Basic Science and Pathogenesis

Background: Women are disproportionately affected by Alzheimer's disease (AD) and exhibit greater AD neuropathology than men. Women possess two X chromosomes, with one randomly silenced across each cell for dosage compensation. X chromosome inactivation (XCI) is not complete, and XCI-escaping genes provide a promising avenue of discovery for biological pathways driving sex-specific AD risk. Our objective was to examine XCI-escaping genes in association with β-amyloid (Aβ) and tau tangle density, and cognitive decline.

Methods: Using bulk RNAseq from dorsolateral prefrontal cortex tissue, Aβ plaque and tau tangle pathology, and antemortem longitudinal cognition data from ROSMAP, we investigated whether XCI-escaping genes explain significant variance in AD endophenotypes. Propensity scoring based on age-at-death, postmortem interval, race, latency-to-death, education, and APOEε4 status resulted in a matched sample (N = 648, age-at-death_mean(SD) = 87.5(6.5)). Linear regression and mixed-effects models assessed the association between 216 reported XCI-escaping genes and Aβ and tau at autopsy, and a longitudinal global cognitive composite. Analyses were sex-stratified and FDR-corrected. Differential expression analyses assessed sex-biased mean gene expression.

Results: 22 XCI-escaping genes were associated with Aβ (20 female-specific, 2 male-specific), 49 genes with tau (43 female-specific, 6 male-specific), and 48 genes with cognitive decline (46 female-specific, 2 male-specific). In women, 40%(8/20) were negatively associated with Aβ, 56%(24/43) negatively associated with tauopathy, and 43%(20/46) were negatively associated with cognitive decline. Of note, higher GRIPAP1 expression was associated with lower Aβ (β = -0.18, p_FDR = 0.02) and tau (β = -0.21, p_FDR = 0.001), and slower cognitive decline (β = 0.02, p_FDR = 0.04) in women. By contrast, ATP11C expression was associated with higher Aβ (β = 0.19, p_FDR = 0.03) and tau (β = 0.15, p_FDR = 0.03), and faster cognitive decline (β = -0.02, p_FDR = 0.03) in women. Unexpectedly, of 216 XCI-escaping genes tested, only 4% were expressed more highly in females than males.

Conclusion: GRIPAP1 and ATP11C are implicated in endosomal recycling and inflammation, respectively, supporting two pathways associated with AD. Both GRIPAP1 and ATP11C exhibited sex-parity in gene expression suggesting that single-cell RNAseq will be necessary to further characterize XCI-escapism in relation to AD risk. Altogether, this study presents evidence that studying the X chromosome is integral to understanding female resistance, resilience, and vulnerability to AD pathology.