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Research Highlights

Sex-specific differences in aging and Alzheimer’s disease may be tied to genetics

When it comes to cognitive aging and Alzheimer’s disease, the differences between men and women may be related to genetics. According to an NIA-supported study published in JAMA Neurology, August 2021, genes contained in the X chromosome may hold the key to differences between men and women in aging and Alzheimer’s-related cognitive decline.

An older adult man with his arm around an older adult women with Alzheimer’s are sitting on a park bench watching a sunset.

Cognitive changes can affect memory, attention, and executive functions such as planning and self-control. These changes can occur as a result of the natural process of aging or dementia such as Alzheimer’s. Sometimes, cognitive changes are accompanied by changes in the brain such as the formation of neurofibrillary tangles, a hallmark characteristic of the brain tissue associated with Alzheimer’s. The tangles involve the twisting of tau protein threads of the nerve cells in the brain tissue. The rate and degree of cognitive decline, as well as the extent of neurofibrillary tangles, differ between men and women.

In this study, scientists led by a team at the University of California, San Francisco, analyzed genetic and clinical data from a joint cohort consisting of two long-term studies: the Religious Orders Study and the Rush Memory and Aging Project. The scientists gathered genetic data from the brain tissue of 508 autopsied individuals via RNA sequencing, a technique used to measure how many copies of specific genes are present in a human’s cells at a given time.

The scientists also gathered data about participants’ cognitive function over several years to assess changes in cognition, including memory and attention. Participants did not have dementia at the time of their enrollment in the studies and were monitored periodically until their death. Using genetic and clinical data, the scientists examined associations of cognitive changes and levels of neurofibrillary tangles with genes on the X chromosome.

The X chromosome is one of the two sex chromosomes in humans (the Y chromosome is the other). Women have two X chromosomes, and men have one X and one Y. Unlike the Y chromosome, which contains just 50 to 60 genes, the X chromosome contains hundreds of genes, many of which are related to brain function. However, not much is known about how the expression of X chromosome-linked genes affects brain changes in aging and Alzheimer’s. Gene expression is the process by which the instructions in our DNA are converted into a functional product, such as a protein.

The scientists found that the expression levels of 19 genes on the X chromosome were linked to changes in cognition and quantity of neurofibrillary tangles. In women, this increased expression was associated with slower cognitive decline. The expression of these genes was not increased in men. This may suggest that specific genes on the X chromosome help protect women from cognitive decline in aging and Alzheimer’s.

In contrast, the expression of three X chromosome genes associated with neurofibrillary tangles was increased in men. This may suggest that men could be more at risk of developing Alzheimer’s-related pathological changes than women.

Because this study used a sample population that was 98% white, future studies must be conducted on a more diverse sample. Nonetheless, the expression of X chromosome genes may uncover some of the genetic differences in cognitive aging and Alzheimer’s between men and women. Research to further examine the role of X chromosome genes in aging and Alzheimer’s could help advance personalized treatment options for both men and women.

This research was funded in part by NIA grants RF1AG068325, P30AG10161, R01AG15819, R01AG17917, U01AG61356, U01AG46152, R01AG36836, R01AG060393, and R01AG062588.

These activities relate to NIH’s AD+ADRD Research Implementation Milestone 2.D, “Create programs in basic, translational and clinical research aimed at comprehensive understanding of the impact of sex differences on the trajectories of brain aging and disease, phenotypes of AD and ADRD risk and responsiveness to treatment.”

Reference: Davis EJ, et al. Sex-specific association of the X chromosome with cognitive change and tau pathology in aging and Alzheimer Disease. JAMA Neurology. 2021 Aug 23;e212806. doi: 10.1001/jamaneurol.2021.2806.

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