The influence of genetic predisposition to Alzheimer’s disease in cognitive decline differs among sex in cognitively unimpaired individuals in the Alzheimer’s <i>continuum</i>

Abstract Background Evidence shows sex differences in cognitive performance in Alzheimer’s disease (AD). However, studies exploring whether genetic predisposition to AD differs in cognition among sex are scarce. We aimed to evaluate whether the influence of AD genetic liability in cognition differs among sex in cognitively unimpaired (CU) individuals in the AD continuum . Method We included 318 CU individuals from the ALFA+ cohort (Table 1). Cognitive change (∼3‐year follow‐up) was measured with a PACC and for individual cognitive domains. Polygenic scores estimating each participant’s genetic predisposition to AD were calculated with (PRS‐AD) and without (PRS‐ADnoAPOE) considering the APOE region (threshold = 5×10‐6). Amyloid positivity (Aβ+) was defined as cerebrospinal fluid (CSF) Aβ42/40&lt;0.0071. Generalized linear models stratified by sex and amyloid status were performed to assess the association between cognitive change and genetic predisposition to AD. Models were corrected by age, years of education, and time between visits. Models were additionally corrected by baseline Jack’s cortical thickness AD signature as a marker of neurodegeneration. Result In Aβ+ women (n = 65), a higher genetic predisposition to AD was associated with steeper memory ( p PRS_AD = 0.04; p PRS_ADnoAPOE = 0.01) and executive function ( p PRS_ADnoAPOE = 0.001) decline after correcting by brain AD signature. In Aβ+ men (n = 44), a higher genetic predisposition to AD was associated with worse follow‐up performance on attention ( p PRS_AD = 0.05, p PRS_ADnoAPOE = 0.04), and results did not remain significant after correcting by brain AD signature (Figure 1). In Aβ‐, genetic predisposition to AD was also associated with executive function decline in women (n = 122) ( p PRS_AD = 0.16, p PRS_ADnoAPOE = 0.02), while Aβ‐ men (n = 87) showed worse follow‐up performance on visual processing ( p PRS_AD = 0.251, p PRS_ADnoAPOE = 0.001). Results remained significant after correcting by brain AD signature (Figure 2). Conclusion Our results showed that genetic predisposition to AD is associated with changes in different cognitive domains in men and women. These findings will contribute to developing precision medicine approaches in AD encompassing sex‐sensitive strategies for prevention.