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Functional-vs-Cognitive Decline Heterogeneity in Alzheimer’s Disease: LLM-Curation of Decades of Clinical Notes and GLP1RA Trial Design
Murugadoss K, Venkatakrishnan A, Varma G, Ravi SK, Saha G, Soundararajan V.. Preprints.org, 2026-06-09
Topic: Brain imaging, connectivity and assessment
EVOKE and EVOKE+ trials showed no population-level slowing of early symptomatic Alzheimer’s disease (AD) with semaglutide, motivating an assessment of whether clinical-note phenotyping over decades of routine care could identify distinct AD trajectories. Here we analyzed de-identified EHRs from a 29 million-patient federated network using LLMs to extract standardized cognitive, functional, global severity, and neuropsychiatric note-derived scores with high physician-adjudicated accuracy. Among 131,824 AD patients, 42,242 had ≥1 extracted assessment and 341 initiated semaglutide after diagnosis. Composite scores declined from 0.99 at 25.1 years before diagnosis to 0.64 at 4.9 years after diagnosis. Compared with matched non-AD controls, AD patients had lower ADCS-MCI-ADL scores at year 4 (28.1 versus 47.0 points; P<0.001) and higher FAQ impairment across follow-up. In paired score-change analyses, semaglutide-treated patients had more favorable MMSE change than matched controls (+0.4 versus −2.3 points; P=0.022) and more favorable MoCA change (−0.3 versus −2.2 points; P=0.049). Among 2,169 patients with both decline domains, cognitive decline preceded functional decline (“cognitive decline-first”) in 1,123 patients (51.8%), functional decline preceded cognitive decline (“functional decline-first”) in 741 patients (34.2%). Cognitive decline-first trajectories were more prevalent, with 631 patients (29.1%) showing cognitive decline at least 12 months before functional decline, compared with 327 patients (15.1%) showing functional decline at least 12 months before cognitive decline. Cognitive decline-first patients also had higher medication burden and greater note-derived symptom burden. Functional decline-first patients were enriched for APOE ε3/ε3 (OR 2.82; P=0.023) motivating the need for trajectory-aware and genetically stratified approaches to Alzheimer’s disease trial design.
Key findings
- Compared with matched non-AD controls, AD patients had lower ADCS-MCI-ADL scores at year 4 (28.1 versus 47.0 points; P<0.001) and higher FAQ impairment across follow-up.
- In paired score-change analyses, semaglutide-treated patients had more favorable MMSE change than matched controls (+0.4 versus −2.3 points; P=0.022) and more favorable MoCA change (−0.3 versus −2.2 points; P=0.049).
- Cognitive decline-first trajectories were more prevalent, with 631 patients (29.1%) showing cognitive decline at least 12 months before functional decline, compared with 327 patients (15.1%) showing functional decline at least 12 months before cognitive decline.
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Study details
- Participants2,169
- Effect size51.8%; 34.2%; 29.1%
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 34 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 21 of the 62 points we could judge it on, which is 34 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Preprints.org) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 3 / 4 | 2,169 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 21 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 21 of the 62 points we could judge it on is 34 out of 100. |
| Total | 34 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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APA 7th
Murugadoss, K., Venkatakrishnan, A., Varma, G., Ravi, S. K., Saha, G., & Soundararajan, V. (2026). Functional-vs-Cognitive Decline Heterogeneity in Alzheimer’s Disease: LLM-Curation of Decades of Clinical Notes and GLP1RA Trial Design. Preprints.org. https://doi.org/10.20944/preprints202606.0711.v1
Vancouver
Murugadoss K, Venkatakrishnan A, Varma G, Ravi SK, Saha G, Soundararajan V. Functional-vs-Cognitive Decline Heterogeneity in Alzheimer’s Disease: LLM-Curation of Decades of Clinical Notes and GLP1RA Trial Design. Preprints.org. 2026. doi:10.20944/preprints202606.0711.v1.
BibTeX
@article{murugadoss2026-44ef8278,
author = {Murugadoss, K. and Venkatakrishnan, A. and Varma, G. and Ravi, S. K. and Saha, G. and Soundararajan, V.},
title = {{Functional-vs-Cognitive Decline Heterogeneity in Alzheimer’s Disease: LLM-Curation of Decades of Clinical Notes and GLP1RA Trial Design}},
journal = {Preprints.org},
year = {2026},
doi = {10.20944/preprints202606.0711.v1},
url = {https://doi.org/10.20944/preprints202606.0711.v1}
}
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