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Electronic Health Records to Test Multimorbidity Influences to Plasma Biomarker Interpretation for Alzheimer's Disease
Cousins KAQ, Boyle R, Morse C, Verma A, Brown CA, O'Brien KS, Serper M, Dehghani N, Penn Medicine BioBank, McMillan CT, Lee EB, Shaw LM, et al.. Annals of neurology, 2025-12-25
Topic: Amyloid, tau and blood-test diagnosis
Plain-language summary
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.
What this study adds
Evidence grade: Moderate
This is a cross-sectional study of 617 participants. In a real-world diverse clinical population, the ratio of plasma p-tau217 to Aβ42 was most strongly linked to Alzheimer's-related factors, but it was also linked to kidney function, diabetes and hearing loss. This shows that other medical conditions can affect how these blood biomarkers should be interpreted; it is not a treatment.
Taken from this record’s own fields, not from reading the paper. The grade is assigned from the abstract’s wording; what that means.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Cousins, K. A. Q., Boyle, R., Morse, C., Verma, A., Brown, C. A., O'Brien, K. S., et al. (2026). Electronic Health Records to Test Multimorbidity Influences to Plasma Biomarker Interpretation for Alzheimer's Disease. Annals of neurology. https://doi.org/10.1002/ana.78114
Vancouver
Cousins KAQ, Boyle R, Morse C, Verma A, Brown CA, O'Brien KS, et al. Electronic Health Records to Test Multimorbidity Influences to Plasma Biomarker Interpretation for Alzheimer's Disease. Annals of neurology. 2026. doi:10.1002/ana.78114. PMID: 41447112.
BibTeX
@article{cousins2026-41447112,
author = {Cousins, K. A. Q. and Boyle, R. and Morse, C. and Verma, A. and Brown, C. A. and O'Brien, K. S. and Serper, M. and Dehghani, N. and BioBank, Penn Medicine and McMillan, C. T. and Lee, E. B. and Shaw, L. M. and others},
title = {{Electronic Health Records to Test Multimorbidity Influences to Plasma Biomarker Interpretation for Alzheimer's Disease}},
journal = {Annals of neurology},
year = {2026},
doi = {10.1002/ana.78114},
pmid = {41447112},
url = {https://doi.org/10.1002/ana.78114}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- 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.
Why it matters
In a real-world diverse clinical population, the ratio of plasma p-tau217 to Aβ42 was most strongly linked to Alzheimer's-related factors, but it was also linked to kidney function, diabetes and hearing loss. This shows that other medical conditions can affect how these blood biomarkers should be interpreted; it is not a treatment.
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Study details
- Study designcross-sectional
- Participants617
- Evidence strengthModerate
Limitations
Diagnoses came from ICD codes without formal diagnosis or neuropsychological testing, so diagnostic stability and reversion could not be determined; no PET or CSF gold standard was available to test accuracy in people with multimorbidity or whether kidney-adjusted values improve classification; and eGFR was calculated from creatinine rather than cystatin C.
How this study scored 53/100
Published in a leading specialty journal, and it is a snapshot of people at one point in time. Scored zero for effect reported and randomized / blinded because the record does not state it. We have no data on free to read, so that was left out: it earned 52 of the 98 points we could judge it on, which is 53 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Annals of neurology) |
| Journal's citation record | 3 / 4 | Annals of Neurology: journal h-index 437 (OpenAlex, 2026-10-29) |
| Study design | 4 / 12 | A snapshot of people at one point in time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 2 / 4 | 617 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 4 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 2 / 6 | Cited 2.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 4 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author David A. Wolk: h-index 96 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Pennsylvania: institution h-index 1,859 (OpenAlex) |
| Multicenter collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41447112) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 52 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 52 of the 98 points we could judge it on is 53 out of 100. |
| Total | 53 / 100 | — |
What each of these 20 components measures, and what this score is not →
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