Find all causes of Alzheimer's disease and a cure

The Framingham Heart Study (FHS) has tracked more than 14,000 men and women and gathered extensive information about these participants, including their demographics, cardiovascular risk factors, biomarker data, coexisting medical conditions, and the occurrence of diseases including Alzheimer’s disease. The data was analyzed to find clues to explain differences in AD risk between men and women.

The data highlighted that women are 96% more likely to receive a diagnosis of AD dementia at a younger age than men. However, this discrepancy disappears by age 70. Interestingly, education was linked to a decreased risk in women. The study also revealed that blood levels of A42, a longer, toxic form of amyloid beta, were a greater predictor for future memory decline in women than men. This study suggests that factors early in life (education) and later (pathological amyloid beta) may contribute to the higher AD risk for women.

Around two-thirds of individuals affected by Alzheimer’s disease (AD) dementia in the United States are women. Although women live longer than men, this alone doesn’t fully explain their elevated risk. A study funded by Cure Alzheimer’s Fund delved into data collected from the Framingham Heart Study Offspring cohort in pursuit of answers.

Initiated in 1948, the FHS initially tracked a cohort of men and women from Framingham, Massachusetts, to investigate cardiovascular disease. Although its original focus was on cardiovascular health, the FHS has since made valuable contributions to our understanding of brain health and dementia.

Recognizing the need to monitor a younger demographic as they aged, the FHS Offspring cohort was established in 1971, comprised of the offspring of the original participants along with their spouses. Data was collected from this subgroup for over a decade, and this information was used to explore sex-specific disparities in AD risk.

Remarkably, women were found to be 96% more likely than men to receive an AD dementia diagnosis between the ages of 60 and 70. However, this difference between the sexes disappeared after the age of 70. The substantial increase in risk for women at younger ages could be explained by the drastic hormonal changes seen after menopause, but more research is needed to confirm this.

Interestingly, the level of education lowered the AD risk for women in the younger age group. Cognitive reserve refers to the brain’s resilience and ability to cope with increasing damage. This reserve can be developed and strengthened. One of the best ways to do this is through learning and education. Participants in the FHS Offspring cohort were primarily born in the 1930s or earlier, a time when many women married early and often didn’t pursue education beyond high school. This could have contributed to a lower cognitive reserve and increased AD risk. Participants with a college education or higher exhibited a 50% decrease in AD risk compared to those who didn’t finish high school. This suggests that early-life factors might play a role in sex-related differences in AD risk.

Amyloid beta (A) is the protein in the brain that forms amyloid plaques, the earliest sign of AD pathology. Amyloid beta comes in different lengths, and the longer forms (such as A42) tend to clump into pathological plaques. Plasma levels of A42 were more predictive of future memory decline in women than men. The lower the plasma A42 level, the greater the risk for memory decline. Like early-life factors, this suggests that later-life factors also may play a role in AD sex differences.

The strongest genetic risk factor for AD is inheriting one or two copies of the APOE4 gene. There was no discernible difference between sexes in how APOE4 impacted their risk; it raised their risk similarly.

The study also identified a connection between several cardiovascular risk indicators and AD. Cardiovascular disease has long been suspected of influencing AD onset. Plaque accumulation in arteries leads to vascular damage, reducing blood flow to the brain and eventually harming brain cells. Risk indicators for cardiovascular disease, including blood pressure, plasma lipid levels, and glucose levels, were significantly linked to AD development. While no sex differences emerged when assessing these risk factors separately, their combined impact indicated a higher risk for men than women.

This study offers the first insights into sex-specific contributions to AD risk from the comprehensive data collected from the FHS Offspring cohort. However, according to the study’s estimation, demographics, APOE4 status, and biomarkers collectively explained only about 22% of the AD risk, implying that over 75% of the factors are unknown. This underscores the pressing need to identify the remaining risk factors.

Murali Doraiswamy, M.B.B.S., Duke University School of Medicine

Some individuals seem to be resilient to AD. Although these individuals develop the classic hallmarks of the disease—bundles of amyloid plaque and neurofibrillary tau tangles—they do not develop dementia symptoms in their lifetime.

Studies suggest that resilience to the pathology may be associated with reduced levels of neuroinflammation, thought to be universal in symptomatic AD. Instead of promoting neuroinflammation, the essential immune cells in the brain— microglia and astrocytes—remain in their housekeeping state and do not become disease-associated despite a significant burden of amyloid plaques and tau tangles. Therefore, identifying predictive markers of resilience and understanding the underlying mechanisms involved may be key to therapeutically mimicking the brain’s natural protection against amyloid beta and tau, and developing novel therapies for AD that preserve cognition.

Teresa Gomez-Isla, Massachusetts General Hospital