Elevated serum cortisol associated with early-detected increase of brain amyloid deposition in Alzheimer's disease imaging biomarkers among menopausal women: The Framingham Heart Study

INTRODUCTION: This study investigates whether midlife cortisol levels predict Alzheimer's disease (AD) biomarker burden 15 years later, with particular attention to sex differences and menopausal status. METHODS: We analyzed data from 305 cognitively unimpaired Framingham Heart Study participants (48.5% female; mean age: 39.6 ± 8.1 years). Serum cortisol was categorized into tertiles, with amyloid ([¹¹C]PiB) and tau ([¹⁸F]Flortaucipir) positron emission tomography (PET) imaging conducted 15 years later. We performed multivariable regression analyses adjusted for confounders including, apolipoprotein E4 (APOE4) status. RESULTS: Elevated midlife cortisol correlated with increased amyloid deposition, specifically in post-menopausal women, predominantly in posterior cingulate, precuneus, and frontal-lateral regions (p < 0.05). No significant associations were observed with tau burden or in males. DISCUSSION: These findings reveal post-menopausal women with high midlife cortisol are at increased risk of AD. Results highlight the importance of identifying early risk factors when biomarkers are detectable but cognitive impairment is absent. Highlights: High midlife cortisol is linked to increased amyloid deposition in post-menopausal women. Cortisol showed no association with tau pathology. Post-menopausal hormone changes may amplify cortisol's effects on amyloid.