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

Abstract

Recent studies in cognitively unimpaired elderly individuals suggest that the APOE ε4 allele exerts a dosage-dependent effect on brain tau deposition. The aim of this study was to investigate sex differences in APOE ε4 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, 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 ε4 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. Magnetic resonance images were used for PET spatial normalization. Twelve regional standardized uptake value ratios relative to the cerebellum were computed in standard space. APOE ε4 dosage × 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 ε4 dosage × 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). The medial temporal, entorhinal cortex, amygdala and parahippocampal gyrus regions retained a significant APOE ε4 dosage × sex interaction effect on tau deposition after adjusting for global cortical amyloid-β (P < 0.05). In sex-stratified analysis, there was no significant difference in tau deposition between female homozygotes and heterozygotes (P > 0.05). In contrast, male homozygotes standardized uptake value ratios were significantly greater than heterozygotes or non-carriers throughout all 12 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 voxel-wise analysis were similar to the ones obtained from regions of interest analysis. Our findings indicate that an APOE ε4 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 APOE ε4-associated Alzheimer's risk in males and females.

Keywords: 18F-flortaucipir PET; Alzheimer’s disease; apolipoprotein E; dose effect; sex.

Figure 1

APOE ε4 dose effect on region of interest ¹⁸F-flortaucipir SUVRs in the study cohort of cognitively impaired individuals. Mean (± SD) of SUVR for APOE ε4 non-carriers (green), heterozygotes (purple) and homozygotes (red) are depicted. P-value was defined using a generalized linear model, adjusting for age, years of education and sex. SUVR: Standardized uptake value ratio. *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 2

Mean images with and without PVC illustrate that sex modulates the APOE ε4 dose effect on ¹⁸F-flortaucipir SUVR in cognitively impaired participants. PVC images show (A) increased contrast and spatial resolution compared to images without PVC (B). Both PVC and non-PVC images visually demonstrate an interaction effect between sex and APOE ε4 status.

Figure 3

Sex modifies the APOE ε4 dosage effect on region of interest-based analysis of ¹⁸F-flortaucipir PET in cognitively impaired individuals. Box plots depict median value and the interquartile ranges of regional SUVRs for APOE ε4 non-carriers (green), heterozygotes (purple) and homozygotes (red) in females and males. P-value was defined using a generalized linear model, adjusting for age and years of education. F = female; M = male. Bold significance lines indicate comparison between APOE ε4 dosage groups. *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 4

Sex modifies the APOE ε4 dose effect on voxel-wise analysis of ¹⁸F-flortaucipir PET in cognitively impaired participants. APOE ε4 dose effect on voxel-wise SUVR is depicted in (A) females and (B) males. Female heterozygotes (A, left) and homozygotes (A, right) display increased ¹⁸F-flortaucipir SUVR compared to non-carriers. No significant differences in SUVR were observed between female heterozygotes and homozygotes. Male homozygotes demonstrate increased ¹⁸F-flortaucipir SUVR compared to male heterozygotes (B, left) and male non-carriers (B, right). No significant differences in SUVR were observed between male heterozygotes and male non-carriers. T-values are expressed on blue–red scale from 0 to 5 depicting voxels level with P < 0.001 (adjusted for age and years of education).