January 2025

NEUROSCIENCES

EXPLORING GENETIC SEX DIFFERENCES IN ALZHEIMER’S

Featuring: Robert Vassar, PhD

​An international team of scientists has uncovered new insights into how the previously understudied duplicate X chromosome in women may contribute to Alzheimer’s disease risk, according to a multicenter study published in the journal Molecular Psychiatry.

Alzheimer’s disease is the most common cause of dementia in older adults and is the seventh leading cause of death in the U.S., according to the National Institute on Aging.

Although previous research has shown women to be at higher risk for Alzheimer’s Disease, the current study is the first to investigate genetic risk factors emerging from their second copy of the X chromosome.  

In female mammals, including humans, two X chromosomes exist in each cell. To ensure that the genes on the X chromosomes are not overexpressed, one of the X chromosomes is “silenced” during early embryonic development. This process, known as X-inactivation, equalizes gene expression between females and males.

​Historically, genetic studies of Alzheimer’s excluded the X chromosome because methodologies were not advanced enough to account for the genetic effects of X-inactivation. With the recent development of newer analytical tools, it became possible to more deeply investigate the genetics of the under-studied X chromosome, which represented an unexplored direction in Alzheimer’s research, according to Robert Vassar, PhD, the Davee Professor of Alzheimer Research and director of the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, who was a co-author of the study.

“Women have two X chromosomes, and even though one of them is inactivated, the patterns of the inactivation can be variable,” Vassar said. “The inactivated chromosome still could influence genetic risk in women compared to men, who do not experience X-inactivation. That was the rationale behind the study.”

In the study, investigators led by Celine Bellenguez, MD, PhD, at the Pasteur Institute of Lille, performed an in-depth X-chromosome-wide association study of more than 115,000 cases of Alzheimer’s disease and more than 613,000 controls.

While the analysis did not reveal any significant genome-wide associations, it did identify seven X-chromosome-wide significant loci, or locations, on the genome where mutations were associated with increased risk of Alzheimer’s, according to the study.

​“These seven suggestive loci are near genes which have functions involved in the brain and intellectual ability,” said Vassar, who is also a professor of Cell and Developmental Biology and the scientific director of Behavioral Neurology in the Ken and Ruth Davee Department of Neurology. “Those seven loci warrant further investigations.”

Now that the loci have been identified, scientists can examine these regions more closely in hopes of finding more specific genetic markers and clues to the mechanisms that underlie Alzheimer’s risk in women, Vassar said.

“Genetics has been the foundation of all of the advances we’ve seen in Alzheimer’s disease research over the last three decades,” Vassar said. “I think this, along with the immunotherapies that have been developed from that genetic research, do indicate that we’re on the right track. If we keep staying the course, we hope to see a day when Alzheimer’s disease will be just a memory.”

This study was supported by grants from the Fondation pour la Recherche sur Alzheimer (convention 2022-A-01 and cluster grant) and the JPco-fuND-2 ‘Multinational research projects on Personalized Medicine for Neurodegenerative Diseases’ PREADAPT project (ANR-19-JPW2-0004).

This article was originally published in the Feinberg School of Medicine News Center on January 7, 2025. 
Robert Vassar, PhD, the Davee Professor of Alzheimer Research and director of the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, was a co-author of the study published in Molecular Psychiatry.

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