Kirsebom Bjørn-Eivind, Gonzalez-Ortiz Fernando, Vigneswaran Sinthujah, Bråthen Geir, Skogseth Ragnhild Eide, Gísladóttir Berglind, Harrison Peter, Jarholm Jonas Alexander, Pålhaugen Lene, Rongve Arvid, Selnes Per, Tjims Betty, Turton Michael, Van Harten Argonde C, Waterloo Knut, Zetterberg Henrik, Fladby Tormod, Blennow Kaj
Department of Neurology, University Hospital of North Norway, Tromsø, Norway.
Department of Psychology, Faculty of Health Sciences, The Arctic University of Norway, Tromsø, Norway.
Alzheimers Dement. 2025 May;21(5):e70319. doi: 10.1002/alz.70319.
Heterogeneity of clinical progression in Alzheimer's disease (AD) complicates the assessment of disease progression and treatment effects in trials. This study evaluates the potential of plasma phosphorylated tau-217 (p-tau217) to capture this heterogeneity.
We used k-means clustering to analyze cognitive trajectories in amyloid beta -positive (Aβ+) cognitively normal (CN) and mild cognitive impairment (MCI) participants from two independent cohorts. Cohort 1 included 186 participants (71 CN, 115 MCI; 507 observations) and Cohort 2 included 207 participants (64 CN, 144 MCI; 781 observations), both with up to 10 years of follow-up.
Three progression clusters emerged in both cohorts: stable cognition, slow decline, and rapid decline-each including cases initially classified as CN or MCI. Baseline plasma p-tau217 was linked to progression risk in both cohorts, whereas longitudinal increases in Cohort 1 were steepest in rapid decliners.
Plasma p-tau217 may aid in capturing clinical heterogeneity and support stratification and monitoring of disease progression in clinical trials.
k-Means found stable, slow, and rapid cognitive decline clusters in amyloid beta-positive (Aβ+) cases. Higher baseline plasma phosphorylated tau-217 (p-tau217) levels predicted faster cognitive decline. Longitudinal increases in plasma p-tau217 were steepest in rapid decliners. Plasma p-tau217 tracks clinical progression heterogeneity in Aβ+ cases. Cognitive stage and amyloid alone may miss severity and risk in early-stage Alzheimer's disease.
阿尔茨海默病（AD）临床进展的异质性使疾病进展评估以及试验中的治疗效果评估变得复杂。本研究评估了血浆磷酸化tau-217（p-tau217）捕捉这种异质性的潜力。
我们使用k均值聚类分析法，分析了来自两个独立队列的淀粉样β蛋白阳性（Aβ+）认知正常（CN）和轻度认知障碍（MCI）参与者的认知轨迹。队列1包括186名参与者（71名CN，115名MCI；507次观察），队列2包括207名参与者（64名CN，144名MCI；781次观察），两者均有长达10年的随访数据。
两个队列均出现了三个进展簇：认知稳定、缓慢衰退和快速衰退——每个簇都包括最初分类为CN或MCI的病例。两个队列中，基线血浆p-tau217均与进展风险相关，而队列1中快速衰退者的纵向升高最为显著。
血浆p-tau217可能有助于捕捉临床异质性，并支持临床试验中疾病进展的分层和监测。
k均值聚类法在淀粉样β蛋白阳性（Aβ+）病例中发现了认知稳定、缓慢和快速衰退簇。较高的基线血浆磷酸化tau-217（p-tau217）水平预示着更快的认知衰退。快速衰退者血浆p-tau217的纵向升高最为显著。血浆p-tau217追踪Aβ+病例中的临床进展异质性。仅认知阶段和淀粉样蛋白可能会遗漏早期阿尔茨海默病的严重程度和风险。
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