Midlife Steroid‐Binding Globulin Levels and In Vivo Neuroimaging Measures of Tau in Older Men and Women

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Objective In men and women, sex steroid hormones have been associated with increased risk of Alzheimer's disease (AD) dementia. We aimed to investigate the influence of midlife testosterone and sex hormone binding globulin (SHBG) levels on later‐life in vivo markers of β‐amyloid (Aβ) and tau deposition in clinically healthy older men. Methods This time‐lagged study includes participants enrolled in the Framingham Heart Study (FHS) Third Generation cohort. One hundred fifty‐nine men (mean agePET‐scan = 58 [±/9] years) underwent blood (hormones) collection in 2002 to 2005, and then a single Aβ 11C‐Pittsburgh Compound B (PiB) PiB‐positron emission tomography (PET) and 18F‐Flortaucipir (FTP)‐PET scan in 2016 to 2020. Linear regressions examined sex‐stratified associations among total testosterone, and SHBG with Aβ‐PET, and tau‐PET after adjusting for age. Separate models examined the moderating effect of Aβ‐PET and APOEε4. Results In men, the elevated SHBG level was associated with lower tau‐PET in entorhinal (Bunstandardized = −0.001 [SE = 0.0005], p = 0.007), inferior temporal (Bunstandardized = −0.001 [SE = 0.0004], p = 0.04), and rostral middle frontal regions (Bunstandardized = −0.001 [SE = 0.0004], p = 0.02). These findings were largely driven by APOEε4 non‐carriers. Testosterone levels were not associated with the Aβ‐PET or tau‐PET signal. Interpretation We report a potential protective effect of SHBG levels on tau‐PET burden in men. Higher levels of SHBG have been associated with lower risk of vascular‐related comorbidities, such as obesity and diabetes, and is regulated by modifiable lifestyle factors. Given mounting evidence of a link between vascular injury and tauopathy in preclinical AD, our findings suggest an intriguing protective cardiovascular pathway for men against higher tau burden later in life. ANN NEUROL 2025;98:524–532

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