Electronic Health Records to Test Multimorbidity Influences to Plasma Biomarker Interpretation for Alzheimer's
Katheryn A Q Cousins1, Rory Boyle1, Colleen Morse2
1Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
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-tau217), β-amyloid 1-42/1-40 (Aβ42/Aβ40) and p-tau217/Aβ42-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-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.
Interpretation:
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.
