Transcriptomic and proteomic sex differences in the Alzheimer’s cortex are large but do not scale with pathology

Abstract Background Alzheimer’s disease (AD) shows sex differences in prevalence, progression, and disease phenotypes, and molecular studies routinely report hundreds of sex-associated genes in the AD cortex. Most of these reports quantify the difference between the sexes within a diagnostic group, or compare gene lists obtained by analyzing women and men separately. Neither approach tests whether the molecular response to accumulating pathology itself differs between the sexes. Methods We estimated the sex-by-pathology interaction, defined as the difference between female and male slopes of molecular abundance on Braak stage, in three donor-level datasets: single-nucleus RNA sequencing of dorsolateral prefrontal cortex from up to 303 ROSMAP donors across nine cell types, an independent single-nucleus cohort of 80 SEA-AD donors, and tandem mass tag proteomics of 777 AMP-AD donors. All tests were performed on donor-level summaries, and aggregated gene set and co-expression analyses were referenced to expression-matched or sex-label permutation nulls. Results Sex-linked molecular differences were abundant and highly reproducible, led by sex-chromosome genes and X-inactivation escapees, but none of them scaled detectably with pathology. No gene showed a Braak-by-sex interaction among 71,360 tests and no protein did so among 8,435, while in the same donors and the same models thousands of proteins tracked Braak stage and clinical diagnosis. Gene-set scores, cross-cohort replication, rank divergence, and co-expression rewiring were all consistent with their matched nulls, and the familiar asymmetry between sex-stratified gene lists fell within its permutation null. Conclusions In the AD cortex, sex acts predominantly as a large and stable offset rather than as a detectable modifier of the molecular pathological trajectory. Interactions larger than 0.082–0.274 log2 units per Braak stage, depending on cell type, would have been detectable with 80% power, and resolving effects of the size actually present would require roughly 11,300 donors.