Abstract
Women show greater pathological Tau biomarkers than men along the Alzheimer’s disease (AD) continuum, particularly among apolipoprotein ε-E4 (APOE4) carriers; however, the reason for this sex difference in unknown. Sex differences often indicate an underlying role of sex hormones. We examined whether testosterone levels might influence this sex difference and the modifying role of APOE4 status. Analyses included 172 participants (25 cognitively normal, 97 mild cognitive impairment, 50 AD participants) from the Alzheimer’s Disease Neuroimaging Initiative (34% female, 54% APOE4 carriers, aged 55–90). We examined the separate and interactive effects of plasma testosterone levels and APOE4 on cerebrospinal fluid phosphorylated-tau181 (p-Tau) levels in the overall sample and the sex difference in p-Tau levels before and after adjusting for testosterone. A significant APOE4-by-testosterone interaction revealed that lower testosterone levels related to higher p-Tau levels among APOE4 carriers regardless of sex. As expected, women had higher p-Tau levels than men among APOE4 carriers only, yet this difference was eliminated upon adjustment for testosterone. Results suggest that testosterone is protective against p-Tau particularly among APOE4 carriers. The lower testosterone levels that typically characterize women may predispose them to pathological Tau, particularly among female APOE4 carriers.
Highlights
There are critical gaps in our understanding of sex differences in Alzheimer’s disease (AD) including the higher prevalence of AD [1, 2], the steeper cognitive decline [3,4,5], and a stronger effect of the apolipoprotein E ε4 allele (APOE4) on AD risk in women versus men [6,7,8]
apolipoprotein ε-E4 (APOE4) carriers were younger, showed poorer global cognition, had higher p-Tau levels, were less likely to be cognitively normal, and more likely to be AD dementia patients compared to non-carriers
Explanatory role of testosterone in sex difference in pTau In testing the mediating role of testosterone in the sex difference in p-Tau levels, we found that the significantly higher p-Tau levels in female APOE4 carriers versus male APOE4 carriers was eliminated after adjusting for testosterone levels (B = 3.21, β = 0.09, SE = 5.78, p = .58; Fig. 1)
Summary
There are critical gaps in our understanding of sex differences in Alzheimer’s disease (AD) including the higher prevalence of AD [1, 2], the steeper cognitive decline [3,4,5], and a stronger effect of the apolipoprotein E ε4 allele (APOE4) on AD risk in women versus men [6,7,8]. Tau. In women, circulating estradiol levels experience a substantial decline during menopause, whereas postmenopausal women continue to demonstrate a range of circulating testosterone levels that continue to be lower than levels in men [17]. In women, circulating estradiol levels experience a substantial decline during menopause, whereas postmenopausal women continue to demonstrate a range of circulating testosterone levels that continue to be lower than levels in men [17] Despite this sex difference in hormone levels, most studies examining links between testosterone and AD-related outcomes have been solely in men [18,19,20,21,22,23], and the link between testosterone and Tau has been minimally examined in humans. Exogenous testosterone supplementation led to improved performance over time in a range of cognitive domains including global cognition [19, 33], psychomotor speed [33], executive function [33], and spatial and verbal memory [34, 35], not always [36]
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