Biomarkers

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.

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.

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.

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.