Background
Alzheimer’s disease (AD) is more prevalent in women than men, and robust evidence shows sex differences in the biological response to the AD neuropathological cascade. However, there is a ...lack of large‐scale genetic studies on sex‐specific genetic predictors of AD‐related cognitive outcomes. Thus, we sought to elucidate the sex‐specific genetic etiology of memory, executive function, and language performance.
Method
This study included six cohorts of cognitive aging (Nmales=7,267, Nfemales=9,518). We applied psychometric approaches to build harmonized memory, executive function, and language composite scores. Next, for all domains, we calculated slopes from the cognitive scores (two or more timepoints) with linear mixed effects models. Then we performed sex‐stratified and sex‐interaction GWAS on these phenotypes, covarying for baseline age and the first three genetic principal components. We meta‐analyzed across cohorts with a fixed‐effects model. Sensitivity analyses for all models restricted the sample to cognitively unimpaired individuals.
Result
In addition to well‐established associations with cognition at the APOE locus, we identified three genetic loci that showed sex‐specific effects with cognition. A chromosome 16 locus (rs114106271), a splicing‐quantitative trait locus for RP11‐152O14.4 and LINC02180 in the testis (GTEx), associated with baseline memory performance in men (β=0.13, P=2.40×10‐8; PInteraction=8.96×10‐6; Figures 1‐2) but not in women (β=‐0.01, P=0.76). A chromosome 14 locus (rs34074573), an expression‐quantitative trait locus (GTEx) for HOMEZ (a homeobox gene), and for BCL2L2 (a previously reported AD risk gene), associated with longitudinal memory performance in men (β=‐0.01, P=4.15×10‐8; PInteraction=5.83×10‐7; Figures 3‐4) but not in women (β=0.001, P=0.09). Finally, a chromosome 6 locus (rs9382966) associated with longitudinal language performance in men with near genome‐wide significance (β=‐0.004, P=6.29×10‐8; PInteraction=2.01×10‐4) but not in women (β=‐0.0003, P=0.61).
Conclusion
Our results highlight some key sex differences in the genetic architecture of cognitive outcomes. Findings further suggest that some sex‐specific genetic predictors have domain‐specific associations, providing an exciting opportunity to better understand the molecular basis of memory, executive function, and language through genomic analysis. Although our findings need to be replicated, our GWAS analyses highlight the contribution of sex‐specific genetic predictors beyond the APOE locus in conferring risk for late‐life cognitive decline.
Background
Approximately 30% of older adults are cognitively normal at death despite presence of Alzheimer’s disease (AD) neuropathology at autopsy. Studying these “resilient” individuals may lead to ...the discovery of novel therapeutic targets. In addition, growing evidence suggests sex differences in downstream neurodegenerative consequences of AD neuropathology, with recent studies highlighting notable sex‐specific genetic drivers of AD pathogenesis. We sought to extend this work by elucidating sex‐specific genetic factors underlying resilience to AD.
Method
We used our published genetic resilience pipeline to assess sex‐specific genetic predictors (Dumitrescu et al., 2020). Briefly, we used modern psychometric approaches to harmonize cognitive measures across four cohorts of cognitive aging (N=5054), in‐vivo amyloid PET across two studies, and leveraged autopsy measures of amyloidosis (CERAD staging) across two studies. A continuous measure of resilience was quantified using a latent variable framework whereby higher scores reflected better‐than‐predicted cognitive performance given amyloidosis level and lower scores reflected worse‐than‐predicted performance. We then performed sex‐stratified GWASs and sex‐interaction GWASs, covarying for age and the first three principal components and meta‐analyzed across cohorts. Finally, we performed sex‐stratified genetic correlation analyses (GNOVA) between our meta‐analysis results and summary statistics from 63 complex traits.
Result
Among individuals with normal cognition, we identified a female‐specific locus on chromosome 10 (rs827389, p(females)=7.4E‐09, p(males)=0.64, p(interaction)=8.3E‐05, MAF=0.46). This variant is a modest eQTL for KIN (p=0.003), a gene encoding a DNA/RNA binding protein (http://www.braineac.org). In our genetic correlation analyses, we observed male‐specific correlations between resilience and two heart rate‐related traits, whereby higher resilience was associated with lower genetic risk for poor heart health. We also observed opposing genetic correlations between resilience and multiple sclerosis such that females with higher resilience scores had lower susceptibility for multiple sclerosis (p.FDR=0.009), whereas males with higher resilience had higher susceptibility (p.FDR=0.001).
Conclusion
Our results highlight sex‐specific genes and pathways that may drive resilience in a biological sex‐dependent manner, although independent replication is needed. The best target to enhance resilience to AD neuropathology may depend on sex and genetic context of an individual. Future work should continue to evaluate sex differences in the genetic architecture of the AD neuropathological cascade.
