Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured By Positron Emission Tomography in Clinically Normal Older Adults

Abstract

This analysis of 2 cross-sectional cohort studies examines the sex differences in the association between β-amyloid and regional tau deposition as measured with positron emission tomography (PET). Do sex differences exist in regional tauopathy, as measured with positron emission tomography, and is this largely driven by higher global amyloid burden? In this study of 2 cross-sectional cohorts of 296 clinically normal adults, women with higher amyloid burden showed greater entorhinal cortical tau signal compared with men with higher amyloid burden. Sex differences did not exist in amyloid load or apolipoprotein E ε4 frequency. In conjunction with this finding, mounting evidence supports the notion that sex differences in the Alzheimer disease pathologic trajectory may well appear downstream of abnormal amyloid burden in the acceleration of tau deposition and brain atrophy. Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals. To examine sex differences in the cross-sectional association between Aβ and regional tau deposition as measured with positron emission tomography (PET). This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aβ PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women [61%]) who underwent carbon 11–labeled Pittsburgh Compound B and flortaucipir F 18 PET and 103 clinically normal individuals from the Alzheimer’s Disease Neuroimaging Initiative (age range, 63-94 years; 55 women [51%]) who underwent florbetapir and flortaucipir F 18 PET. A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aβ as well as sex and APOE ε4 on these regions after controlling for age were also examined. The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers [31%]; 89 individuals [30%] with high Aβ). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: β [male] = −0.11 [0.05]; 95% CI, −0.21 to −0.02; P  = .02), which was associated with individuals with higher Aβ burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: β [male, APOE ε4+] = −0.15 [0.09]; 95% CI, −0.32 to 0.01; P  = .07). Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.