Abstract

Background: Alzheimer’s disease (AD) progression is commonly summarized through cognitive and global staging measures, yet routine care captures multidomain deterioration across cognition, function, neuropsychiatric symptoms, caregiver dependence, and systemic physiology. After EVOKE and EVOKE+ showed no population-level slowing of early symptomatic AD progression with oral semaglutide, a key unresolved question is whether disease phase, functional reserve, multimorbidity, and the temporal ordering of decline identify clinically distinct trajectories that are not captured by average trial effects.

Methods: We conducted a retrospective observational study using de-identified electronic health record data from a federated network of more than 29 million patients. Large language model (LLM)-enabled extraction was used to recover standardized cognitive, functional, global severity, and neuropsychiatric assessment scores from clinical notes. Functional decline was defined from FAQ, ADCS-ADL, and ADCS-MCI-ADL; cognitive decline was defined from MMSE and MoCA. We reconstructed longitudinal AD trajectories, compared outcome-domain representation in contemporary AD trials, characterized patient-level timing of functional versus cognitive decline, and evaluated clinical trajectories among patients who initiated semaglutide after AD diagnosis. Physician adjudication showed high extraction accuracy for the main reportable instrument set.

Findings: Among 131,824 patients with structured AD diagnoses, 42,242 had at least one LLM-derived outcome assessment from clinical notes and 341 initiated semaglutide after AD diagnosis. Normalized trajectories over decades of routine clinical care showed long prediagnostic decline and AD diagnosis-proximal acceleration, with the composite score decreasing from 0.99 at 25.1 years before AD diagnosis to 0.64 at 4.9 years after AD diagnosis. Compared with matched non-AD controls, AD patients showed marked post-index functional separation, including lower ADCS-MCI-ADL scores at year 4 (28.1 versus 47.0 points; P<0.001) and higher FAQ impairment across follow-up. We also evaluated clinical outcome and physiologic trajectories in semaglutide-treated AD patients and matched non-semaglutide AD controls; 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), whereas functional, global severity, and neuropsychiatric comparisons were not statistically significant and were limited by smaller sample sizes. Among 3,467 patients with at least two repeated functional assessments or two repeated cognitive assessments, 2,883 (83.2%) had confirmed functional decline and 2,535 (73.1%) had confirmed cognitive decline, with both functional and cognitive decline observed in 2,169 (62.6%) patients. Among the 2,169 patients, 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%), and both declines were confirmed on the same date in 305 patients (14.1%). Cognitive decline-first was more prevalent. Overall, 631 patients (29.1%) had cognitive decline at least 12 months before functional decline and 327 patients (15.1%) had functional decline at least 12 months before cognitive decline. Cognitive decline-first patients had higher medication burden and greater note-derived symptom burden. Functional decline-first patients were enriched for APOE ε3/ε3 (OR 2.82, 95% CI 1.17–6.76; P=0.023), supporting the need for trajectory-aware and genetically stratified approaches in semaglutide trial design and interpretation. In general, AD was also accompanied by systemic physiologic divergence from matched controls, including prediagnostic weight decline and postdiagnostic albumin and hemoglobin decline. In matched paired score-change analyses, semaglutide-treated AD patients showed more favorable MMSE change than matched non-semaglutide AD controls and more favorable MoCA change, whereas functional, global severity, and neuropsychiatric comparisons were not statistically significant and were limited by smaller sample sizes.

Interpretation: LLM-enabled clinical-note phenotyping reveals that AD progression in routine care is multidomain and temporally heterogeneous, with functional decline-first and cognitive decline-first subsets that differ in medication and note-derived phenotype burden. These findings do not establish semaglutide efficacy in AD, but they suggest that EVOKE and EVOKE+ leave open a stratification question: whether treatment-associated trajectories vary by disease phase, functional reserve, multimorbidity, and the temporal ordering of functional and cognitive decline. Prospective validation, physician adjudication, and matched comparator analyses are needed before these phenotypes can guide trial enrichment or clinical decision-making.