Sex modulates the ApoE ε4 effect on brain tau deposition measured by ¹⁸F-AV-1451 PET in individuals with mild cognitive impairment

Abstract

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 18 F-AV-1451 tau and 18 F-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 18 F-AV-1451 and CSF tau (t-tau, p-tau) were assessed using generalized linear models. The association between 18 F-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 18 F-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. 18 F-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.

Multiparametric imaging hippocampal neurodegeneration and functional connectivity with simultaneous PET/MRI in Alzheimer’s disease

“…1 and Table 4, the statistical significance levels were improved by PET with PVC in testing the ROI FDG SUVR differences between AD and MCI groups in left and right hippocampus, CA2/3/ DG, and right CA1. This is consistent with our previous Alzheimer's Disease Neuroimaging Initiative studies in small ROIs including amygdala and entorhinal cortex, where the PET spatial resolution of 8-mm FWHM [28,29]. In the study, we also performed RBV (region-based voxelwise)-RVC (reblurred Van Cittert iteration) PVC algorithm [46].…”

“…where T 0 (x) = I(x), h(x) is a 3D Gaussian kernel of 4.5-mm FWHM spatial smoothing function, step length α = 1.5, and the iteration was stopped if relative percent change of PVC images < 1% [28,30]. 18 F-FDG SUVR images were calculated on the partial volume corrected PET images using cerebellum as reference tissue.…”

Sex differences in Alzheimer’s-related Tau biomarkers and a mediating effect of testosterone

“…Our ndings may also help to explain inconsistencies in the literature regarding an effect of APOE4 on Tau. Other biomarker [73], neuroimaging [74] and autopsy [75] studies found a more robust association between APOE4 and Tau in women versus men, whereas studies that did not compare by sex have shown inconsistent ndings in the APOE4 and Tau link [73,[76][77][78][79][80]. If the Tau and APOE4 relationship is dependent on testosterone, as our results suggest, the presence of this relationship may be related to the proportion of men versus women in a sample.…”

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer's Disease

“…While the exact cause and pathophysiology remain unknown, a number of mutations and genetic risk factors have been identi ed as associated with AD. Apolipoprotein E (apoE) is the most common genetic risk factor for late onset AD 8,[13][14][15][16][17][18] . ApoE is a lipid binding protein, that plays a central role in lipid transport and metabolism.…”

“…It has been conjectured that the higher prevalence in females is a result of longer life span 8,25 . Alternatively, studies have alluded to sex-speci c hormonal and metabolic changes that interplay with the onset and progression of AD dementia 6,16,28 . Sex also interacts with apoE isoform status, where females with the apoE4 isoform are at increased risk compared to males [29][30][31] .…”