Sex differences in the genetic architecture of cognitive resilience to Alzheimer’s disease
Authors: Eissman Jaclyn M , Dumitrescu Logan , Mahoney Emily R , Smith Alexandra N , Mukherjee Shubhabrata , Lee Michael L , Scollard Phoebe , Choi Seo Eun , Bush William S , Engelman Corinne D , Lu Qiongshi , Fardo David W , Trittschuh Emily H , Mez Jesse , Kaczorowski Catherine C , Hernandez Saucedo Hector , Widaman Keith F , Buckley Rachel F , Properzi Michael J , Mormino Elizabeth C , Yang Hyun Sik , Harrison Theresa M , Hedden Trey , Nho Kwangsik , Andrews Shea J , Tommet Douglas , Hadad Niran , Sanders R Elizabeth , Ruderfer Douglas M , Gifford Katherine A , Zhong Xiaoyuan , Raghavan Neha S , Vardarajan Badri N ,   The Alzheimer’s Disease Neuroimaging Initiative (ADNI),   Alzheimer’s Disease Genetics Consortium (ADGC),   A4 Study Team, Pericak-Vance Margaret A , Farrer Lindsay A , Wang Li San , Cruchaga Carlos , Schellenberg Gerard D , Cox Nancy J , Haines Jonathan L , Keene C Dirk , Saykin Andrew J , Larson Eric B , Sperling Reisa A , Mayeux Richard , Cuccaro Michael L , Bennett David A , Schneider Julie A , Crane Paul K , Jefferson Angela L , Hohman Timothy J 
Published: May 2022

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer’s disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer’s disease neuropathology may uncover novel therapeutic targets to treat Alzheimer’s disease. It is well established that there are sex differences in response to Alzheimer’s disease 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 ageing, 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) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] 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) = 5.76 × 10−09, β (males) = −0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10−04] 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 Alzheimer’s disease 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 Alzheimer’s disease may be personalized based on their biological sex and genetic context.