TY - JOUR
T1 - Sex modifies APOE ϵ4 dose effect on brain tau deposition in cognitively impaired individuals
AU - Yan, Shaozhen
AU - Zheng, Chaojie
AU - Paranjpe, Manish D.
AU - Li, Yanxiao
AU - Li, Weihua
AU - Wang, Xiuying
AU - Benzinger, Tammie L.S.
AU - Lu, Jie
AU - Zhou, Yun
N1 - Publisher Copyright:
© 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - F-flortaucipir PET
KW - apolipoprotein E
KW - dose effect
KW - sex
UR - http://www.scopus.com/inward/record.url?scp=85121099536&partnerID=8YFLogxK
U2 - 10.1093/brain/awab160
DO - 10.1093/brain/awab160
M3 - Article
C2 - 33876815
AN - SCOPUS:85121099536
SN - 0006-8950
VL - 144
SP - 3201
EP - 3211
JO - Brain
JF - Brain
IS - 10
ER -