Sex‐ and APOE Genotype–Dependent Pain Susceptibility and Alzheimer's Risk Mediated by the Lipid Metabolism Enzyme LPCAT2

ABSTRACT Neuropathological changes that precede or accompany early cognitive decline in Alzheimer's disease (AD) may also impact pain processing; however, the molecular connection between these domains remains unclear. In this study, we investigated whether a shared causal factor underlies both increased pain susceptibility and AD progression. Analysis of two ethnically distinct cohorts revealed a significant association between pain susceptibility and cognitive decline from cognitively normal (CN) status to mild cognitive impairment (MCI), particularly in non‐ APOE4 (non‐E4) males, an unexpected finding given that APOE4 females exhibited the highest overall pain susceptibility across sex and genotype groups. To explore potential drivers of this APOE genotype‐ and sex‐specific association, blood transcriptomic analysis identified LPCAT2 expression as correlating with both heightened pain susceptibility and progression from MCI to AD, most notably in non‐E4 males. This relationship was further supported by elevated LPCAT2 protein levels in the hippocampus of postmortem non‐E4 male AD patients. Strengthening this link, our genetic association analysis across four cohorts identified several functional LPCAT2 variants that not only influenced its expression but were also associated with altered pain susceptibility, increased AD risk, and accelerated progression from MCI to AD. To move beyond correlation and assess causality, Mendelian randomization analysis supported a causal role for LPCAT2 in both pain susceptibility and MCI‐to‐AD progression. Collectively, these findings identify LPCAT2 as a key molecular link between altered pain processing and AD progression, highlighting its potential as both a therapeutic target for genotype‐ and sex‐specific subpopulations and a prognostic biomarker for MCI‐to‐AD conversion.