted if they were used together.
 

Potential for Early Detection, Treatment

Researchers examined a number of modifiable dementia risk factors, including hearing loss, depression, hypertension, and physical inactivity. They found self-reported social isolation was the only variable that showed a significant association with effective connectivity, meaning those who are socially isolated were more likely to have a “dementia-like” pattern of DMN effective connectivity. This finding suggests social isolation is a cause, rather than a consequence, of dementia.

The study also revealed associations between DMN effective connectivity and AD polygenic risk score, derived from meta-analysis of multiple external genome-wide association study sources.

A predictive tool that uses rs-fMRI could also help select participants at a high risk for dementia to investigate potential treatments. “There’s good reason to think that if we could go in earlier with, for example, anti-amyloid treatments, they’re more likely to be effective,” said Dr. Marshall.

The new test might eventually have value as a population screening tool, something akin to colon cancer screening, he added. “We don’t send everyone for a colonoscopy; you do a kind of pre-screening test at home, and if that’s positive, then you get called in for a colonoscopy.”

The researchers looked at all-cause dementia and not just AD because dementia subtype diagnoses in the UK Biobank “are not at all reliable,” said Dr. Marshall.

Study limitations included the fact that UK Biobank participants are healthier and less socioeconomically deprived than the general population and are predominantly White. Another study limitation was that labeling of cases and controls depended on clinician coding rather than on standardized diagnostic criteria.
 

Kudos, Caveats

In a release from the Science Media Center, a nonprofit organization promoting voices and views of the scientific community, Sebastian Walsh, National Institute for Health and Care Research doctoral fellow in Public Health Medicine, University of Cambridge, Cambridge, England, said the results are “potentially exciting,” and he praised the way the team conducted the study.

However, he noted some caveats, including the small sample size, with only about 100 people with dementia, and the relatively short time between the brain scan and diagnosis (an average of 3.7 years).

Dr. Walsh emphasized the importance of replicating the findings “in bigger samples with a much longer delay between scan and onset of cognitive symptoms.”

He also noted the average age of study participants was 70 years, whereas the average age at which individuals in the United Kingdom develop dementia is mid to late 80s, “so we need to see these results repeated for more diverse and older samples.”

He also noted that MRI scans are expensive, and the approach used in the study needs “a high-quality scan which requires people to keep their head still.”

Also commenting, Andrew Doig, PhD, professor, Division of Neuroscience, the University of Manchester, Manchester, England, said the MRI connectivity method used in the study might form part of a broader diagnostic approach.

“Dementia is a complex condition, and it is unlikely that we will ever find one simple test that can accurately diagnose it,” Dr. Doig noted. “Within a few years, however, there is good reason to believe that we will be routinely testing for dementia in middle-aged people, using a combination of methods, such as a blood test, followed by imaging.”

“The MRI connectivity method described here could form part of this diagnostic platform. We will then have an excellent understanding of which people are likely to benefit most from the new generation of dementia drugs,” he said.

Dr. Marshall and Dr. Walsh reported no relevant disclosures. Dr. Doig reported that he is a founder, shareholder, and consultant for PharmaKure Ltd, which is developing new diagnostics for neurodegenerative diseases using blood biomarkers.

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

Novel, noninvasive testing is able to predict dementia onset with 80% accuracy up to 9 years before clinical diagnosis.

The results suggest resting-state functional MRI (rs-fMRI) could be used to identify a neural network signature of dementia risk early in the pathological course of the disease, an important advance as disease-modifying drugs such as those targeting amyloid beta are now becoming available.

“The brain has been changing for a long time before people get symptoms of dementia, and if we’re very precise about how we do it, we can actually, in principle, detect those changes, which could be really exciting,” study investigator Charles R. Marshall, PhD, professor of clinical neurology, Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, England, told this news organization.

“This could become a platform for screening people for risk status in the future, and it could one day make all the difference in terms of being able to prevent dementia,” he added.

The findings were published online in Nature Mental Health.

The rs-fMRI measures fluctuations in blood oxygen level–dependent signals across the brain, which reflect functional connectivity.

Brain regions commonly implicated in altered functional connectivity in Alzheimer’s disease (AD) are within the default-mode network (DMN). This is the group of regions “connecting with each other and communicating with each other when someone is just lying in an MRI scanner doing nothing, which is how it came to be called the default-mode network,” explained Dr. Marshall.

The DMN encompasses the medial prefrontal cortex, posterior cingulate cortex or precuneus, and bilateral inferior parietal cortices, as well as supplementary brain regions including the medial temporal lobes and temporal poles.

This network is believed to be selectively vulnerable to AD neuropathology. “Something about that network starts to be disrupted in the very earliest stages of Alzheimer’s disease,” said Dr. Marshall.

While this has been known for some time, “what we’ve not been able to do before is build a precise enough model of how the network is connected to be able to tell whether individual participants were going to get dementia or not,” he added.

The investigators used data from the UK Biobank, a large-scale biomedical database and research resource containing genetic and health information from about a half a million UK volunteer participants.

The analysis included 103 individuals with dementia (22 with prevalent dementia and 81 later diagnosed with dementia over a median of 3.7 years) and 1030 matched participants without dementia. All participants had MRI imaging between 2006 and 2010.

The total sample had a mean age of 70.4 years at the time of MRI data acquisition. For each participant, researchers extracted relevant data from 10 predefined regions of interest in the brain, which together defined their DMN. This included two midline regions and four regions in each hemisphere.
 

Greater Predictive Power

Researchers built a model using an approach related to how brain regions communicate with each other. “The model sort of incorporates what we know about how the changes that you see on a functional MRI scan relate to changes in the firing of brain cells, in a very precise way,” said Dr. Marshall.

The researchers then used a machine learning approach to develop a model for effective connectivity, which describes the causal influence of one brain region over another. “We trained a machine learning tool to recognize what a dementia-like pattern of connectivity looks like,” said Dr. Marshall.

Investigators controlled for potential confounders, including age, sex, handedness, in-scanner head motion, and geographical location of data acquisition.

The model was able to determine the difference in brain connectivity patterns between those who would go on to develop dementia and those who would not, with an accuracy of 82% up to 9 years before an official diagnosis was made.

When the researchers trained a model to use brain connections to predict time to diagnosis, the predicted time to diagnosis and actual time to diagnosis were within about 2 years.

This effective connectivity approach has much more predictive power than memory test scores or brain structural measures, said Dr. Marshall. “We looked at brain volumes and they performed very poorly, only just better than tossing a coin, and the same with cognitive test scores, which were only just better than chance.”

As for markers of amyloid beta and tau in the brain, these are “very useful diagnostically” but only when someone has symptoms, said Dr. Marshall. He noted people live for years with these proteins without developing dementia symptoms.

“We wouldn’t necessarily want to expose somebody who has a brain full of amyloid but was not going to get symptoms for the next 20 years to a treatment, but if we knew that person was highly likely to develop symptoms of dementia in the next 5 years, then we probably would,” he said.

Dr. Marshall believes the predictive power of all these diagnostic tools could be boosted if they were used together.
 

Potential for Early Detection, Treatment

Researchers examined a number of modifiable dementia risk factors, including hearing loss, depression, hypertension, and physical inactivity. They found self-reported social isolation was the only variable that showed a significant association with effective connectivity, meaning those who are socially isolated were more likely to have a “dementia-like” pattern of DMN effective connectivity. This finding suggests social isolation is a cause, rather than a consequence, of dementia.

The study also revealed associations between DMN effective connectivity and AD polygenic risk score, derived from meta-analysis of multiple external genome-wide association study sources.

A predictive tool that uses rs-fMRI could also help select participants at a high risk for dementia to investigate potential treatments. “There’s good reason to think that if we could go in earlier with, for example, anti-amyloid treatments, they’re more likely to be effective,” said Dr. Marshall.

The new test might eventually have value as a population screening tool, something akin to colon cancer screening, he added. “We don’t send everyone for a colonoscopy; you do a kind of pre-screening test at home, and if that’s positive, then you get called in for a colonoscopy.”

The researchers looked at all-cause dementia and not just AD because dementia subtype diagnoses in the UK Biobank “are not at all reliable,” said Dr. Marshall.

Study limitations included the fact that UK Biobank participants are healthier and less socioeconomically deprived than the general population and are predominantly White. Another study limitation was that labeling of cases and controls depended on clinician coding rather than on standardized diagnostic criteria.
 

Kudos, Caveats

In a release from the Science Media Center, a nonprofit organization promoting voices and views of the scientific community, Sebastian Walsh, National Institute for Health and Care Research doctoral fellow in Public Health Medicine, University of Cambridge, Cambridge, England, said the results are “potentially exciting,” and he praised the way the team conducted the study.

However, he noted some caveats, including the small sample size, with only about 100 people with dementia, and the relatively short time between the brain scan and diagnosis (an average of 3.7 years).

Dr. Walsh emphasized the importance of replicating the findings “in bigger samples with a much longer delay between scan and onset of cognitive symptoms.”

He also noted the average age of study participants was 70 years, whereas the average age at which individuals in the United Kingdom develop dementia is mid to late 80s, “so we need to see these results repeated for more diverse and older samples.”

He also noted that MRI scans are expensive, and the approach used in the study needs “a high-quality scan which requires people to keep their head still.”

Also commenting, Andrew Doig, PhD, professor, Division of Neuroscience, the University of Manchester, Manchester, England, said the MRI connectivity method used in the study might form part of a broader diagnostic approach.

“Dementia is a complex condition, and it is unlikely that we will ever find one simple test that can accurately diagnose it,” Dr. Doig noted. “Within a few years, however, there is good reason to believe that we will be routinely testing for dementia in middle-aged people, using a combination of methods, such as a blood test, followed by imaging.”

“The MRI connectivity method described here could form part of this diagnostic platform. We will then have an excellent understanding of which people are likely to benefit most from the new generation of dementia drugs,” he said.

Dr. Marshall and Dr. Walsh reported no relevant disclosures. Dr. Doig reported that he is a founder, shareholder, and consultant for PharmaKure Ltd, which is developing new diagnostics for neurodegenerative diseases using blood biomarkers.

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

TOPLINE:

Taking antidepressants in midlife was not associated with an increased risk of subsequent Alzheimer’s disease (AD) or AD-related dementias (ADRD), data from a large prospective study of US veterans show.

METHODOLOGY:

• Investigators analyzed data from 35,200 US veterans aged ≥ 55 years diagnosed with major depressive disorder from January 1, 2000, to June 1, 2022, and followed them for ≤ 20 years to track subsequent AD/ADRD diagnoses.
• Health information was pulled from electronic health records of the Veterans Health Administration (VHA) Corporate Data Warehouse, and veterans had to be at the VHA for ≥ 1 year before diagnosis.
• Participants were considered to be exposed to an antidepressant when a prescription lasted ≥ 3 months.

TAKEAWAY:

• A total of 32,500 individuals were diagnosed with MDD. The mean age was 65 years, and 91% were men. 17,000 patients received antidepressants for a median duration of 4 years. Median follow-up time was 3.2 years.
• There was no significant association between antidepressant exposure and the risk for AD/ADRD (events = 1056; hazard ratio, 0.93; 95% CI, 0.80-1.08) vs no exposure.
• In a subgroup analysis, investigators found no significant link between different classes of antidepressants and dementia risk. These included selective serotonin reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors.
• Investigators emphasized the need for further research, particularly in populations with a larger representation of female patients.

IN PRACTICE:

“A possibility for the conflicting results in retrospective studies is that the heightened risk identified in participants on antidepressants may be attributed to depression itself, rather than the result of a potential pharmacological action. So, this and other clinical confounding factors need to be taken into account,” the investigators noted.

SOURCE:

The study was led by Jaime Ramos-Cejudo, PhD, VA Boston Healthcare System, Boston. It was published online May 8 in Alzheimer’s & Dementia.

LIMITATIONS:

The cohort’s relatively young age limited the number of dementia cases captured. Data from supplemental insurance, including Medicare, were not included, potentially limiting outcome capture.

DISCLOSURES:

The study was supported by the National Institutes of Health and the National Alzheimer’s Coordinating Center. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Taking antidepressants in midlife was not associated with an increased risk of subsequent Alzheimer’s disease (AD) or AD-related dementias (ADRD), data from a large prospective study of US veterans show.

METHODOLOGY:

• Investigators analyzed data from 35,200 US veterans aged ≥ 55 years diagnosed with major depressive disorder from January 1, 2000, to June 1, 2022, and followed them for ≤ 20 years to track subsequent AD/ADRD diagnoses.
• Health information was pulled from electronic health records of the Veterans Health Administration (VHA) Corporate Data Warehouse, and veterans had to be at the VHA for ≥ 1 year before diagnosis.
• Participants were considered to be exposed to an antidepressant when a prescription lasted ≥ 3 months.

TAKEAWAY:

• A total of 32,500 individuals were diagnosed with MDD. The mean age was 65 years, and 91% were men. 17,000 patients received antidepressants for a median duration of 4 years. Median follow-up time was 3.2 years.
• There was no significant association between antidepressant exposure and the risk for AD/ADRD (events = 1056; hazard ratio, 0.93; 95% CI, 0.80-1.08) vs no exposure.
• In a subgroup analysis, investigators found no significant link between different classes of antidepressants and dementia risk. These included selective serotonin reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors.
• Investigators emphasized the need for further research, particularly in populations with a larger representation of female patients.

IN PRACTICE:

“A possibility for the conflicting results in retrospective studies is that the heightened risk identified in participants on antidepressants may be attributed to depression itself, rather than the result of a potential pharmacological action. So, this and other clinical confounding factors need to be taken into account,” the investigators noted.

SOURCE:

The study was led by Jaime Ramos-Cejudo, PhD, VA Boston Healthcare System, Boston. It was published online May 8 in Alzheimer’s & Dementia.

LIMITATIONS:

The cohort’s relatively young age limited the number of dementia cases captured. Data from supplemental insurance, including Medicare, were not included, potentially limiting outcome capture.

DISCLOSURES:

The study was supported by the National Institutes of Health and the National Alzheimer’s Coordinating Center. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Taking antidepressants in midlife was not associated with an increased risk of subsequent Alzheimer’s disease (AD) or AD-related dementias (ADRD), data from a large prospective study of US veterans show.

METHODOLOGY:

• Investigators analyzed data from 35,200 US veterans aged ≥ 55 years diagnosed with major depressive disorder from January 1, 2000, to June 1, 2022, and followed them for ≤ 20 years to track subsequent AD/ADRD diagnoses.
• Health information was pulled from electronic health records of the Veterans Health Administration (VHA) Corporate Data Warehouse, and veterans had to be at the VHA for ≥ 1 year before diagnosis.
• Participants were considered to be exposed to an antidepressant when a prescription lasted ≥ 3 months.

TAKEAWAY:

• A total of 32,500 individuals were diagnosed with MDD. The mean age was 65 years, and 91% were men. 17,000 patients received antidepressants for a median duration of 4 years. Median follow-up time was 3.2 years.
• There was no significant association between antidepressant exposure and the risk for AD/ADRD (events = 1056; hazard ratio, 0.93; 95% CI, 0.80-1.08) vs no exposure.
• In a subgroup analysis, investigators found no significant link between different classes of antidepressants and dementia risk. These included selective serotonin reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors.
• Investigators emphasized the need for further research, particularly in populations with a larger representation of female patients.

IN PRACTICE:

“A possibility for the conflicting results in retrospective studies is that the heightened risk identified in participants on antidepressants may be attributed to depression itself, rather than the result of a potential pharmacological action. So, this and other clinical confounding factors need to be taken into account,” the investigators noted.

SOURCE:

The study was led by Jaime Ramos-Cejudo, PhD, VA Boston Healthcare System, Boston. It was published online May 8 in Alzheimer’s & Dementia.

LIMITATIONS:

The cohort’s relatively young age limited the number of dementia cases captured. Data from supplemental insurance, including Medicare, were not included, potentially limiting outcome capture.

DISCLOSURES:

The study was supported by the National Institutes of Health and the National Alzheimer’s Coordinating Center. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.