Researchers are beginning to assess how genetic variation influences sex differences in Alzheimer’s disease. True, women who have an ApoE4 allele are more likely to develop Alzheimer’s than are male carriers, but what about the many other variants that have been implicated in this genetically complex disease? In the June 27 Brain, researchers led by Anders Dale at the University of California, San Diego, report that polygenic hazard scores for AD are sex-specific, i.e., different when calculated for men and women separately. Sex-matched scores better predicted disease onset, progression, and neuropathology than did scores calculated for all study participants together, as is usual in genetics studies in AD. “The finding suggests that sex differences in genetic risk go beyond ApoE4,” Chun Chieh Fan, co-first author, told Alzforum.
- Sex differences in genetic risk for AD are uncertain.
- Researchers calculated sex-specific polygenic hazard scores.
- These better predict clinical diagnosis, pathology, and cognitive decline.
Fan, co-first author Sarah Banks, and colleagues capitalized on a polygenic hazard score developed by Dale and the late Rahul Desikan (Mar 2017 news; Aug 2019 news). To identify sex differences in genetic risk, the researchers correlated genetic variants with AD in men and women separately by way of genome-wide association of 7,158 men and 10,697 women who had volunteered for the Alzheimer’s Disease Genetic Consortium. Using this sex-based GWAS data, the researchers calculated polygenic hazard scores (PHS) and polygenic risk score (PRS), again separately, for 2,628 men and 3,448 women in the National Alzheimer’s Coordinate Cohort (NACC). Then, in a crossover design, they calculated how polygenic scores for women predicted outcomes in women and in men, and ditto for the polygenic scores for men.
The crossover analysis was based on genetic, diagnostic, and pathology data from NACC and from ROSMAP, a combination of the Religious Orders Study and Memory and Aging Project both being conducted at Rush University, Chicago.
It turned out that the male and female polygenic scores had stronger predictive power when applied to their matched gender. One standard-deviation uptick in the sex-matched PHS increased the odds of a clinical AD diagnosis by 26 percent, whereas for male scores applied to female cohorts, or vice versa, the hazard ratio increase was only 14 percent.
The sex-matched PHS also better predicted neuropathologically confirmed AD and annual progression of dementia, as judged by change in CDR sum-of-boxes scores. In the ROSMAP data, the matched PHS associated much more strongly with plaque burden, neurofibrillary tangles, Braak staging, and CERAD neuropathology scores than did the mismatched PHS.
All told, the study indicates that the genetic risk associated with AD is tied to a person’s sex. This seems to affect only progression, not prevalence, because male and female PRS scores equally foretold AD in men and women. While PRS predict whether a person will get AD, PHS predicts at what age he or she is likely to become symptomatic.
What variants are involved in this sex difference? Figuring this out will require more study and many more samples. Still, some hints emerged from the male/female GWAS. Effect sizes for BIN1, MS4A6A, DNAJA2, and FERMT2 were all higher in women, while FAM193B, C2ord47, and TYW5 variants appeared stronger in men. To get a handle on this, Fan believes it will be important to correlate sex-dependent cognitive scores and genetic data with biomarkers and gene-expression analysis. “Only then can we be confident about the underlying biology we predict from genetics,” he said.—Tom Fagan
- Deming Y, Dumitrescu L, Barnes LL, Thambisetty M, Kunkle B, Gifford KA, Bush WS, Chibnik LB, Mukherjee S, De Jager PL, Kukull W, Huentelman M, Crane PK, Resnick SM, Keene CD, Montine TJ, Schellenberg GD, Haines JL, Zetterberg H, Blennow K, Larson EB, Johnson SC, Albert M, Moghekar A, Del Aguila JL, Fernandez MV, Budde J, Hassenstab J, Fagan AM, Riemenschneider M, Petersen RC, Minthon L, Chao MJ, Van Deerlin VM, Lee VM, Shaw LM, Trojanowski JQ, Peskind ER, Li G, Davis LK, Sealock JM, Cox NJ, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Alzheimer Disease Genetics Consortium (ADGC), Goate AM, Bennett DA, Schneider JA, Jefferson AL, Cruchaga C, Hohman TJ. Sex-specific genetic predictors of Alzheimer's disease biomarkers. Acta Neuropathol. 2018 Dec;136(6):857-872. Epub 2018 Jul 2 PubMed.
- Fan CC, Banks SJ, Thompson WK, Chen CH, McEvoy LK, Tan CH, Kukull W, Bennett DA, Farrer LA, Mayeux R, Schellenberg GD, Andreassen OA, Desikan R, Dale AM. Sex-dependent autosomal effects on clinical progression of Alzheimer's disease. Brain. 2020 Jul 1;143(7):2272-2280. PubMed.