Sex modifies APOE ε4 dose effect on brain tau deposition in cognitively impaired individuals.

Recent studies in cognitively unimpaired elderly individuals suggest that the APOE e4 allele exerts a dosage-dependent effect on brain tau deposition. The aim of this study was to investigate sex differences in APOE e4 gene dosage effects on brain tau deposition in cognitively impaired individuals using quantitative 18F-flortaucipir PET. Preprocessed 18F-flortaucipir tau PET images, T1-weighted structural MRI images, demographic information, global cortical amyloid-β burden measured by 18F-florbetapir PET, CSF total tau and phosphorylated tau measurements were obtained from the Alzheimer's Disease Neuroimaging Initiative database. Two hundred and sixty-eight cognitively impaired individuals with 146 APOE e4 non-carriers and 122 carriers (85 heterozygotes and 37 homozygotes) were included in the study. An iterative reblurred Van Cittert iteration partial volume correction method was applied to all downloaded PET images. MRI images were used for PET spatial normalization. Twelve regional standardized uptake value ratios relative to the cerebellum were computed in standard space. APOE e4 dosage by sex interaction effect on 18F-flortaucipir standardized uptake value ratios was assessed using generalized linear models and sex-stratified analysis. We observed a significant APOE e4 dosage by sex interaction effect on tau deposition in the lateral temporal, posterior cingulate, medial temporal, inferior temporal, entorhinal cortex, amygdala, parahippocampal gyrus regions after adjusting for age and education level (P 0.05). In contrast, male homozygotes standardized uptake value ratios were significantly greater than heterozygotes or non-carriers throughout all twelve regions of interest (P < 0.05). Female heterozygotes exhibited significantly increased tau deposition compared to male heterozygotes in the orbitofrontal, posterior cingulate, lateral temporal, inferior temporal, entorhinal cortex, amygdala and parahippocampal gyrus (P < 0.05). Results from voxelwise analysis were similar to the ones obtained from regions of interest analysis. Our findings suggest that an APOE e4 dosage effect on brain region-specific tau deposition exists in males, but not females. These results have important clinical implications towards developing sex and genotype-guided therapeutics in Alzheimer's disease and uncovers a potential explanation underlying differential apolipoprotein E e4-associated Alzheimer's risk in males and females.