Population Studies & Health Disparities

NIH population studies reveal new links to brain changes associated with Alzheimer’s and related dementias

Dementia-related brain changes can start a decade or more before a person experiences symptoms and may result from a complex interplay among abnormal tau and beta-amyloid proteins and several other factors. Recent results from the following NIH-funded studies shed more light on how brain health in general affects the risk of developing Alzheimer’s disease:

• People who have Alzheimer’s often have multiple types of brain lesions , and this is more common in people with worse symptoms of dementia. Data from 5,272 individuals from the National Alzheimer’s Coordinating Center showed that most people with Alzheimer’s have both brain changes that are specific to the disease, such as tau tangles and amyloid plaques in the case of Alzheimer’s, and brain changes more commonly associated with other related dementias.
• People who have a stroke that is moderate or severe or who have multiple strokes may have a significantly higher risk of dementia than people who have had a mild stroke . According to data from more than 1,000 participants in the NIH-funded Atherosclerosis Risk in Communities cohort study, people who have two or more moderate or severe strokes are almost seven times more likely to develop dementia than people who have not had a stroke. Having a stroke before age 75 can also significantly raise the risk of dementia. The findings emphasize the importance of stroke prevention as a means of mitigating dementia risk.
• People who develop mental disorders early in life have an increased risk of all types of dementia and of developing dementia at a younger age . These findings, obtained from an analysis of hospitalization records for 1.7 million individuals from New Zealand’s national health system, suggest that effectively treating mental disorders earlier in life may lower the risk of developing dementia.

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NIH funding helps to unravel links between dementia and COVID-19 and other infectious diseases

NIH is playing a critical role in COVID-19 response efforts concerning older adults, who are at a much greater risk of severe illness and death from this infectious disease. In 2021, an NIA-funded study based on the electronic health records of about 61.9 million U.S. adults from all 50 states showed that people with any type of dementia have twice the risk of getting COVID-19 than people without dementia do. People with dementia are also more likely to have severe or fatal cases of COVID-19, and this risk is even higher for Black people living with dementia.

Current NIA and National Institute of Neurological Disorders and Stroke (NINDS) studies are expanding our knowledge of how COVID-19 affects brain health in older adults with and without dementia, including the effects of prolonged symptoms of COVID-19, technically called post-acute sequelae of SARS-CoV-2 infection (PASC) and more commonly referred to as “Long COVID.” In 2021, NIH launched the Researching COVID to Enhance Recovery (RECOVER) Initiative , a national-level, patient-centered study of national scale with thousands of diverse participants from across the lifespan, that will include research into the disease’s effects on cognition, cognitive decline, and dementia.

NIA has also funded a number of research projects on whether viral infections and other microbial pathogens contribute to Alzheimer’s. NIA held a workshop on the infectious etiology of Alzheimer’s in 2021. Additionally, in a study partially funded by NIA, researchers discovered a link between mononucleosis and Alzheimer’s .

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NIH-funded population studies analyze genetic risk factors for Alzheimer’s

The NIA Alzheimer’s Disease Genetics Portfolio supports research to identify genes that raise or lower the risk of Alzheimer’s and to understand how these genes influence the processes in cells that lead to the disease.

To date, scientists have identified more than 70 genetic regions associated with Alzheimer’s.

The APOE4 gene variant has been found to be one of the most significant genetic risk factors for Alzheimer’s; however, the link between APOE4 and Alzheimer’s risk differs between racial and ethnic groups. For example, an NIA-supported study published in 2022 found that the APOE4 variant is not linked to dementia-related brain changes or cognitive impairment in American Indians .

APOE4 is linked with Alzheimer’s risk in people of African ancestry, but not to the same degree as in people of European ancestry . A recent study helps explain why this may be the case. It found that people of European ancestry have higher levels of APOE4 protein in their brains than people of African ancestry . The authors think that the region around the APOE4 gene differs by ancestry and controls how much APOE protein is made. These findings and the critical nuances in APOE4 and disease risk by population group underscore the importance of studying Alzheimer’s in diverse populations.

• In people of European ancestry, an Alzheimer’s polygenic risk score (an estimate of a person’s risk of Alzheimer’s based on many known genetic risk factors) gives an accurate estimate of the risk for the disease. However, the risk score, which was produced from studies involving mostly people of European ancestry, was not a good predictor in people of African ancestry. This highlights the importance of more diverse population studies in order to determine specific genetic risk factors across racial and ethnic groups and create polygenic risk scores that apply to people of non-European ancestry.
• Specific regions of DNA may control the levels of proteins linked to neurological disorders in various tissue types. Proteins that are controlled by the same regions of DNA may work together in a biological process to raise or lower a person’s risk of dementia .
• A new technique examines how changes to a gene will affect the 3D structure of proteins made from that gene , which can help scientists identify rare gene variants linked to Alzheimer’s. Using the new method, researchers identified new variants of four genes, two of which (TREM2 and SORL1) are known to be linked to the disease. The other two are CSF1R, which has been suggested but not confirmed as contributing to Alzheimer’s, and EXOC3L4, a novel Alzheimer’s risk gene. Because changes to a protein’s structure can interfere with its function, studying these gene variants can help researchers understand the roles these genes play in raising the risk of dementia and how to use this information to develop new therapeutic targets.

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Health disparities negatively affect dementia diagnosis and care

Following specific priorities identified using its Health Disparities Research Framework , NIA has awarded grants to explore the environmental, sociocultural, behavioral, and biological determinants of health disparities related to aging. In 2021, findings from these studies underscored the following.

• Among people who participate in research studies on Alzheimer’s, Black participants with symptoms of the disease are less likely than White participants to have received a clinical diagnosis of Alzheimer’s than White participants . Additionally, Black participants with Alzheimer’s have more risk factors for the disease and more severe symptoms than White participants do. Another study showed that racial disparities in dementia prevalence between Black and White individuals did not improve from 2000 to 2016 .
• Although researchers found that more people living with dementia received a dementia diagnosis from 2006 to 2013, the condition is still underdiagnosed in Black and Hispanic individuals , highlighting the need for improved diagnostic methods among racial and ethnic minority populations. In this study, researchers compared the number of people diagnosed with dementia using three sources of data: cognitive tests, detailed neuropsychological tests, and diagnosis codes from Medicare claims. They found that over the years, the difference in estimated prevalence of dementia from these three data sources has lessened, showing that dementia underdiagnosis is decreasing overall.
• Compared with older adults living in urban areas, older adults who live in rural communities are less likely to receive a clinical diagnosis of Alzheimer’s or a related dementia, are often diagnosed at later stages of dementia, and have a shorter survival time after diagnosis . Increased measures to promote dementia screening in rural areas could help address these disparities.
• People who do not have easy access to primary care have a higher risk of cognitive impairment . Improving health care access may help lower the risk of cognitive decline and dementia.

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Program update: An NIH genomics data program enables population studies around the world

NIH established the Alzheimer’s Disease Sequencing Project (ADSP) in 2012 to sequence and analyze genomic data from large Alzheimer’s studies conducted worldwide. The overarching goals in 2022 are to:

• Identify new gene variants that increase the risk of Alzheimer’s and related dementias
• Identify gene variants that protect against dementia
• Provide insights into why some people with known risk factor genes do not develop dementia symptoms
• Identify potential avenues for therapeutic approaches to prevent or treat dementias
• Examine all of these factors in diverse populations

ADSP data have revealed several potential genetic risk or protective factors for Alzheimer’s. For example, in 2021, researchers found that although genome-wide association studies and family-based studies often identify different sets of Alzheimer’s-related genes, many of these genes function in the same or similar processes in brain cells . This strengthens the evidence for the involvement of specific underlying processes in the disease. To understand how these and other gene variants lead to Alzheimer’s, NIA funded six projects in 2021 through the ADSP Functional Genomics Consortium , which will utilize a multipronged team science strategy and large-scale, high-throughput approaches.

Also in 2021, ADSP researchers launched two important initiatives:

• The Phenotype Harmonization Consortium is a major effort to combine and organize clinical data from all ADSP studies and share these data with the research community, with the goal of stimulating new drug development. The consortium’s efforts will improve the usability of ADSP data and facilitate research to identify well-targeted therapeutic approaches for Alzheimer’s and related dementias.
• The ADSP Follow-Up Study 2.0: The Diverse Population Initiative will expand ADSP data to represent a more diverse population. Current ADSP data are derived mostly from White clinical study participants, and results based on these data might not be an accurate reflection of the genetic factors linked to Alzheimer’s in all populations. The new follow-up study will help researchers identify not only common gene variants but also rare variants that may play an important role in Alzheimer’s and related dementias.

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