The strongest genetic risk factor for
Alzheimer's disease (AD) is the
Apolipoprotein E type 4 allele (
ApoE ε4). The interaction between sex and
ApoE ε4 carrier status on AD risk remains an area of intense investigation. We hypothesized that sex modulates the relationship between
ApoE ε4 carrier status and brain tau deposition (a quantitative endophenotype in AD) in individuals with
mild cognitive impairment (MCI). Methods: Preprocessed 18F-AV-1451 tau and
18F-AV-45 amyloid PET images, T1-weighted structural magnetic resonance imaging (MRI) scans, demographic information, and cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) measurements from 108 MCI subjects in the
Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included. After downloading pre-processed images from ADNI, an iterative reblurred Van Cittertiteration partial volume correction (
PVC) method was applied to all PET images. MRIs were used for PET spatial normalization. Regions of interest (ROIs) were defined in standard space, and standardized uptake value ratio (SUVR) images relative to cerebellum were computed.
ApoE ε4 by sex interaction analyses on 18F-AV-1451 and CSF tau (t-tau, p-tau) were assessed using generalized linear models. The association between 18F-AV-1451 SUVR and CSF tau (t-tau, p-tau) was assessed. Results: After applying
PVC and controlling for age, education level and global cortical
18F-AV-45 SUVR, we found that the entorhinal cortex, amygdala, parahippocampal gyrus, posterior cingulate, and occipital ROIs exhibited a significant
ApoE ε4 by sex interaction effect (false discovery rate P < 0.1) among MCI individuals. We also found a significant
ApoE ε4 by sex interaction effect on CSF t-tau and p-tau. 18F-AV-1451 SUVR in the 5 ROIs with
ApoE ε4 by sex interaction was significantly correlated with CSF p-tau and t-tau. Conclusions: Our findings suggest that women are more susceptible to
ApoE ε4-associated accumulation of neurofibrillary tangles in MCI compared to males. Both CSF tau (p-tau, t-tau) and brain tau PET are robust quantitative
biomarkers for studying
ApoE ε4 by sex effects on brain tau deposition in MCI participants.