Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease.

Jaclyn M Eissman
Logan Dumitrescu
Emily R Mahoney
Alexandra N Smith
Shubhabrata Mukherjee
Michael L Lee
Phoebe Scollard
Seo-Eun Choi
William S Bush
Corinne D Engelman
Qiongshi Lu
David W Fardo
Emily H Trittschuh
Jesse Mez
Catherine C Kaczorowski, The Jackson Laboratory
Hector Hernandez Saucedo
Keith F Widaman
Rachel F Buckley
Michael J Properzi
Elizabeth C Mormino
Hyun-Sik Yang
Theresa M Harrison
Trey Hedden
Kwangsik Nho
Shea J Andrews
Douglas Tommet
Niran Hadad
R Elizabeth Sanders
Douglas M Ruderfer
Katherine A Gifford
Xiaoyuan Zhong
Neha S Raghavan
Badri N Vardarajan
Margaret A Pericak-Vance
Lindsay A Farrer
Li-San Wang
Carlos Cruchaga
Gerard D Schellenberg
Nancy J Cox
Jonathan L Haines
C Dirk Keene
Andrew J Saykin
Eric B Larson
Reisa A Sperling
Richard Mayeux
Michael L Cuccaro
David A Bennett
Julie A Schneider
Paul K Crane
Angela L Jefferson
Timothy J Hohman


Approximately 30% of elderly adults are cognitively unimpaired at time of death despite presence of Alzheimer's disease (AD) neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of AD neuropathology may uncover novel therapeutic targets to treat AD. It is well-established that there are sex differences in response to AD pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large-scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive aging, in-vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified (N(males) = 2,093, N(females) = 2,931) and sex-interaction (N(both sexes) = 5,024) genome-wide association studies (GWAS), gene- and pathway-based tests, and genetic correlation analyses to clarify the variants, genes, and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 (rs827389, β(females) = 0.08, P(females) = 5.76E-09, β(males)=-0.01, P(males) = 0.70, β(interaction) = 0.09, P(interaction) = 1.01E-04) in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus, and highlighted numerous sex-specific molecular pathways that may underly resilience to AD pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with AD may be personalized based on their biological sex and genetic context.