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

Objective 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‐tau 217 ), β‐amyloid 1–42/1–40 (Aβ 42 /Aβ 40 ) and p‐tau 217 /Aβ 42 —in a real‐world, diverse clinical population with multimorbidities. Methods 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”). Results Plasma p‐tau 217 /Aβ 42 had the strongest association with known AD‐related factors—MCI, ADD, future progression to MCI/ADD, age, and APOE ε4—compared to p‐tau 217 and Aβ 42 /Aβ 40 . Plasma p‐tau 217 /Aβ 42 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 217 /Aβ 42 , whereas medical morbidities were most frequent/severe for Intermediate classification. Exploratory analyses test p‐tau 217 /Aβ 42 adjusted for eGFR to eliminate its influence on plasma levels. Interpretation In this real‐world dataset, we identified effects of multimorbidities on plasma biomarkers, especially kidney function. The p‐tau 217 /Aβ 42 ratio had low rates of Intermediate classification and may help to account for multimorbidity effects on plasma levels. ANN NEUROL 2026;99:1030–1045