Abstract
Background The SPARE‐AD (Spatial Pattern of Abnormalities for Recognition of Early Alzheimer's Disease [AD]) index effectively captures the level of AD‐association patterns of brain atrophy present in elderly individuals. APOE ε4, the strongest genetic risk factor for AD, demonstrates sex‐dependent effects with greater risk in females compared to males. Given SPARE‐AD's sensitivity to AD‐related brain changes, we investigated whether APOE‐ε4 carrier status influences brain atrophy patterns measured by SPARE‐AD and if these effects are modified by sex. Method This study included 3,289 non‐Hispanic White participants (mean SPARE‐AD=‐0.79; mean age=72.3; 55.2% cognitive normal; 33.1% MCI; 11.1% AD; 54.1% female) from 4 AD and cognitive aging cohorts (ADNI, NACC, ROS/MAP, WRAP). The SPARE‐AD index was calculated using a high‐dimensional, non‐linear pattern classification method with positive values indicating AD‐like brain atrophy and negative values indicating normal brain structure. In cross‐sectional analyses at baseline, we evaluated the dominant effects of APOE‐ε4 carrier status on SPARE‐AD using multiple linear regression, adjusting for age, sex, and education levels. Sex‐stratified analyses were conducted to examine effect modification. In longitudinal analyses, we applied linear mixed‐effects models with time (years from baseline) and the intercept as fixed and random effects. We first evaluate the longitudinal progression of SPARE‐AD among cognitively unimpaired participants versus participants with MCI at baseline. We then assessed the effects of APOE‐ε4 carrier status on SPARE‐AD progression rates and their modification by sex. All analyses were meta‐analyzed across cohorts. Result APOE‐ε4 carriers showed significantly higher SPARE‐AD indices at baseline versus non‐carriers (β=0.34; SE=0.16; p = 0.029), with this effect being significant only among females (β‐females=0.37; p‐females=0.0021; Figure 1). The utility of SPARE‐AD as a prodromal biomarker was validated in longitudinal analyses, where cognitively unimpaired individuals demonstrated significantly slower SPARE‐AD progression compared to those with MCI (β=‐0.11; SE=0.04; p = 0.0052). APOE‐ε4 carriers exhibited accelerated SPARE‐AD progression (β=0.05; SE=0.025; p = 0.047; Figure 2), with no sex differences observed. Conclusion Our multi‐cohort study demonstrates that APOE‐ε4 carrier status influences both brain atrophy patterns and their progression. While baseline APOE‐ε4 effects were female‐specific, progression rates were sex‐independent. These findings advance our understanding of sex‐specific genetic influences on AD‐related brain changes.