Understanding Risk and Protective Factors for Dementia

NIH-funded research has uncovered many new factors that influence the risk for dementia, including genetic, environmental, sociocultural, behavioral, and other factors. Understanding how these factors affect dementia risk is leading to new strategies for risk assessment and reduction as well as identification of new therapeutic targets.

Identification of genetic risk and protective factors

In 2010, we knew of just 10 genetic areas associated with Alzheimer’s. Today, thanks in large part to the work of NIH-funded researchers, we know of at least 80 genetic areas associated with this disease. The identification of genetic risk and protective factors is important to enable better risk assessment and find new therapeutic targets.

Protective gene variants

Scientists are uncovering rare forms of genes that may help protect against Alzheimer’s, including a variant of the RELN gene called RELN-COLBOS and a variant of the APOE gene (a gene known to be associated with Alzheimer’s risk) called APOE3ch . In a recent study in mice, researchers found that APOE3ch enhances the activity of immune cells called microglia , leading to reduced tau tangle formation in the brain. Understanding how these rare variants promote dementia resilience opens new avenues for developing treatments. For example, APOE3ch-inspired antibodies are already being developed as a potential Alzheimer’s therapeutic.

Genetic factors for Alzheimer’s-related dementias

Scientists are also uncovering genetic risk factors for Alzheimer’s-related dementias. By combining cutting-edge computer algorithms with machine learning, NIH researchers identified large genetic changes , known as structural variants, that contribute to dementia risk in Lewy body dementia and frontotemporal dementia, paving the way for new research in this area. To accelerate the pace of discovery, the analysis code and data are now available to the scientific community, along with an interactive app to explore the presence of structural variants in genes of interest.

Exploring genetic factors in diverse populations

To help identify new pathways for therapeutic approaches and prevention, researchers must be sure to include representatives from diverse populations. For example, the identification of the RELN-COLBOS and APOE3ch protective variants would not have been possible without inclusion of international populations — in this case, the participation of a large extended family in Colombia with more than 6,000 members, including more than 1,200 individuals who carry a specific gene variant that causes them to develop Alzheimer’s in their 40s. Likewise, the APOE variant APOE ε3[R145C] was identified as an Alzheimer’s risk variant in adults of African ancestry and indicates a potential new biomarker for genetic risk assessment in this population. In addition, studies of closely related “genetic founder” groups can help to clarify the genetic basis for Alzheimer’s. For example, NIH-funded researchers were able to identify potential genetic risk factors for Alzheimer’s in people of Ashkenazi Jewish descent.

NIH also funds Alzheimer’s research focused on individuals with Down syndrome, who have an elevated risk of developing the disease. For example, NIH-funded Molecular Subtypes of Cognitive Impairment Cognitive impairment, which may consist of memory or thinking problems and typically precedes dementia, is itself a complex condition with multiple underlying causes. Scientists continue to make key advances in understanding this condition. NIH-funded researchers recently identified additional molecular subtypes of cognitive impairment, which may help better inform how cognitive impairment is diagnosed and lead to novel treatments in the future. researchers found that Alzheimer’s progression in Down syndrome appears similar to other genetic, early-onset forms of the disease, suggesting common disease mechanisms. This indicates that individuals with Down syndrome may benefit from participating in a broad range of studies of Alzheimer’s therapies meant to prevent and treat dementia.

Spotlight: Molecular subtypes of cognitive impairment

Cognitive impairment, which may consist of memory or thinking problems and typically precedes dementia, is itself a complex condition with multiple underlying causes. Scientists continue to make key advances in understanding this condition. NIH-funded researchers recently identified additional molecular subtypes of cognitive impairment, which may help better inform how cognitive impairment is diagnosed and lead to novel treatments in the future.

gray An association between sensory loss and dementia

Recent research studies have highlighted associations between sensory impairment and cognitive decline and dementia. For example, one NIH-funded study found that having a good sense of smell is associated with slower loss of brain volume and cognitive decline in older adults. Another found an association between vision impairment and dementia . Further, protein deposits in the retina are linked with retinal abnormalities. As noted earlier in this report, these same protein deposits may serve as a noninvasive way to detect Alzheimer’s. These findings suggest that monitoring sensory changes and addressing loss may help detect and prevent dementia. For example, NIH-funded researchers estimate that as many as 100,000 U.S. dementia cases could potentially have been prevented with improved eye care.

In addition, as also referenced in an earlier part of this report, researchers recently found that hearing aids may slow cognitive decline in some people experiencing hearing loss and who have certain risk factors for dementia.

Identifying psychological, social, behavioral, and environmental factors

Many aspects of a person’s life can affect their risk of developing dementia, including factors ranging from education, job complexity, and social status to where someone lives and more. NIH-funded researchers are discovering how these factors, collectively called the “exposome,” affect dementia.

NIH-funded studies have identified several factors associated with an increased risk of dementia, including but not limited to:

  • Exposure to air pollution , including pollution associated with agriculture and open fires. This suggests that interventions that reduce air pollution may decrease the lifelong risk of developing dementia.
  • Living in lower income neighborhoods with less green space . This finding could inform interventions targeting disadvantaged neighborhoods.
  • Sedentary behavior . This supports the idea that more time spent not moving — such as sitting while watching TV, working on a computer, or driving — may be a risk factor for dementia.

Other factors were associated with a lower risk of cognitive decline, including:

  • A higher measure of purpose in life , which may promote resilience against brain changes and better cognitive function.
  • Holding positive attitudes toward aging , which may aid in recovery from mild cognitive impairment. Older adults with “positive age beliefs” were 30% more likely to recover from mild cognitive impairment, and displayed faster recovery, than those with “negative age beliefs.”

Compared with White Americans, Hispanic Americans are about 1.5 times more likely to develop dementia, and Black Americans are about twice as likely. NIH-funded research has focused on identifying the factors that contribute to disparities in dementia rates.

Spotlight: Blood pressure and dementia risk

High blood pressure is an established risk factor for dementia. In 2019, the NIH-funded SPRINT MIND trial showed that intensive blood pressure control (i.e., a systolic blood pressure target of less than 120 mmHg) reduced the risk of mild cognitive impairment, a well-established precursor to dementia, and slowed accumulation of white matter lesions, a risk factor for dementia.

Results from SPRINT MIND have informed the ongoing NIH Mind Your Risks public health campaign, which aims to help people — particularly Black men ages 28-45, who are at increased risk for midlife high blood pressure and late-life dementia — learn about the importance of taking charge of their health to prevent stroke and dementia. The campaign encourages medical, behavioral, and lifestyle modifications such as taking appropriate medications, healthy eating, exercising, quitting smoking, and talking to a health care provider to help develop a blood pressure management plan.

In addition, NIH-funded researchers have developed a low-cost, universal attachment for use with a smartphone to measure blood pressure from their fingertips. The “BPClip” is designed for at-home access to blood pressure monitoring, especially for people who find it difficult to access health care services. While more research is needed before the BPClip becomes available, this early pilot study demonstrates the potential of smartphone-based blood pressure devices, which could help improve the accessibility of long-term blood pressure monitoring.

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