Alzhemier’s Disease Risk Factors

• While estimates vary, studies to date find that as many as 5.1 million Americans age 65 and older have Alzheimer’s disease.
• The greatest risk factor for Alzheimer’s is age. The number of people with the disease doubles for every 5-year interval beyond age 65.
• The Bureau of the Census estimates that the number of people age 65 and older in the United States will almost double to 74.1 million by 2030.
• Further, the number of Americans over age 85—those at highest risk—is expected to increase from 5.5 million in 2010 to 9.1 million in 2030.

The implication is clear: Unless we find effective interventions to prevent or treat Alzheimer’s disease, the number of affected Americans will soar in the coming decades.

Preparing for the human, financial, and societal challenges of Alzheimer’s disease and related dementias requires an understanding of the disease not just at the level of molecules and cells, but at the level of communities and populations. The National Institutes of Health (NIH) supports a broad range of population studies to address these and related questions.

Studies to date have told us a great deal about who may be at risk for Alzheimer’s, factors that influence the disease, and societal impacts, but it is critical to refine and update this knowledge. Researchers are expanding our understanding of this complex and devastating disease to further the 2025 goal of identifying effective interventions by addressing:

• Who develops Alzheimer’s disease, and who seems to be protected?
• What other conditions are associated with development of the disease?
• What are the financial, economic, social, and policy costs of the disease?

The NIH-led Precision Medicine Initiative^® (now known as the All of Us Research Program), which plans to launch a national cohort study of a million or more Americans to propel the understanding of diseases such as Alzheimer’s and related dementias, will take population studies to the next level. The Precision Medicine Initiative’s ultimate goal is to develop therapies that take into account the variability in genes, environment, and lifestyle of each patient.

Progress in Identifying Risk and Protective Factors

Advancing age and genetics are known risk factors for Alzheimer’s disease, but it is becoming evident that a highly complex mix of genetic, environmental, and lifestyle factors may also influence the disease’s onset and progression. Scientists are trying to not only identify risk factors, but tease out how these factors interact with one another, in the search for effective interventions. Recent studies have suggested directions to pursue:

Dementia risk and commonly used drugs

Older adults who take anticholinergic drugs may be at significantly higher risk of developing dementia—and the greater the use of the drugs, the higher the potential risk. Anticholinergics are prescribed for many health conditions, including overactive bladder, seasonal allergies, and depression. Some are available over the counter and are often used as sleep aids. These medications block a neurotransmitter, acetylcholine, in the brain and body and may cause side effects such as impaired cognition, especially in older people.

This side effect was thought to be reversible once the person stopped taking the medication. However, researchers showed that these medications may have a lasting impact (Gray et al., 2015). By analyzing records and data on drugs prescribed over 10 years to 3,434 adults age 65 and older, they calculated cumulative exposure to drugs with strong anticholinergic effects. They found that 78 percent of the study participants used anticholinergics at least once in 10 years and that nearly 800 participants (23 percent) developed dementia, usually Alzheimer’s. They noted that the higher the use of anticholinergics, the higher the risk of dementia, regardless of whether the drugs had been taken recently or years ago.

The findings suggest that physicians treating older people should prescribe alternatives to anticholinergics when possible or lower doses of the drugs. More studies are needed to determine to what extent stopping anticholinergics can reduce the risk of developing permanent dementia.

Is reduced brain blood flow a risk factor?

Having a maternal history of Alzheimer’s disease may put one at greater risk for developing Alzheimer’s-associated reduced blood flow in the brain by midlife. Scientists studied cerebral blood flow using a technique called arterial spin labeling magnetic resonance imaging in middle-aged and older volunteers. The study involved 252 cognitively normal people with an average age of 59 and 75 volunteers with an average age of 75. People in the older group were either cognitively normal, had mild cognitive impairment (MCI) or had Alzheimer’s disease (Okonkwo et al., 2014).

The researchers found that the older participants with MCI or Alzheimer’s disease showed reduced blood flow to the frontoparietal cortex and hippocampus. Reductions in blood flow to these brain regions were also seen in the middle-aged volunteers with normal cognition but who had a maternal history of Alzheimer’s disease. This finding suggests reduced cerebral blood flow in midlife might be a marker for Alzheimer’s risk.

Brain amyloid, sleep-disordered breathing, and mild cognitive impairment

Sleep disturbances, including sleep apnea and other abnormal breathing patterns, are common in people with MCI and Alzheimer’s disease. Researchers studied the possible link between sleep disturbances and levels of brain beta-amyloid in eight cognitively normal volunteers (average age, 69) and five with MCI (average age, 75) (Spira et al., 2014).

For two consecutive nights, the participants’ sleep and breathing patterns were followed by tests that monitor body functions such as eye movements, muscle activity, and heart rhythm during sleep. Their blood oxygen levels and brain beta-amyloid burden were measured as well.

Among participants with MCI, greater severity of sleep disturbance and lower blood oxygen levels were strongly associated with higher levels of brain beta-amyloid deposition. This association was not seen in volunteers with normal cognition.

These results suggest that in people with MCI, abnormal breathing during sleep may contribute to beta-amyloid deposition and possibly speed progression to Alzheimer’s disease. In addition, most of the MCI participants in this study were found to have moderate to severe disordered breathing during sleep that had not been previously diagnosed, compared with only one of the eight participants with normal cognition. Increased clinical screening for sleep-disordered breathing could aid the identification of people at risk for developing Alzheimer’s disease.

BDNF proteins may protect against dementia

Brain-derived neurotrophic factor (BDNF) is a protein found in the blood and brain that promotes the survival of neurons and long-term memory in animal models. New research suggests that BDNF also may help maintain cognitive health in some older people (Weinstein et al., 2014).

Researchers measured BDNF levels in serum samples from 2,131 volunteers from the NIH-supported Framingham Heart Study (whose average age at the start of this particular study was 72) and then tracked their cognitive function over 10 years. During the follow-up period, 140 of the participants developed dementia, including 117 with Alzheimer’s disease.

Participants with higher serum BDNF levels at the start of the study were significantly less likely to develop dementia than those with lower BDNF levels. The reduction in dementia risk was 50 percent for those with the highest serum BDNF levels compared to those with the lowest. Of note, the association between higher BDNF and lower dementia risk was seen only in women, people older than 80, and people with college degrees.

This research suggests that further study should explore treatment with BDNF in preventing dementia, especially in women and in older and more highly educated people. Because BDNF levels can be increased by physical activity and reduced caloric intake, the findings also suggest that exercise and a healthy diet may help reduce dementia risk—but more research is needed.

Diabetes may speed age-related cognitive decline

Diabetes is an established risk factor for Alzheimer’s disease. A research team has now found that diabetes may also increase one’s risk of age-related cognitive decline (Rawlings et al., 2014). The team followed 13,351 black and white volunteers, age 48 to 67 years, participating in the NIH-supported Atherosclerosis Risk in Communities (ARIC) Study. Participants received cognitive tests at the start and twice more during the 20-year study that began in 1985.

After two decades, the researchers found, cognitive decline was 19 percent more severe in participants who had diabetes at the start of the study than in those who were diabetes-free. Of the cognitive abilities tested, processing speed and executive function were the most strongly affected; a smaller impact was seen on verbal memory.

The participants’ blood sugar levels, which are elevated in prediabetes and diabetes, were also measured at the start of the study. People with levels indicative of prediabetes at the start of the study showed greater cognitive decline than those with normal levels, as did people whose diabetes was poorly controlled or of longer duration. The association between diabetes and cognitive decline was similar for black people and white people.

This study suggests that having diabetes or prediabetes in middle age significantly increases one’s risk of cognitive decline in later years. As diabetes and prediabetes are usually treatable, screening for these conditions and managing diabetes may influence cognitive decline. Clinical trials have not yet demonstrated specifically that diabetes management will reduce the risk of cognitive decline or Alzheimer’s. As studies pursue this question, there are many reasons for people to manage diabetes and prediabetes.

Examining Health Disparities

NIH funds research that evaluates whether certain racial, ethnic, and socioeconomic groups may be at greater risk than others for cognitive decline and dementia. Understanding these differences is critical to developing appropriate risk assessments and diagnostic tools and providing the most effective interventions to prevent and treat Alzheimer’s disease for everyone.

Earlier age of dementia onset in Hispanics

Past studies suggest that U.S. Hispanics have a younger age of dementia onset than white non-Hispanics. However, most of those studies were performed on the East Coast. Since backgrounds and family origins of Hispanics differ in various regions of the United States, investigators set out to determine if the same pattern was true for Hispanics living on the West Coast (Fitten et al., 2014).

In a study of 110 Hispanic and 180 white non-Hispanic adults age 50 and older with either Alzheimer’s disease or vascular dementia at the time of their entry into the study, researchers found that on average, Hispanics were 4 years younger than white non-Hispanics at the time of diagnosis of both forms of dementia. This age difference was not explained by the apolipoprotein ε4 genotype, gender, years of education, or history of vascular disease or diabetes.

This study suggests that the age of dementia onset tends to be younger for Hispanics living on both coasts of the United States compared with non-Hispanic peers. More research is needed to identify and better understand the factors that may contribute to this disparity.

Education and literacy contribute to disparities in late-life cognition

A number of studies have found that cognitively normal, older black adults have lower performance on cognitive tests compared with white peers, even given equal years and levels of education. Research suggests that more subtle factors related to education and literacy contribute to the racial disparity in late-life cognitive performance (Sisco et al., 2015).

The researchers studied data from 1,679 non-Hispanic, community-dwelling adults age 65 to 102 (71 percent black, 29 percent white, and 70 percent women) participating in the Washington Heights-Inwood Columbia Aging Project in New York City. They assessed the participants’ early-life educational quality (based on a variety of measures, such as school location and teacher-student ratios) and current literacy (based on scores on reading and writing tasks) and scored their performance on a battery of cognitive tests.

As has been found previously, the black volunteers scored lower on the cognitive tests than whites of the same age. Accounting for early educational quality and current literacy substantially reduced but did not eliminate the racial disparity in test performance, with literacy generally having a stronger effect than educational quality. More research is needed to fully understand these disparities.

Promising Research Opportunities

Population studies offer insights into the “who, what, and why” of Alzheimer’s disease: Who is at risk or protected from developing the disorder? What genetic, lifestyle, and environmental factors are involved? Why do certain populations experience higher rates of dementia and cognitive decline compared with other groups?

NIH investment into population studies is guided by the research milestones developed following the Alzheimer’s Disease Research Summits held in 2012 and 2015, with additional input. Please see the full list of milestones (PDF, 123K) aimed at prevention and treatment by 2025. In future research, the NIH hopes to move progress forward by:

• Investigating the impact of environmental exposures on Alzheimer’s pathogenesis and/or response to treatment
• Increasing under-represented populations involved in studies to help identify the diverse genetic variants and other risk and protective factors involved in Alzheimer’s
• In existing longitudinal cohorts, adding molecular phenotyping studies (genomic, epigenomic, proteomic) and incorporating the collection of nontraditional data using wearable sensors and mobile health technology