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Population Studies and Health Disparities

Large, long-term population studies have enabled scientists to examine the influence of a spectrum of risk and protective factors for developing Alzheimer’s and related dementias. Because of scientific progress made possible by NIH investments in this research, scientists have discovered that these conditions usually develop from the combined effects of certain behaviors and lifestyle choices, as well as genetic, social, economic, educational, and environmental factors.

NIH-supported population studies are part of the overall effort to find ways to prevent and treat Alzheimer’s and related dementias. These large studies explore the health of populations over a long period of time, which helps researchers determine why some people develop these diseases while others do not.

For this research, scientists aim to involve a large group of people who represent the diversity of the U.S. population. The ongoing analysis of risk and protective factors will help precision medicine researchers develop interventions that can address underlying disease processes, as well as symptoms, and that can be tailored to a person’s unique disease risk profile.

Identifying new genetic factors for dementia

Large-scale analyses of data collected from population studies have been revealing the many possible genetic risk factors for Alzheimer’s and related dementias. These large datasets have enabled the discovery and analysis of many genetic variants. Ten years ago, we knew of only 10 genes associated with Alzheimer’s. Today scientists are studying more than 50 genes — that’s a 400% advancement in this area!

NIH’s Genetics of Alzheimer’s Disease Portfolio supports research to discover long-term treatments for the disease by the identification of risk factor and protective genes and the underlying molecular pathways. Within this portfolio, the Alzheimer’s Disease Sequencing Project supports studies to discover genes involved in Alzheimer’s.

This project involves more than 150 international investigators at 33 institutions. Data come from more than 60 cohorts of research participants. The aim of the sequencing project is to identify — in diverse populations — genes that increase risk for Alzheimer’s and those that confer protection, as well as to provide insight into why some people with known risk factor genes do not develop the disease. Through this effort, researchers also aim to identify potential avenues to prevent and treat Alzheimer’s.

Genetic discoveries provide more possible avenues for scientific exploration into preventing and treating Alzheimer’s and related dementias. Over the past year, multiple research teams reported results from studies of genetic factors that may influence the risk of developing these diseases:

  • Potential genes for Alzheimer’s discovered: A research team reported finding 11 genes (ACE, CARHSP1, CTSH, DOC2A, ICA1L, LACTB, PLEKHA1, RTFDC1, SNX32, STX4, and STX6) that might contribute to Alzheimer’s. The team analyzed more than 8,000 proteins generated from about 400 brain samples from the NIA-supported Religious Orders Study and Memory and Aging Project (ROSMAP) and integrated results with a genetic dataset from about 72,000 people with Alzheimer’s. Scientists can build on these findings by exploring how these 11 genes might play a role in this disease.
  • APOE ε2 gene variant appears to lower risk: A recent study of more than 4,000 autopsy-confirmed Alzheimer’s cases from the NIA-funded Alzheimer’s Disease Genetics Consortium suggests that having two copies of the APOE ε2 gene variant may lower risk even more than previously thought. An improved understanding of how gene variants can be protective can help scientists develop better strategies for treatment and prevention.
  • KLOTHO gene variant and APOE ε4: Having one copy of a KLOTHO gene variant reduced the risk of Alzheimer’s among those who also had the APOE ε4 gene variant, despite the fact that APOE ε4 usually increases risk. In addition, people with one copy of the KLOTHO variant had lower levels of amyloid in the brain and spinal fluid. Data for this large-scale analysis included more than 20,000 people from these NIA-supported studies: the National Alzheimer’s Coordinating Centers, Religious Orders Study and Memory Again Project (ROSMAP), and the Alzheimer’s Disease Neuroimaging Initiative.
  • Genetic risk for Alzheimer’s among Black/African Americans: Genetic risk can differ substantially between racial and ethnic groups, and identifying the differences might partially explain health disparities. A recent study provided new insights about the biological pathways and genetic factors that contribute to the development of Alzheimer’s in Black/African Americans. The researchers also found a link between kidney system development and Alzheimer’s risk in Black/African Americans, suggesting another novel disease mechanism to explore to better understand unique differences in disease risk among ethnic groups — which is essential to developing effective treatments.
  • Genetic variants and cognitive resilience: Three genetic variants linked to cognitive resilience were identified near the ATP8B1 gene, which is involved in the process of breaking down fats to produce energy for the body. The scientists also found that the level of resilience — whether it was high or low — was associated with genetic patterns for traits related to years of education, cardiovascular disease risk, and some mental health disorders such as obsessive-compulsive disorder. For example, people with genetic traits linked to more years of education showed higher cognitive resilience.

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Exploring social and economic factors for dementia

In 2020, NIH-supported population studies found new evidence about social and economic factors linked to a decline in the ability to clearly think, learn, and remember, and linked to dementia:

  • Cognitive decline and lower wealth: A study of more than 5,000 adults in the United Kingdom found that while everyone had a decline in cognitive function over time, the largest drops occurred in people with the least wealth. These results add to the growing evidence showing that social and economic status can affect physical and mental health over time.
  • Memory loss and less education: Findings from a large sample of older adults in New York suggested that having fewer years of education is associated with worse memory later in life. This study suggests that having more years of education could play an important role in protecting the brain from age-related cognitive decline and dementia.
  • Faster memory decline among women who did not have jobs: An analysis of 6,000 women taking part in the NIA-supported Health and Retirement Study showed that women who were not in the workforce during early adulthood and midlife had faster rates of memory decline than those who were employed. This study adds to evidence that participation in the workforce may be a protective factor for cognitive health later in life.

Also during the past year, NIA invited researchers to design studies and apply for research grants to examine sex and gender differences in the risk, development, progression, diagnosis, and clinical presentation of Alzheimer’s and related dementias.

To address the economic and health impacts of these diseases with population studies, NIA has expanded long-standing investments in the demography and economics of aging to support three new centers:

Researchers at these centers examine health care delivery, quality, and disparities, as well as the role of technology diffusion and care needs of Alzheimer’s.

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Linking physical and other characteristics with dementia

Many researchers use data from population studies to analyze whether certain characteristics are common among people with dementia. Results over the past year from NIA-funded research suggest that dementia risk might be associated with many different physical factors, including:

  • Slower walking speed: An international research team led by NIA analyzed data from more than 8,000 older adults in multiple long-term studies of aging, including the NIA’s Baltimore Longitudinal Study of Aging. The team reported that people who have both a decline in memory and walking speed were at increased risk of dementia.
  • Impaired vision: An NIA-supported study of about 1,000 women showed that impaired vision may increase the risk of mild cognitive impairment or dementia.
  • Gum disease: NIA scientists analyzed data from more than 6,000 people who took part in the National Health and Nutrition Examination Survey, a large population study. The results suggest that bacteria that cause gum disease may also be associated with the development of Alzheimer’s and related dementias, especially vascular dementias.
  • Obesity: Confirming findings from other population studies, NIA-supported researchers in the United Kingdom found that participants who were overweight or obese were more likely to develop dementia.
  • Pain: A research team funded in part by NIH analyzed data from the Whitehall II study of more than 10,000 British civil servants collected over 27 years. The team reported that people who were later diagnosed with dementia had pain that was increasing rapidly in the years before cognitive decline or other obvious symptoms of dementia.

It is important to keep in mind that when a population study detects a physical characteristic that is linked to dementia, the results can suggest an association but do not prove causation. Additional research, especially through clinical trials, can provide stronger evidence.

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Examining health disparities for dementia

Before NIH can work to reduce or eliminate health disparities for Alzheimer’s and related dementias, scientists must learn more about the many factors that make certain groups more vulnerable to developing these conditions. NIH-supported discoveries have already shown that the development of dementia can be associated with race, ethnicity, sex, level of education, geography, and social and economic factors.

Not only do these research findings help NIH progress toward the goal of reducing health disparities, but research findings that explain how and why many diseases affect diverse communities in different ways are crucial for the discovery of tailored treatments and prevention methods for Alzheimer’s and related dementias.

  • DISCOVERY: NIH funds several large initiatives and research consortia with a special focus on populations that experience health disparities, including a new study called Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on RecoverY (DISCOVERY). This six-year prospective clinical research study was designed to determine the specific kinds of stroke events that cause cognitive impairment and dementia and which events do not. The investigators are studying people who have had a stroke to determine which clinical factors and conditions, along with the characteristics of the stroke itself, contribute to cognitive impairment and dementia outcomes. Because the study was designed to address these important questions in racial and ethnic minority groups, the research team is developing clinical and recruitment tools that are culturally appropriate and effective across all populations.
  • Health and Retirement Study: To further facilitate health disparities research, the NIA-funded Health and Retirement Study, a nationally representative study of more than 20,000 U.S. residents age 50 and older, added 2,000 additional racial and ethnic minority respondents.
    By continuing to diversify this cohort, researchers using Health and Retirement Study data will be better able to design studies that provide insights into potential racial/ethnic differences in the incidence, prevalence, and impact of Alzheimer’s and related dementias. Health and Retirement Study researchers gather cognitive testing results using the Harmonized Cognitive Assessment Protocol. They also collect DNA and blood samples that are critical to ensuring that the biomarkers being developed will be applicable to the widest range of people possible.
  • National Health and Aging Trends Study: NIH also increased the number of diverse participants in other studies to enhance health disparities research on other aspects of Alzheimer’s and related dementias. The nationally representative National Health and Aging Trends Study and the associated National Study of Caregiving provide data on the health and function of people in the United States age 65 and older and their caregivers.
    Supplemental funding is enabling the researchers to include an additional 2,000 Hispanic/Latino participants, primarily of Mexican and Puerto Rican origin. The researchers are collecting new cognition and health data on study participants, as well as conducting interviews with caregivers to support research on disparities in caregiving.
  • Longitudinal Aging Study in India: To foster research on cross-national disparities, NIH also supports studies in many other countries that harmonize with the NIA-funded Health and Retirement Study in the U.S. One notable example is the Longitudinal Aging Study in India (LASI), which includes the Diagnostic Assessment of Dementia (LASI-DAD). LASI’s nationally representative core study is supplemented by a sample of 4,100 community-residing older adults from 19 states in India, representing about 92% of the ethnically diverse population that receives LASI-DAD. Innovations in LASI-DAD include measurement of personal exposure to air pollution. In addition, NIA has funded the genetic study of about 2,700 participants in LASI-DAD to search for gene variants associated with Alzheimer’s and related dementias.

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Program Spotlight: NIH expands capacity for health disparities research

The NIA-funded Alzheimer’s Disease Research Center (ADRC) network has long been one of the cornerstones of NIH’s Alzheimer’s and related dementias research infrastructure. Building on the success of the ADRCs, NIA in 2020 added four new exploratory centers to the network. The new centers are enhancing research initiatives with underrepresented populations, such as Black/African Americans, Native Americans, and those in rural communities.

Map showing the location of NIA-funded ADRCs

The four centers also expand the network’s reach into new geographic areas, with locations at:

Each exploratory center is designed to address regional health disparities. In Las Vegas, researchers are collecting high-quality standardized clinical data from people in rural settings, and in Nashville, they focus on vascular risk factors among Black/African Americans. The Albuquerque center prioritizes rural communities, particularly American Indians, and in Birmingham, the focus is on people in this Deep South region, especially Black/African Americans.

Established in 1984, the ADRCs are recognized for excellence in:

  • Fostering research collaboration
  • Promoting data sharing and open science
  • Providing information and research participation opportunities for people and families most affected by Alzheimer’s and related dementias

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