Sex-specific genes put some people at higher risk for Alzheimer’s

July 22, 2019

New research reported during the Alzheimer’s Association International Conference (AAIC) 2019 in Los Angeles (July 14-18) identified several differences in the progression and risk of Alzheimer’s disease between women and men, including newly identified sex-specific risk genes and contrasting presentation of Alzheimer’s biology in the brain.

Two-thirds of people living with Alzheimer’s disease in the U.S. are women, according to the Alzheimer’s Association’s 2019 Alzheimer's Disease Facts & Figures report. There are several potential reasons why more women than men have Alzheimer’s or other dementias; a long-held view has been that it is due to women living longer than men, on average, but new evidence suggests that may not be the whole story.

Findings from researchers at the Vanderbilt University Medical Center found sex-specific differences in the spread of abnormal tau protein, a toxic substance associated with cognitive decline in Alzheimer’s. Complementary to these findings, researchers at University of California San Diego School of Medicine found sex differences in levels of energy usage in the form of brain glucose metabolism.

Research from the University of Miami found novel sex-specific genes that are associated with risk and resilience for Alzheimer’s disease, which could provide unique risk profiles for men and women.

Finally, in a large study of women, researchers from the UCLA Fielding School of Public Health found a faster rate of memory decline among women who never engaged in waged employment compared to women who participated in the paid labor force.

Work-family demands and late-life memory decline in women: The researchers found that women in the study who participated in the paid labor force between early adulthood and middle age, including mothers and non-mothers, experienced slower memory decline in late life. Rate of memory decline was fastest among women who did not engage in waged employment. For example, compared with married mothers who participated in the paid labor force:

  • average memory performance between ages 60 and 70 years declined 61 percent faster for married women with children who never engaged in waged employment, and
  • average memory performance between ages 60 and 70 years declined 83 percent faster for women who experienced a prolonged period of single motherhood without waged employment.

Based on these findings, the scientists suggest that participation in the paid labor force may play an important role in late-life cognitive health for women in the United States. This builds on prior research that has found participation in the workforce is associated with higher levels of cognitive stimulation and increase in cognitive reserve.

Glucose metabolism supports verbal memory in women with moderate amyloid plaque deposition: Women typically outperform men on verbal memory tests, including through the early stages of Alzheimer’s disease. This is true even when women and men have similar degrees of Alzheimer’s-related brain changes — or pathology. Because of the better verbal memory performance in women versus men at early Alzheimer’s stages, verbal memory tests may fail to detect mild cognitive impairment and Alzheimer’s disease in women until they are further along in the disease.

Researchers compared the brain’s ability to metabolize glucose, a measure of brain function, between men and women at different stages of Alzheimer’s pathology and whether a difference contributes to women’s verbal memory advantage.

Women outperformed men on the verbal memory test when amyloid plaque deposition was minimal to moderate, indicating early-stage Alzheimer’s. However, this difference was absent when amyloid deposition was severe, indicating a later stage of the disease. In parallel to the verbal memory findings, the researchers also found that women showed higher levels of brain glucose metabolism than men at minimal to moderate levels of amyloid deposition. This suggests that women may be better able than men to compensate for early-stage Alzheimer’s-related brain changes by maintaining brain metabolic function and this ability may contribute to women’s verbal memory advantage at this disease stage.

Novel sex-specific genes for Alzheimer’s disease: Researchers analyzed two large datasets from the Alzheimer’s Disease Sequencing Project whole-exome sequencing study to identify potential additional sex-specific genetic associations with Alzheimer’s. Replication analyses were conducted using the Alzheimer’s Disease Genetics Consortium (ADGC) Haplotype Reference Consortium (HRC).

Sex-specific associations with Alzheimer’s disease risk were found for 11 different genes, many of which have functions that may be relevant to development of Alzheimer’s. These include genes related to risk only in men, MCOLN3 and CHMP2B, both of which are involved in endocytosis, a process critical to the development of Alzheimer’s, and genes related to risk only in females, CD1E and PTPRC, which play essential roles in immunity.

Sex differences identified in the spread of tau pathology in the brain: The biological hallmarks of Alzheimer’s involve the abnormal accumulation of proteins in the brain. Much past work has focused on amyloid, but Alzheimer’s disease is also characterized by the abnormal accumulation of tau, a protein that, when clumped into tangles, causes brain cell death. Previous research has established that there are sex-specific differences in how brain regions are connected, and this may influence the pattern of how tau spreads through the brain in men and women.

Researchers examined positron emission tomography (PET) scans to model the brain as a network of tau-connected regions. They examined the architecture of these networks to identify global pathways of tau propagation and to test for differences between men and women.

The study included healthy individuals and people with mild cognitive impairment (MCI: 101 men, 60 women) enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. For each group, the tau-connectivity networks were characterized to indicate (1) the overall number of connections, (2) areas within the brain with higher tau connectivity than the rest of the brain (communities), and (3) regions that influenced the spread of tau across different communities.

The researchers found that the tau network of women with MCI looked very different than the other three groups. Women with MCI had the highest network density (0.38 ± 0.03 compared to 0.21 ± 0.02 in MCI-male, 0.11 ± 0.02 in CN-male and 0.12 ± 0. 02 in CN-female) and, at the same time, increased brain-wide tau burden. The researchers found that healthy women in the study had several key brain regions that served as hubs and connected different brain areas within the network. They speculate that this may favor an accelerated brain-wide tau spread in women, which may lead to cognitive decline.