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.

Background: Glucagon-like peptide-1 (GLP-1) and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists reduce cardiovascular events, but the underlying cardiac structural remodeling remains unclear. Objectives: This study evaluated longitudinal cardiac remodeling associated with semaglutide and tirzepatide in a real-world cohort and determined its weight-loss dependency. Methods: Using electronic health records from a federated network, we analyzed longitudinal echocardiograms of patients prescribed semaglutide or tirzepatide, stratified by 12-month weight loss into super-responders (>15%), moderate-responders (5%-15%), and minimal-responders (5% weight loss were propensity-matched with non-GLP-1/GIP weight-loss medication control patients on demographics and baseline body mass index. Results: Among 3,500 GLP-1/GIP patients (422 weight-loss super-responders, 1,426 moderate-responder, 1,652 minimal-responders), left ventricular (LV) mass decreased across all groups proportional to weight loss (super-responders: 198.4 ± 69.6 to 176.6 ± 66.0 g; moderate-responders: 210.7 ± 74.0 to 195.8 ± 68.1 g; minimal-responders: 216.1 ± 68.4 to 204.8 ± 67.4 g; p < 0.001). Left atrial volume and LV systolic and diastolic function did not change. Among weight-loss super-responders, semaglutide (n = 159) showed greater LV mass reduction than tirzepatide (n = 89) (Cohen’s d = -0.389 vs. -0.263), while tirzepatide showed small improvements in right ventricular function. Compared to matched non-GLP-1/GIP controls (n = 118/group), GLP-1/GIP patients exhibited significant LV mass reduction not observed in controls despite similar weight loss. Conclusions: Real-world findings demonstrate that incretin-based therapies are associated with reverse cardiac remodeling characterized by weight-loss-dependent and incretin-specific mechanisms, with potentially distinct structural targets among agents.