Sex hormone binding globulin and total testosterone levels are associated with <i>in vivo</i> tau burden differentially between the sexes: findings from the Framingham Study
Bibliographic record
Abstract
Abstract Background In men and women, sex steroid hormones are associated with increased risk of Alzheimer’s disease (AD) dementia. In older men, lower levels of testosterone are associated with higher rates of AD dementia. The relationship between estradiol levels on AD dementia risk in post‐menopausal women, however, is less clear, with studies reporting protective, deleterious and no effects. Finally, higher levels of sex hormone binding globulin (SHBG), a glycoprotein that regulates, and actively influences sex hormones, has been consistently linked with increased risk for AD dementia. Studies have yet to examine mid‐life hormonal levels in association with later‐life in vivo AD biomarkers in cognitively healthy adults. Method 175 women and 159 men from the Framingham Study 3rd Generation cohort underwent blood (hormones) collection in 2002‐2005, and 18F‐Flortaucipir (FTP)‐PET and 11C‐PiB‐PET scans in 2016‐2020 (Table1). We examined FTP‐PET signal (referenced to cerebellar grey) in six a priori regions that previously demonstrated sex differences (entorhinal, inferior temporal, rostral middle frontal, inf/sup parietal and lateral occipital). Linear regressions examined sex‐stratified analyses of free/total testosterone, estradiol, and SHBG in each region, adjusting for age, age2, PET camera and plasma‐PET date‐difference (mean = 15(±2)yrs). Separate models examined interactions with a neocortical PiB‐PET composite and APOEε4. Result In men, elevated SHBG was associated with lower FTP‐PET in entorhinal (p = 0.007), inferior temporal (p = 0.04) and rostral middle frontal regions (p = 0.02; Table2). Higher total testosterone was marginally associated with lower FTP‐PET signal in the latter region (p = 0.06), but other relationships were apparent. In women, higher total testosterone associated with lower FTP‐PET signal in inferior temporal (p = 0.05) and parietal regions (p = 0.04). Women APOEε4 carriers with higher estradiol showed higher levels of entorhinal FTP‐PET signal (p = 0.03;Table3). Conclusion Higher levels of SHBG are associated with lower risk of AD‐related comorbidities, such as osteoporosis, diabetes, and visceral weight gain. A strong link between higher SHBG levels and higher HDL‐cholesterol may suggest a potential protective cardiovascular pathway for men against higher tau burden later in life. A lack of protective effect of pre‐menopausal estradiol in female APOEε4 carriers supports the notion that the role of estrogen in AD risk is centered around timing of decline.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".