Sex-specific early cognitive changes are linked to global and pathway-specific genetic risk for Alzheimer's disease in at-risk individuals.

Alzheimer's disease (AD) is a progressive neurodegenerative condition in which genetic predisposition plays a key role, yet the sex-specific mechanisms linking genetic risk to early cognitive changes remain unclear. This study examined the impact of polygenic risk scores (PRS) on early cognitive changes in 318 cognitively unimpaired participants from the ALFA+ cohort, a nested longitudinal cohort from the ALFA study (see details in Study Participants Section, Methods). Participants were followed for three years, with assessments across five cognitive domains and a preclinical composite (PACC). Global AD PRS, including and excluding the apolipoprotein E (APOE) gene, alongside five biologically informed pathway-specific PRS (amyloid, immune, external stimuli signaling, cholesterol efflux, lipoprotein metabolism) were computed. Generalized linear models including interaction by sex and stratified by sex and amyloid status (CSF Aβ42/40 < 0.071) assessed associations between PRS and cognitive change. In women, APOE-independent AD genetic risk predicted worse executive function, particularly via cholesterol efflux and external stimuli signaling pathways. Among Aβ + women, PRS also predicted lower memory performance, partially modulated by reproductive span. In Aβ - women, worse executive functioning performance was linked to amyloid, immune, and signaling pathways. In contrast, men showed associations between AD PRS and worse visual (Aβ-) and attentional (Aβ+) performance, independent of pathway-specific mechanisms. These findings reveal distinct, domain-specific cognitive vulnerabilities to AD genetic risk by sex and amyloid status, highlighting APOE-independent and mechanistic contributions to early and subtle cognitive changes. Results support the need for sex-aware, biologically informed genetic models in preclinical AD for risk stratification and early intervention. Alzheimer’s disease (AD) is a condition that slowly damages the brain, affecting memory, thinking, and behavior over time. Some people are more likely to develop Alzheimer’s because of their genetic profile. One well-known gene, the APOE gene, increases AD genetic risk. Nonetheless, many other genes also play a role, and we still do not fully understand how these genes affect brain health, especially in the very early stages of the disease, before any symptoms appear.In this study, we looked at 318 healthy adults who may be at higher genetic risk of AD. We followed their cognitive abilities over three years. We used genetic scores to estimate each person’s overall risk of developing AD and focused on specific genetic pathways related to processes like inflammation, cholesterol, and how brain cells communicate.We found that women and men showed different patterns. In women, genetic risk (even without APOE) was linked to lower performance in specific cognitive abilities, such as memory and executive function. In women displaying AD-specific pathological burden in the brain, lower cognitive performance was stronger. In men, the genetic risk was tied to changes in visual and attention skills, but through different biological routes.Our findings suggest that AD risk genes affect men and women differently, even before symptoms appear. Understanding these early, sex-specific patterns could help doctors predict who is at higher risk and lead to more personalized prevention strategies. This study highlights the importance of considering both sex and biology when studying AD.