Electronic Health Records to Test Multimorbidity Influences to Plasma Biomarker Interpretation for Alzheimer's Disease.

Abstract

Plasma biomarkers of Alzheimer's disease (AD) pathology are frequently tested in specialized research settings, which limits the generalizability of findings. Using electronic health records and banked plasma, we evaluated plasma biomarkers-phosphorylated tau 217 (p-tau₂₁₇), β-amyloid 1-42/1-40 (Aβ₄₂/Aβ₄₀) and p-tau₂₁₇/Aβ₄₂-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 (eg, estimated glomerular filtration rate [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-tau₂₁₇/Aβ₄₂ had the strongest association with known AD-related factors-MCI, ADD, future progression to MCI/ADD, age, and APOE ε4-compared to p-tau₂₁₇ and Aβ₄₂/Aβ₄₀. Plasma p-tau₂₁₇/Aβ₄₂ was also associated with eGFR, diabetes, and history of hearing loss. Importantly, AD-related factors were most frequent/severe for AD+ classification by p-tau₂₁₇/Aβ₄₂, whereas medical morbidities were most frequent/severe for Intermediate classification. Exploratory analyses test p-tau₂₁₇/Aβ₄₂ adjusted for eGFR to eliminate its influence on plasma levels. In this real-world dataset, we identified effects of multimorbidities on plasma biomarkers, especially kidney function. The p-tau₂₁₇/Aβ₄₂ ratio had low rates of Intermediate classification and may help to account for multimorbidity effects on plasma levels. ANN NEUROL 2026;99:1030-1045.