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

Abstract

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.

Sex-specific transcriptional rewiring in the brain of Alzheimer’s disease patients

“…TSHZ1 is also essential for olfactory bulb development and olfaction ( Ragancokova et al, 2014 ). Further, GATA3, a transcription factor crucial in the differentiation of Th2 cells, was identified as a female-specific gene of AD implicated in RNA processing ( Eissman et al, 2022 ).…”

“…Consistent with the pathway analysis, some transcription factors are associated with insulin signaling. For example, CREB3, STAT1, and STAT3 are important regulators of glucose and lipid metabolism in models of high-fat diet and obesity (Bone et al, 2020;Yao et al, 2021;Kiran et al, 2022;Opazo-Rios et al, 2022;Smith et al, 2022). In the context of neurodegeneration, CREB3 and STAT3 are involved in neuroprotective mechanisms.…”

Sex differences in associations betweenAPOE ε2and longitudinal cognitive decline

“…Fourth, a challenge to studying sex differences in AD is that women are more likely than men to survive to older ages. 3 When a gene, such as APOE , has pleiotropic effects on risk for mortality and AD, 49 this survival bias can cause spurious associations. Finally, given the rarity of APOE ε2 homozygosity, we were unable to investigate sex differences in allelic dose effects.…”

Sex difference in evolution of cognitive decline: studies on mouse model and the Dominantly Inherited Alzheimer Network cohort

“…Neurological examination findings in AD (AD-NEF) from mutation carriers and non-carriers from the Dominantly Inherited Alzheimer Network (DIAN) revealed that AD-NEF are associated with a rapid cognitive decline and higher hippocampal atrophy [ 22 ]. Sex differences in the genetic make-up of resilience and multiple sex-specific molecular mechanisms may underlie resilience to AD pathology [ 23 ]. Perimenopausal and postmenopausal women aged 40 to 60 had more AD endophenotype than premenopausal women [ 24 ].…”