Evidence suggests that sex-specific risk factors may contribute to women developing AD at twice the rate of men. In a study scanning the whole genome of more than 2,000 individuals from 605 families, four novel sex-specific AD genes were identified that had opposite effects on AD risk for men and women. Variations in three of these genes increased AD risk in men but seemed to be protective in women. However, the strongest association with AD risk was with the ZBTB7C gene, variants of which conferred high risk for women but protection for men. The type of protein that the ZBTB7C gene encodes has been shown to play a role in blood-brain barrier function, potentially linking increased female risk of AD to the state of the brain’s vasculature.
The study was co-led by Dr. Rudy Tanzi, Chair of the CureAlz Research Leadership Group, and CureAlz investigator and biostatistician Dr. Christoph Lange, both from Massachusetts General Hospital. Other CureAlz contributing researchers were Drs. Winston Hide (Beth Israel Deaconess Medical Center) and Lars Bertram (University of Lübeck, Germany). The results appeared in the journal Scientific Reports.
While the disproportionate impact of AD on women has been long thought to be a result of women living longer than men, research in recent years also suggests that there may be more to that than age alone and some scientists are turning their focus to genetics. With the technological advancements in DNA sequencing, all DNA in the genome can be scanned via a method known as Whole Genome Sequencing. This method allows for the search of genetic differences that associate with AD with a precision that other technologies do not provide. However, researchers are also faced with a challenge: the statistical tools needed to reliably identify positive hits from large-scale genetic data are lagging behind the technological breakthroughs and therefore also need to be advanced.
The study led by Drs. Tanzi and Lange developed robust approaches to overcome the statistical challenges and implemented the new tools in the first large family-based Whole Genome Sequencing association study for sex-specific AD risk genes.
At first, the study’s genetic association analysis identified four new genes that affected AD risk in women and men differently. Implementing the new statistical tools and filtering steps revealed that the most robust gene associated with AD risk was the ZBTB7C gene. The specific genetic variant of the gene, rs1944572, conferred increased risk for AD in women and protection from AD in men.
The exact molecular mechanisms by which ZBTB7C may be contributing to risk for AD in women are yet to be elucidated and require further study. Nevertheless, the research is first of its kind and magnitude and has provided AD researchers with new opportunities to investigate genetic susceptibility to AD in women.
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Winston Hide, Ph.D., Beth Israel Deaconess Medical Center. Lars Bertram, M.D., University of Lübeck, Christoph Lange, Ph.D., Harvard Medical School, Rudolph Tanzi, Ph.D., Massachusetts General Hospital