Sex Modulates the ApoE ε4 Effect on Tau ¹⁸F-AV-1451 PET Imaging in Individuals with Normal Aging and Mild Cognitive Impairment

Objectives: The strongest genetic risk factor for Alzheimer’s disease (AD) is the Apolipoprotein E type 4 allele (ApoE ε4). Previously, an ApoE ε4:sex interaction effect has been shown in CSF tau levels (Hohman et al,. 2018). We report that sex modulates the relationship between ApoE ε4 and brain tau deposition in Mild Cognitive Impairment using AV1451-PET. These findings improve our understanding of the role of sex and ApoE ε4 as risk factors in preclinical AD and will help develop precision-medicine based therapeutics in AD. The objective of the study is to evaluate sex differences in the association between ApoE ε4 status and brain tau deposition measured using 18F-AV-1451 positron emission tomographic (PET) imaging among healthy older and Mild Cognitive Impairment (MCI) participants.

Methods: This cross-sectional study involved 131 cognitively normal (CN) elderly controls and 97 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Preprocessed ¹⁸F-AV-1451 PET images, T1-weighted structural MRI scans and demographic information were included. After downloading pre-processed images from ADNI, an partial volume correction (PVC) method was applied on all PET images, as previous described (Tohka and Reilhac, 2008). Structural MRIs were used for PET spatial normalization. Regions of interest (ROI) were defined in standard space and standardized uptake value ratio (SUVR) images were computed. ApoE 4 by sex interaction analysis and the main effect of ApoE ε4 on brain tau deposition stratified by sex were assessed in CN and MCI participants. All statistical analyses were performed after controlling for baseline age and education.

Results: Of the 131 CN participants, 66 were women, and the mean (SD) age was 77.56 (6.91) years (Table 1). Of the 97 MCI participants, 39 were women, and the mean age (SD) was 77.97 (7.24) years (Table 1). Chi-squared analysis revealed no significant differences in the proportion of ε4ε4/ε4ε3/ε4ε2 genotype individuals between men and women in either the CN group or MCI group (Table 2). After applying PVC and controlling for age and education level, we found the occipital cortex, and hippocampus exhibited a significant ApoE ε4 by sex interaction effect (p<.05) among CN individuals (Figure 1; Supplementary Table 1). The occipital cortex, hippocampus, lateral temporal, medial temporal, parietal, post central gyrus, posterior precuneus, posterior cingulate, amygdala, fusiform gyrus and parahippocampal gyrus exhibited a significant ApoE ε4 by sex interaction effect (p<.05) among MCI individuals (Figure 1; Supplementary Table 1). Using sex stratified analyses, we further found that all regions with significant ApoE ε4:sex interaction effect in MCI individuals had a significant ApoE ε4 main effect in MCI women but not MCI men.

Conclusions: Our findings suggest that effect of ApoE ε4 on brain tau deposition differs in women and men with MCI. Our work offers a potential explanation for epidemiological evidence demonstrating an increased penetrance of the ApoE e4 allele in females compared to males (Sundermann et al. 2018). In such a model, we propose that female ApoE ε4 carriers are more susceptible to tau-accumulation in preclinical AD compared to their male counterparts. By using a partial volume correction algorithm and correcting for age and education level, we are confident that our findings are related to genuine changes in brain tau rather than due to volume-related or technical biases.ReferencesHohman, T.J., et. al 2018. Sex-specific association of apolipoprotein e with cerebrospinal fluid levels of tau. JAMA Neurol. Sundermann, et. al, 2018. Sex differences in the association between apolipoprotein E ε4 allele and Alzheimer’s disease markers. Alzheimer’s Dement. Diagnosis, Assess. Dis. Monit. Tohka, J., Reilhac, A., 2008. Deconvolution-based partial volume correction in Raclopride-PET and Monte Carlo comparison to MR-based method. Neuroimage 39, 1570-1584.

• Download figure
• Open in new tab
• Download powerpoint