Cousins Katheryn A Q, Boyle Rory, Morse Colleen, Verma Anurag, Brown Christopher A, O'Brien Kyra S, Serper Marina, Dehghani Nadia, McMillan Corey T, Lee Edward B, Shaw Leslie M, Wolk David A
Department of Neurology, Perelman School of Medicine, University of Pennsylvania; 3600 Spruce Street, Philadelphia, PA 19104.
Penn Medicine BioBank, Perelman School of Medicine, University of Pennsylvania; 3600 Spruce Street, Philadelphia, PA 19104.
medRxiv. 2025 Aug 19:2025.08.16.25333799. doi: 10.1101/2025.08.16.25333799.
Plasma biomarkers of Alzheimer's disease (AD) pathology are frequently tested in specialized research settings, limiting generalizability of findings. Using electronic health records and banked plasma, we evaluated plasma biomarkers - phosphorylated tau 217 (p-tau), β-amyloid 1-42/1-40 (Aβ/Aβ) and p-tau/Aβ - in a real-world, diverse clinical population with multimorbidities.
Participants (n=617; 44% Black/African American; 41% female) were selected from the University of Pennsylvania Medicine BioBank with plasma assayed using Fujirebio Lumipulse. International Classification of Diseases (ICD) Ninth and Tenth Revision codes determined AD dementia (ADD; n=43), mild-cognitive impairment (MCI; n=140), unspecified/non-AD cognitive impairment (CI; n=106), and cognitively normal cases (n=328), and other medical histories. APOE ε4, body mass index (BMI), metrics of kidney function (., eGFR), and liver disease were derived from electronic health records. Multivariable models identified factors related to plasma levels. Previously established cutpoints classified AD status ("AD+", "AD-", or "Intermediate").
Plasma p-tau/Aβ had the strongest association with known AD-related factors - MCI, ADD, future progression to MCI/ADD, age, and APOE ε4 - compared to p-tau and Aβ/Aβ. Plasma p-tau/Aβ was also associated with eGFR, diabetes, and history of hearing loss. Importantly, AD-related factors were most frequent/severe for AD+ classification by p-tau/Aβ, while medical morbidities were most frequent/severe for Intermediate classification. Exploratory analyses test p-tau/Aβ adjusted for eGFR to eliminate its influence on plamsa levels.
In this real-world dataset, we identified effects of multimorbidities on plasma biomarkers, especially kidney function. The p-tau/Aβ ratio had low rates of Intermediate classification and may help to account for multimorbidity effects on plasma levels.
阿尔茨海默病（AD）病理学的血浆生物标志物通常在专门的研究环境中进行检测，这限制了研究结果的普遍性。我们利用电子健康记录和储存的血浆，在一个患有多种疾病的真实世界多样化临床人群中评估了血浆生物标志物——磷酸化tau 217（p-tau）、β淀粉样蛋白1-42/1-40（Aβ/Aβ）和p-tau/Aβ。
参与者（n = 617；44%为黑人/非裔美国人；41%为女性）选自宾夕法尼亚大学医学生物样本库，血浆使用富士瑞必欧Lumipulse进行检测。国际疾病分类（ICD）第九版和第十版编码确定了AD痴呆（ADD；n = 43）、轻度认知障碍（MCI；n = 140）、未指定/非AD认知障碍（CI；n = 106）和认知正常病例（n = 328），以及其他病史。APOE ε4、体重指数（BMI）、肾功能指标（如估算肾小球滤过率[eGFR]）和肝病信息来自电子健康记录。多变量模型确定了与血浆水平相关的因素。先前确定的切点对AD状态进行分类（“AD +”、“AD -”或“中间状态”）。
与p-tau和Aβ/Aβ相比，血浆p-tau/Aβ与已知的AD相关因素——MCI、ADD、未来进展为MCI/ADD、年龄和APOE ε4——的关联最强。血浆p-tau/Aβ还与eGFR、糖尿病和听力损失史相关。重要的是，对于p-tau/Aβ分类为AD +的情况，AD相关因素最为常见/严重，而对于中间状态分类，医疗合并症最为常见/严重。探索性分析对eGFR调整后的p-tau/Aβ进行检测，以消除其对血浆水平的影响。
在这个真实世界的数据集中，我们确定了多种疾病对血浆生物标志物的影响，尤其是肾功能。p-tau/Aβ比值的中间状态分类率较低，可能有助于解释多种疾病对血浆水平的影响。
