X Marks the Spot: Chromosome Genes Protective Against AD?

Batya Swift Yasgur, MA, LSW

August 31, 2021

The X chromosome is associated with important measures of the brain in aging and Alzheimer's disease (AD) in sex-specific ways, new research suggests.

In a cohort study, differential gene expression in the X chromosome was assessed in autopsy specimens from more than 500 elderly individuals. Of these patients, about one third had received a clinical diagnosis of AD at death, and more than half had received a pathologic diagnosis of AD at death.

After adjusting for age at death, education, and AD pathology, results showed that X chromosome gene expression in 29 genes was significantly associated with cognitive change at the genome-wide level in women but not in men. Of these genes, 19 were associated with slower cognitive decline in the women.

By contrast, the X chromosome expression of three genes was associated with neuropathologic tau burden at the genome-wide level in men but not in women.

"The X chromosome associates differently with aging and Alzheimer's disease, depending on biologic sex. It associates with cognitive change in women and tau pathology in men," senior author Dena Dubal, MD, PhD, associate professor of neurology, Weill Institute for Neurosciences, School of Medicine, University of California, San Francisco, told Medscape Medical News.

"This is important because X factors could contribute basic understanding of sex differences in aging and AD ― and ultimately lead to paths to personalized treatments against pathological processes," Dubal said.

The findings were published online August 23 in JAMA Neurology.

Understudied X

"The X chromosome is 5% of the genome for both men and women but largely understudied in aging and AD," Dubal noted.

Historically, "technical limitations have led to an exclusion of the X from major genetic association studies," she said.

That is changing with advances in informatics and "a robust interest" in how the X chromosome influences the brain in aging ― and how it could contribute to sex differences, said Dubal.

"It is particularly intriguing and important, since the X harbors the most brain-related genes compared to any other single chromosome," she added.

The researchers investigated the RNA sequencing datasets from two cohorts: the Religious Orders Study, and the Rush Memory and Aging Project joint cohorts. These were used to "measure transcriptional levels of X gene expression in the dorsolateral prefrontal cortex, a cortical hub of multiple cognitive circuits targeted by aging and AD," they write.

They particularly focused on whether X expression was associated with cognitive change during aging and AD, independently of AD pathology, and whether it was associated with tau pathology, such as neurofibrillary tangle (NFT) burden. The latter is "a major component of AD pathology linked with cognitive decline" in both sexes.

Participants (n = 508; 62% women, 98.2% non-Hispanic White) who had been free of known dementia at enrollment between 1994 and 2007 were followed longitudinally for a mean of 6.3 years until death (mean age at death, 88.4 years). Their brains were subsequently examined at autopsy.

Of the participants, 38.8% were given a clinical diagnosis of AD, and 58.2% were given a pathologic diagnosis of AD.

Greater Resilience

In women, 29 select X chromosome genes were significantly associated with cognitive change at the genome-wide level after adjustment for age, education, and AD pathologic burden.

Of these genes, 19 (65.5%) showed a positive β score, "indicating increased messenger RNA expression associated with slower cognitive decline," the investigators write. In men, X genes were not significantly associated with cognitive change ― although men and women experienced similar cognitive decline (β = -0.18; P = .86).

Given the lower numbers of men in the cohorts, the researchers analyzed a male-equivalent-sized cohort subsample of women. The findings from this analysis remained significant.

On the other hand, X chromosome gene expression was associated with NFT burden at the genome-wide level in three genes in men but not in women. This occurred despite the fact that NFT burden was lower in the men than in the women (β = −0.06; P = .07).

"We found that the X chromosome, an important part of the genome for both men and women, linked with important measures of the brain in aging and Alzheimer's disease in sex-specific ways," Dubal noted.

"In women, select genes from the X chromosome in the brain associated with cognitive change. For the majority of these X genes, higher expression associated with slower cognitive decline, suggesting they may confer resilience in women," she said.

"In men, it was a different story. Select X genes associated with tau pathology, a major contributor to Alzheimer's, suggesting that male-specific biology could shape how the X chromosome influences Alzheimer's pathology," she added.

Dubal noted that findings that subsequently lead to changes in clinical practice stem from rigorous studies.

"Our findings are part of studies growing in number that seek to unravel how the X could influence brain aging and AD in men compared to women," she said.

"In an even bigger picture, it could help inform why AD can be so different in men compared to women," Dubal added.

Women "at the Epicenter"

Commenting on the study for Medscape Medical News, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer's Association, called it "important work that is moving forward our understanding of the underlying disease progression" of AD in men and women, as well as the contributors to those changes.

Snyder, who was not involved with the study, noted that research aimed at better understanding how disease risk and trajectories differ in men and women has been a priority for the Alzheimer's Association, because women are "at the epicenter of Alzheimer's."

She noted that it is understood that there are "biological contributors" to an individual's risk of developing AD. This new research "furthers our understanding into these potential biological differences" between men and women.

Dubal added, "Maybe one day we could have diagnoses, prognoses, and therapies that are tailored to where individuals lie on the spectrum of sex biology [thereby] increasing accuracy and efficacy in the clinic."

The study was supported by grants from the National Institutes of Health, the Simons Foundation, Bakar Family Foundation, and the American Federation for Aging Research. Dubal reports having received grants from the National Institutes of Health, the American Federation for Aging Research, the Simons Foundation, and Philanthropy and other support from Unity Biotechnology during the conduct of the study. She also had a patent for methods for improving cognition filed by the UC Regents and issued. The other authors' disclosures are listed in the original article. Snyder reports no relevant financial relationships.

JAMA Neurol. Published online August 23, 2021. Full article

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