Jaclyn M. Eissman, Vanderbilt University Medical Center
Logan Dumitrescu, Vanderbilt University Medical Center
Emily R. Mahoney, Vanderbilt University Medical Center
Alexandra N. Smith, Vanderbilt University Medical Center
Shubhabrata Mukherjee, University of Washington
Michael L. Lee, University of Washington
Phoebe Scollard, University of Washington
Seo Eun Choi, University of Washington
William S. Bush, Case Western Reserve University
Corinne D. Engelman, University of Wisconsin - Madison
Qiongshi Lu, University of Wisconsin-Madison
David W. Fardo, University of Kentucky
Emily H. Trittschuh, Puget Sound Veterans Affairs Health Care System
Jesse Mez, Boston University
Catherine C. Kaczorowski, The Jackson Laboratory
Hector Hernandez Saucedo, University of California, Davis
Keith F. Widaman, University of California - Riverside
Rachel F. Buckley, Harvard Medical School
Michael J. Properzi, Harvard Medical School
Elizabeth C. Mormino, Stanford University
Hyun Sik Yang, Harvard Medical School
Theresa M. Harrison, University of California - Berkeley
Trey Hedden, Icahn School of Medicine at Mount Sinai
Kwangsik Nho, Indiana University School of Medicine
Shea J. Andrews, Icahn School of Medicine at Mount Sinai
Douglas Tommet, Brown University School of Medicine
Niran Hadad, The Jackson Laboratory
R. Elizabeth Sanders, University of Washington
Douglas M. Ruderfer, Vanderbilt University Medical Center
Katherine A. Gifford, Vanderbilt University Medical Center
Xiaoyuan Zhong, University of Wisconsin - Madison
Neha S. Raghavan, Columbia University
Badri Vardarajan, Boston University
Margaret A. Pericak-Vance, University of Miami
Lindsay A. Farrer, Boston University
Li San Wang, University of Pennsylvania Perelman School of Medicine
Carlos Cruchaga, Washington University School of Medicine
Gerard D. Schellenberg, University of Pennsylvania
Nancy J. Cox, Vanderbilt University Medical Center
Jonathan L. Haines, Case Western Reserve University
C. Dirk Keene, University of Washington
Andrew J. Saykin, Indiana University
Eric B. Larson, University of Washington
Reisa A. Sperling, Harvard University
Richard Mayeux, Columbia University
Michael L. Cuccaro, University of Miami
David A. Bennett, Rush University Medical Center
Julie A. Schneider, Rush University Medical Center
Paul K. Crane, University of Washington
Angela L. Jefferson, Vanderbilt University Medical Center
Timothy J. Hohman, Vanderbilt University


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.

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