Interactive rather than independent effect of APOE and sex potentiates tau deposition in women

The apolipoprotein E gene (APOE) is the most important genetic risk factor for sporadic Alzheimer disease, with the ε4 allele being associated with increased cerebral amyloid-β and tau pathologies. Although APOE has been suggested to have a stronger effect in women as compared to men, there is a lack of comprehensive assessment on how the interactive effect of APOE and sex modulates regional vulnerability to tau accumulation. We previously have shown the regional vulnerability to the interactive effect of tau and APOE, yet the sex difference was not specifically addressed. In this study, we leveraged PET imaging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University Research Centre for Studies in Aging to elucidate the APOE-by-sex interactive effect on tau burden. We hypothesized sex-dependent regional vulnerability to tau deposition. PET radiopharmaceuticals [¹⁸F]AZD4694 and [¹⁸F]MK6240 were used to assess amyloid-β and tau level respectively in 277 subjects from the Translational Biomarkers in Aging and Dementia cohort. We found that the interaction between APOE and sex, rather than their independent main effects, was associated with abnormal tau accumulation in medial temporal regions. Specifically, we found that female APOEε4 carriers showed significantly higher tau burden in early tau deposition regions including the hippocampus, entorhinal and parahippocampal cortices, after accounting for age, educational attainment, clinical diagnosis and neocortical amyloid load. We replicated these findings in 221 subjects from the Alzheimer's Disease Neuroimaging Initiative cohort, in which a different tau-PET radioligand, [¹⁸F]flortaucipir, was used to assess tau burden. In conclusion, this study provides evidence from two cohort studies that interactive rather than independent effect of APOE and sex potentiates early tau deposition in women. Our results have important implications for clinical trials and practice, which should take into consideration both APOEε4 carriage status and sex for identifying individuals with the highest probability of developing tau accumulation and clinical progression.