ImportancePostmenopausal females represent around 70% of all individuals with Alzheimer disease. Previous literature shows elevated levels of tau in cognitively unimpaired postmenopausal females compared with age-matched males, particularly in the setting of high β-amyloid (Aβ). The biological mechanisms associated with higher tau deposition in female individuals remain elusive.ObjectiveTo examine the extent to which sex, age at menopause, and hormone therapy (HT) use are associated with regional tau at a given level of Aβ, both measured with positron emission tomography (PET).Design, Setting, and ParticipantsThis cross-sectional study included participants enrolled in the Wisconsin Registry for Alzheimer Prevention. Cognitively unimpaired males and females with at least 1 18F-MK-6240 and 11C-Pittsburgh compound B PET scan were analyzed. Data were collected between November 2006 and May 2021.ExposuresPremature menopause (menopause at younger than 40 years), early menopause (menopause at age 40-45 years), and regular menopause (menopause at older than 45 years) and HT user (current/past use) and HT nonuser (no current/past use). Exposures were self-reported.Main Outcomes and MeasuresSeven tau PET regions that show sex differences across temporal, parietal, and occipital lobes. Primary analyses examined the interaction of sex, age at menopause or HT, and Aβ PET on regional tau PET in a series of linear regressions. Secondary analyses investigated the influence of HT timing in association with age at menopause on regional tau PET.ResultsOf 292 cognitively unimpaired individuals, there were 193 females (66.1%) and 99 males (33.9%). The mean (range) age at tau scan was 67 (49-80) years, 52 (19%) had abnormal Aβ, and 106 (36.3%) were APOEε4 carriers. There were 98 female HT users (52.2%) (past/current). Female sex (standardized β = −0.41; 95% CI, −0.97 to −0.32; P < .001), earlier age at menopause (standardized β = −0.38; 95% CI, −0.14 to −0.09; P < .001), and HT use (standardized β = 0.31; 95% CI, 0.40-1.20; P = .008) were associated with higher regional tau PET in individuals with elevated Aβ compared with male sex, later age at menopause, and HT nonuse. Affected regions included medial and lateral regions of the temporal and occipital lobes. Late initiation of HT (>5 years following age at menopause) was associated with higher tau PET compared with early initiation (β = 0.49; 95% CI, 0.27-0.43; P = .001).Conclusions and RelevanceIn this study, females exhibited higher tau compared with age-matched males, particularly in the setting of elevated Aβ. In females, earlier age at menopause and late initiation of HT were associated with increased tau vulnerability especially when neocortical Aβ elevated. These observational findings suggest that subgroups of female individuals may be at higher risk of pathological burden.

Insulin sensitivity, pancreatic β-cell function, fasting glucose, and 2-h post-load glucose were related to cognition in cognitively healthy nondiabetic older adults. Thirty-five adults (⩾65 years) underwent a 2-h oral glucose tolerance test and cognitive testing. Seventeen had normal glucose tolerance and 18 had intermediate hyperglycaemia or prediabetes (World Health Organization criteria). Fasting glucose and 2-h post-load glucose and oral glucose tolerance test–derived measures of β-cell function (oral disposition index) and insulin sensitivity were analysed as predictors of four cognitive domains: verbal episodic memory, verbal fluency, executive function, and working memory. The prediabetes group had significantly worse working memory performance than the normal glucose tolerance group. Controlling for age and education, decreased oral disposition index, and increased 2-h post-load glucose were significantly related to worse working memory performance. Prediabetes may worsen working memory in healthy older adults. Reduced pancreatic β-cell function should be investigated as a contributor to age-related cognitive decline.

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Considerable research has shown that testosterone regulates many physiological systems, modulates clinical disorders, and contributes to health outcome. However, studies on the interaction of testosterone levels with depression and the antidepressant effect of testosterone replacement therapy in hypogonadal men with depression have been inconclusive. Current findings indicate that low circulating levels of total testosterone meeting stringent clinical criteria for hypogonadism and testosterone deficiency induced by androgen deprivation therapy are associated with increased risk for depression and current depressive symptoms. The benefits of testosterone replacement therapy in men with major depressive disorder and low testosterone levels in the clinically defined hypogonadal range remain uncertain and require further investigation. Important considerations going forward are that major depressive disorder is a heterogeneous phenotype with depressed individuals differing in inherited polygenic determinants, onset and clinical course, symptom complexes, and comorbidities that contribute to potential multifactorial differences in pathophysiology. Furthermore, polygenic mechanisms are likely to be critical to the biological heterogeneity that influences testosterone-depression interactions. A genetically informed precision medicine approach using genes regulating testosterone levels and androgen receptor sensitivity will likely be essential in gaining critical insight into the role of testosterone in depression.

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