Studies have shown that women on the Alzheimer’s disease (AD) continuum have more pathological tau in the brain and cerebrospinal fluid (CSF), than men. Some studies have found that higher levels of tau biomarkers are more strongly associated with clinical AD, cognitive decline and neurodegeneration in women than in men. Despite major developments in the use of plasma tau phosphorylated at threonine 181 (p-tau181) as an AD biomarker, it is unknown whether these sex differences apply to plasma p-tau181. In 1060 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants (47% women, 73.8 ± 7.6 years old), we examined sex differences in plasma p-tau181 levels and their association with other biomarkers, cognitive decline and incident AD. Linear regressions tested for an effect of sex on plasma p-tau181 levels and for plasma p-tau181 × sex interactions on CSF p-tau181, as well as entorhinal cortex tau, cortical amyloid-β (Aβ) deposition, and brain glucose metabolism, quantified using PET imaging. Linear mixed effects models tested for a sex × baseline plasma p-tau181 interaction on change in cognition over time. Finally, Cox models tested for a sex × plasma p-tau181 interaction on the risk of AD dementia in participants who were free of dementia at baseline. Despite similar plasma p-tau181 levels between sexes, women had lower brain glucose metabolism, greater brain Aβ and entorhinal cortex tau deposition, higher CSF p-tau181 and faster cognitive decline in relation to higher baseline plasma p-tau181 levels compared with men. Among Aβ positive, dementia-free participants, women had higher rates of incident AD dementia associated with increasing baseline plasma p-tau181 levels, relative to men. Our results suggest that sex may impact the clinical interpretation of plasma p-tau181 concentrations. If replicated, these findings could have important implications for the use of plasma p-tau181 as an accessible AD biomarker and screening tool for preventive and therapeutic clinical trials.

研究表明，患有阿尔茨海默氏病 (AD) 连续体的女性大脑和脑脊液 (CSF) 中的病理性 tau 蛋白多于男性。一些研究发现，与男性相比，更高水平的 tau 生物标志物与女性的临床 AD、认知能力下降和神经退行性变的相关性更强。尽管在使用苏氨酸 181 磷酸化的血浆 tau (p-tau181) 作为 AD 生物标志物方面取得了重大进展，但尚不清楚这些性别差异是否适用于血浆 p-tau181。在 1060 名阿尔茨海默氏病神经影像学倡议 (ADNI) 参与者（47% 的女性，73.8 ± 7.6 岁）中，我们检查了血浆 p-tau181 水平的性别差异及其与其他生物标志物、认知能力下降和事件 AD 的关联。线性回归测试了性别对血浆 p-tau181 水平的影响以及血浆 p-tau181 × 性别相互作用对脑脊液 p-tau181 以及内嗅皮质 tau、皮质淀粉样蛋白-β (Aβ) 沉积和脑葡萄糖代谢的影响，使用 PET 成像进行量化。线性混合效应模型测试了性别×基线血浆 p-tau181 相互作用对认知随时间变化的影响。最后，Cox 模型测试了性别×血浆 p-tau181 相互作用对基线时未患痴呆症的参与者患 AD 痴呆症的风险。尽管两性之间的血浆 p-tau181 水平相似，但与男性相比，女性具有较低的脑葡萄糖代谢、更多的脑 Aβ 和内嗅皮层 tau 沉积、更高的脑脊液 p-tau181 和更快的认知能力下降与更高的基线血浆 p-tau181 水平相关。在 Aβ 阳性、无痴呆症的参与者中，相对于男性，女性与基线血浆 p-tau181 水平升高相关的 AD 痴呆事件发生率更高。我们的结果表明，性别可能会影响血浆 p-tau181 浓度的临床解释。如果被复制，这些发现可能对使用血浆 p-tau181 作为可及的 AD 生物标志物和筛查工具进行预防和治疗临床试验具有重要意义。