AAIC19: Genes Linked to Why Women Are More Prone to Alzheimer’s

Alzheimer's Woman

It is well-known that women are more likely to get Alzheimer’s disease than men, but exactly why hasn’t been clearly understood. Research presented at the Alzheimer’s Association International Conference (AAIC) in Los Angeles today describes several genes linked to the disease only in men and others related to risk only in women.

Brian Kunkle, a genetic epidemiologist and associate scientist at the University of Miami, along with genomics teams at several institutions, analyzed two large datasets from the Alzheimer’s Disease Sequencing project whole-exome sequencing study. The goal was to identify possible additional sex-specific genetic associations with Alzheimer’s.

Replication analysis was conducted using the Alzheimer’s Disease Genetics Consortium (ADGC) Haplotype Reference Consortium.

Kunkle told BioSpace, “Women comprise nearly two-thirds of all Alzheimer’s disease (AD) cases, suggesting sex-specific risk and protective factors. For example, a number of studies have established that apolipoprotein E (APOE) genotype contributes to risk of AD differently in men and women.”

The researchers found 11 different genes that produce varying levels of risk for, or protection against, Alzheimer’s disease in men and women.

“These genes appear to have functions that are relevant to Alzheimer’s disease, including endocytosis and immunity,” Kunkle said. “These genes would not have been discovered in analyses that combine men and women, highlighting the importance of analyses that consider sex for novel gene discovery and precision medicine.”

Four genes, in particular, caught the researchers’ attention, MCOLN3 and CHMP2B in men and CD1E and PTPRC in women.

“MCOLN3 and CHMP2B regulate endocytosis,” Kunkle said, “the process whereby the cell cleans itself through transport of molecules for recycling or degradation. This process may reduce Alzheimer’s risk through reduction of buildup of amyloid and tau, two key Alzheimer disease proteins. CD1E and PTPRC are immune response genes, another known Alzheimer process. These genes could help refine biomarker and therapy development by providing gene targets that differentiate Alzheimer disease pathology in men and women.”

The bottom line is this research supports the theory that the different risks for men and women for Alzheimer’s disease are gene-related.

“This study strongly supports the hypothesis that some genetic factors contributing to AD are not identical for men and women,” Kunkle told BioSpace. “Understanding the different genetic landscape and risk profiles for Alzheimer disease between men and women provides information critical for precision medicine, helps refine targets for therapy, and improves diagnosis and prediction.”

Related research about gender differences in Alzheimer’s was also presented at the AAIC meeting.

Elizabeth Rose Mayeda, assistant professor of epidemiology at UCLA Fielding School of Public Health, led a research study of women born between 1935 and 1956 and how changes in patterns of employment and family circumstances have affected late-life memory decline.  The women in the research reported wage employment, marital and parenthood status between ages 16 and 50.

Mayeda’s research found that the women in the study who were in the paid workforce between early adulthood and middle age, both mothers and non-mothers, had slower memory decline in late-life. The fastest rate of memory decline was in women who didn’t engage in paid work. The average memory performance between the ages of 60 and 70 dropped 61% faster for married women with children who never engaged in paid jobs, and the average memory performance between ages 60 and 70 dropped 83% faster for women who had prolonged single motherhood without paid employment.

Erin Sundermann, a neuropsychologist at UC San Diego School of Medicine, led research studying the brain’s ability to metabolize glucose, a measure of brain function, between men and women at various stages of Alzheimer’s and whether the difference explained why women have better verbal memory than men in early Alzheimer’s. The differences appear to disappear when amyloid plaque accumulation grows later in the disease. The research suggests that women might be compensating better than men in early-stage Alzheimer’s by maintaining brain metabolic function.

Sepideh (Sepi) Shokouhi, assistant professor of psychiatry and behavioral sciences at Vanderbilt University Medical Center, led research into how the tau protein accumulates differently in men and women. The researchers used positron emission tomography (PET) scans to model the brain as a network of tau-connected regions, looking for differences in men and women. It looked at 123 healthy men and 178 healthy women, and 101 men and 60 women with mild cognitive impairment (MCI) enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. They found that the tau network of women with mild cognitive impairment was very different from the men and normal patient groups. Women with MCI had the highest network density as well as increased brain-wide tau burden. The healthy women studied had key brain regions, the parahippocampus, superior parietal, insular, and superior temporal, that acted as hubs and connected different brain areas within the network. The researchers that these connections might speed the spread of tau throughout the brain in women, which might lead to cognitive decline.


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