Buckley Rachel F, Scott Matthew, McGrath Emer R, Coughlan Gillian, Seto Mabel, Ghosh Saptaparni, Jacobs Heidi I L, Satizabal Claudia L, Thibault Emma, Ramachandran Vasan, Murabito Joanne M, Sperling Reisa A, Johnson Keith A, Jasuja Ravi, Bhasin Shalender, Seshadri Sudha, Beiser Alexa S
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Boston, MA.
Ann Neurol. 2025 Sep;98(3):524-532. doi: 10.1002/ana.27266. Epub 2025 Jun 14.
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.
This time-lagged study includes participants enrolled in the Framingham Heart Study (FHS) Third Generation cohort. One hundred fifty-nine men (mean age = 58 [±/9] years) underwent blood (hormones) collection in 2002 to 2005, and then a single Aβ C-Pittsburgh Compound B (PiB) PiB-positron emission tomography (PET) and F-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.
In men, the elevated SHBG level was associated with lower tau-PET in entorhinal (B = -0.001 [SE = 0.0005], p = 0.007), inferior temporal (B = -0.001 [SE = 0.0004], p = 0.04), and rostral middle frontal regions (B = -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.
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.
在男性和女性中，性类固醇激素与阿尔茨海默病（AD）痴呆风险增加有关。我们旨在研究中年男性睾酮和性激素结合球蛋白（SHBG）水平对临床健康老年男性晚年体内β-淀粉样蛋白（Aβ）和tau蛋白沉积标志物的影响。
这项时间滞后研究纳入了弗雷明汉心脏研究（FHS）第三代队列的参与者。159名男性（平均年龄=58[±9]岁）于2002年至2005年接受血液（激素）采集，然后于2016年至2020年接受单次Aβ C-匹兹堡化合物B（PiB）正电子发射断层扫描（PET）和氟代托品（FTP）-PET扫描。线性回归分析在调整年龄后，研究总睾酮和SHBG与Aβ-PET和tau-PET之间按性别分层的关联。单独的模型研究了Aβ-PET和APOEε4的调节作用。
在男性中，较高的SHBG水平与内嗅区较低的tau-PET相关（B=-0.001[标准误=0.0005]，p=0.007），颞下回（B=-0.001[标准误=0.0004]，p=0.04），以及额中回前部（B=-0.001[标准误=0.0004]，p=0.02）。这些发现主要由非APOEε4携带者驱动。睾酮水平与Aβ-PET或tau-PET信号无关。
我们报告了SHBG水平对男性tau-PET负担的潜在保护作用。较高的SHBG水平与肥胖和糖尿病等血管相关合并症的较低风险有关，并且受可改变的生活方式因素调节。鉴于临床前AD中血管损伤与tau病变之间联系的证据越来越多，我们的发现提示了一条有趣的心血管保护途径，可使男性在晚年免受更高的tau负担。《神经病学纪事》2025年；98：524-532。
