Sex and APOE-ε4 carrier effects on early-onset Alzheimer’s disease pathology

Abstract

BackgroundPreviously, we found that female sex is associated with greater pathology burden in early-onset Alzheimer’s disease (EOAD) in the Longitudinal EOAD Study (LEADS). Here, we have expanded our analyses by adding APOE-ε4 carrier status as a further predictor of EOAD pathologic burden.MethodWe included 180 EOAD LEADS participants with available APOE genotype, Flortaucipir PET, Florbetaben PET, and MRI data. Demographic and biomarker differences were analyzed using ANOVA. EOAD participants were split by sex and APOE-ε4 carrier status. Box plots were created in R and a voxel-wise multiple linear regression in SPM12 yielded statistical brain maps of gray matter density (GMD), amyloid and tau burden.ResultCompared to males, EOAD females showed significantly greater global amyloid uptake (mean SUVR, p=0.002) and greater tau SUVR in the MetaROI, Braak 3&4 and 5&6 regions (p=0.0007, p=0.001, p=0.01, resp., Table 1). Female APOE-ε4 carriers showed greater tau SUVR in Braak regions 1&2 than female non-carriers (p<0.01, Figure 2B). Male APOE-ε4 carriers showed trend-level thinner entorhinal cortex than male non-carriers (p=0.06, Figure 1). Interestingly however, femaleAPOE-ε4 non-carriers showed greater global amyloid SUVR than female carriers (p<0.01, Figure 2A). Further, APOE-ε4 non-carriers showed significantly thinner medial temporal cortices than carriers in both sexes (M, p<0.05; F, p<0.01). Male APOE-ε4 non-carriers also showed significantly lower mean cortical thickness than male carriers (p<0.05, Figure 1). Female APOE-ε4 non-carriers showed trend-level lower mean cortical thickness than female carriers (p=0.06, Figure 1). The FWE corrected SPM12 maps showed significantly greater GM atrophy in the right temporal lobe and greater amyloid burden in a right lateralized occipitoparietal pattern in female APOE-ε4 non-carriers compared to female carriers. Further, male APOE-ε4 non-carriers showed greater tau uptake in the left frontal lobe than male carriers (Figure 3).ConclusionThese results suggest that APOE-ε4 non-carrier status is associated with greater atrophy, amyloid and tau deposition in EOAD. This might be due to the presence of other strong genetic drivers of disease pathology in EOAD.