Mapping sex differences in brain and cognition in relation to APOE ε4 and amyloid burden: A longitudinal normative modelling study

Abstract INTRODUCTION Sex differences in Alzheimer's disease (AD) risk are increasingly recognized, with females exhibiting higher global prevalence rates. Yet, it remains unclear how genetic and biomarker indicators of AD risk, such as apolipoprotein E ( APOE ) ε4 and amyloid burden, relate to sex differences in brain and cognitive health during the preclinical stage. METHODS Using established normative models trained on ≈ 58,000 healthy participants, we computed regional Z scores from T1‐weighted magnetic resonance imaging scans in 372 cognitively normal participants from the Insight 46 cohort. Scans were acquired at two timepoints, ≈ 3 years apart, beginning at age 70. Regions with Z scores < –1.96 were classified as brain‐structure outliers and summarized as total outlier count (tOC). We used linear mixed effects models to examine how sex, age, and AD risk ( APOE ε4 status and amyloid burden) predict tOC and cognitive outcomes (Preclinical Alzheimer Cognitive Composite [PACC] scores). We examined cross‐sectional associations and longitudinal changes in tOC and PACC scores, and tested whether the effects of APOE ε4 status and amyloid burden on brain and cognitive measures differed by sex. RESULTS Cross‐sectional analyses showed that males had greater tOC than females at younger ages. At timepoint 1, spatial maps showed more outlier regions in males, though high outlier proportions were limited to occipital areas. By timepoint 2, sex differences became more spatially distinct, with males and females showing deviations in different regions. Longitudinally, older males exhibited steeper increases in tOC over time compared to females. Greater tOC and amyloid burden were both associated with poorer cognitive outcomes, with a trend toward stronger associations in female APOE ε4 carriers. We found no evidence that AD risk influenced age‐related changes in tOC or cognition over time. DISCUSSION These findings highlight normative modelling's utility in revealing the complex interplay among sex, age, and AD risk in shaping brain structure and cognition in later life. Highlights Normative models detect sex‐ and Alzheimer's disease risk‐related brain changes in older adults. Sex‐specific brain outlier patterns emerge in distinct regions over time. Younger males show more brain outliers (greater cortical thinning) than females. Older males exhibit faster accumulation of brain‐structure outliers. More outliers and amyloid predict worse cognition, stronger in female apolipoprotein E ε4 carriers.