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 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 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. MRI 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 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 ε4 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). The medial temporal, entorhinal cortex, amygdala and parahippocampal gyrus regions retained a significant APOE ε4 dosage by 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 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 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 apolipoprotein E ε4-associated Alzheimer’s risk in males and females.

Influence of Gender on Tau Precipitation in Alzheimer’s Disease According to ATN Research Framework

“…In the study, we found more tau deposition in women than men among those who entered the AD disease spectrum and were tau-positive. Previous studies have shown that women have a greater tau burden than men, which is consistent with our findings (Yan et al 2021). In addition, based on ROI analysis, we also found inconsistent regions of interest in the ADNI cohort and the Huashan cohort in which sex caused differences in tau deposition.…”

Apolipoprotein E genotype modulates longitudinal atrophy at the temporal lobe after mild traumatic brain injury

“…There were several limitations in the present study. First, the APOE ε4 allele is termed as the genetic risk factor of AD, which is also exerts a dosage-dependent effect on the risk of AD [49]. Nevertheless, the APOE ε4/ε4 homozygotes only take nearly 10% of AD affected individuals [50,51].…”

Tracer‐specific reference tissues selection improves detection of 18F‐FDG, 18F‐florbetapir, and 18F‐flortaucipir PET SUVR changes in Alzheimer's disease

“…SUVR images were calculated relative to the cerebellum GM (SUVR Cereb_GM ), centrum semiovale (SUVR CS ), and pons (SUVR Pons ) reference tissues. The ROI SUVR values were calculated by applying ROIs on the SUVR images in the standard MNI space for minimizing variance related to the variability of ROI volume and shape in native space (Gottesman et al, 2017; Liu et al, 2019; Paranjpe et al, 2019; Tudorascu et al, 2018; Yan et al, 2021). A total of 18 ROIs including three reference tissues (cerebellum GM, centrum semiovale, and pons) and an additional 15 ROIs including the orbital frontal, prefrontal, superior frontal, medial temporal, inferior temporal, lateral temporal, parietal, posterior precuneus, anterior cingulate, posterior cingulate, occipital, entorhinal cortex, amygdala, hippocampus, and parahippocampal gyrus regions were manually delineated on the MRI template using the PMOD software program (PMOD 4.002, PMOD Technologies Ltd., Zürich, Switzerland) in standard MNI space.…”

“…The PET and MRI data were further processed by partial volume correction (PVC) and spatial normalization, both using Statistical Parametric Mapping (SPM12, Wellcome Department of Imaging Neuroscience, Institute of Neurology, London, UK) in the MATLAB R2020b (The MathWorks Inc., Natick, MA) environment, as reported in our earlier studies (Paranjpe et al, 2019;Yan et al, 2020Yan et al, , 2021. PVC was performed to minimize the possibility of underestimation in PET images, especially for small brain regions such as amygdala and striatum.…”

“…A total of 18 ROIs including three reference tissues (cerebellum GM, centrum semiovale, and pons) and an additional 15 ROIs including the orbital frontal, prefrontal, superior frontal, medial temporal, inferior temporal, lateral temporal, parietal, posterior precuneus, anterior cingulate, posterior cingulate, occipital, entorhinal cortex, amygdala, hippocampus, and parahippocampal gyrus regions were manually delineated on the MRI template using the PMOD software program (PMOD 4.002, PMOD Technologies Ltd., Zürich, Switzerland) in standard MNI space. These ROI templates were previously developed in the Johns Hopkins Department of Radiology and have been validated in our former studies (Liu et al, 2019;Paranjpe et al, 2019;Yan et al, 2020Yan et al, , 2021Zhou et al, 2021).…”