Blood biomarkers indicating elevated amyloid-β (Aβ) pathology in preclinical Alzheimer’s disease are needed to facilitate the initial screening process of participants in disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient Aβ pathology, but a comprehensive comparison with other putative blood biomarkers is lacking. In the ALFA+ cohort, all tested plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NfL and Aβ42/40) were significantly changed in preclinical Alzheimer’s disease. However, plasma p-tau231 reached abnormal levels with the lowest Aβ burden. Plasma p-tau231 and p-tau217 had the strongest association with Aβ positron emission tomography (PET) retention in early accumulating regions and associated with longitudinal increases in Aβ PET uptake in individuals without overt Aβ pathology at baseline. In summary, plasma p-tau231 and p-tau217 better capture the earliest cerebral Aβ changes, before overt Aβ plaque pathology is present, and are promising blood biomarkers to enrich a preclinical population for Alzheimer’s disease clinical trials.

需要表明临床前阿尔茨海默病中淀粉样蛋白-β (Aβ) 病理学升高的血液生物标志物，以促进疾病改善试验参与者的初步筛选过程。以前的生物流体数据表明磷酸化 tau231 (p-tau231) 可能表明初期 Aβ 病理学，但缺乏与其他推定的血液生物标志物的全面比较。在 ALFA+ 队列中，所有测试的血浆生物标志物（p-tau181、p-tau217、p-tau231、GFAP、NfL 和 Aβ42/40）在临床前阿尔茨海默病中都发生了显着变化。然而，血浆 p-tau231 达到异常水平，Aβ 负荷最低。血浆 p-tau231 和 p-tau217 与早期积累区域中的 Aβ 正电子发射断层扫描 (PET) 保留最相关，并且与基线时没有明显 Aβ 病理学的个体中 Aβ PET 摄取的纵向增加相关。总之，血浆 p-tau231 和 p-tau217 在明显的 Aβ 斑块病理出现之前更好地捕获最早的脑 Aβ 变化，并且是有希望的血液生物标志物，以丰富阿尔茨海默病临床试验的临床前人群。