GLP-1 Receptor Agonists and Alzheimer's Disease: A Multi-National Target Trial Emulation

West China Hospital213,891 enrolled

Overview

Background: Seven large real-world cohort studies (N \> 4 million) have consistently reported that glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with a 19-54% lower incidence of Alzheimer's disease (AD). However, in November 2025, the phase 3 EVOKE and EVOKE+ trials of oral semaglutide in 3,808 patients with biomarker-confirmed early-stage AD failed to slow clinical progression. This paradox between real-world evidence (RWE) and randomised evidence has not been systematically examined. Moreover, prior RWE studies were conducted predominantly in North American and European populations, leaving a critical generalisability gap for East Asian populations, who face the world's largest AD burden. Objective: To resolve the RWE-RCT paradox by testing whether the GLP-1RA effect on AD differs between cognitively unimpaired adults (primary prevention paradigm) and patients with established cognitive impairment (treatment paradigm), and to assess whether the protective effect is consistent across European, African, and East Asian ancestries. Study Design: This is a multi-centre, retrospective, observational cohort study using a target trial emulation framework. The investigator analysed patient-level electronic health records (EHR) from five cohorts across four continents: Optum® Clinformatics® (USA), Mass General Brigham Biobank (USA), CPRD Aurum (UK), the Swedish National Diabetes Register (Sweden), and the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System (HKHA CDARS), which covers approximately the entire Hong Kong population. Study Population: A total of 2,138,917 adults aged ≥ 40 years with type 2 diabetes or obesity, with ≥ 2 years of continuous enrolment and no prior neurodegenerative disease diagnosis. GLP-1RA initiators (n = 612,418) were compared with DPP-4 inhibitor initiators (n = 1,526,499) using propensity-score overlap weighting, Fine-Gray competing-risk adjustment, negative-control outcomes, and instrumental-variable analysis to address confounding and surveillance bias.

Study Type

OBSERVATIONAL

Enrollment

213,891

Conditions

Alzheimer Disease

Eligibility

Sex: ALLMin age: 40 Years

Medical Language ↔ Plain English

Inclusion Criteria: * • Age ≥ 40 years * Diagnosis of type 2 diabetes (ICD-10 E11) or obesity (E66) * ≥ 2 years of continuous enrolment in the cohort * Baseline HbA1c \< 10.5% * No prior diagnosis of any neurodegenerative disease * No prior use of any GLP-1RA or DPP-4i Exclusion Criteria: * • Prior diagnosis of Alzheimer's disease or other neurodegenerative diseases * Prior use of GLP-1 receptor agonists or DPP-4 inhibitors * Age \< 40 years * Baseline HbA1c ≥ 10.5% * Less than 2 years of continuous enrolment

Outcomes

Primary Outcomes

Incidence of Alzheimer's Disease

Measurement Tool: International Classification of Diseases, Tenth Revision (ICD-10) diagnostic code G30 (Alzheimer's disease), extracted from linked electronic health records (EHR) and hospitalization databases across all participating cohorts. Diagnostic validity was confirmed via chart review against biomarker-confirmed AD (amyloid PET, CSF Aβ42, or plasma p-tau217), with a positive predictive value (PPV) ranging from 68.9% to 71.3% in validation samples. Unit of Measure: Time to first incident diagnosis, expressed as Hazard Ratio (HR) with 95% confidence intervals, comparing GLP-1 receptor agonist initiators versus DPP-4 inhibitor initiators. Incidence rates are also reported as number of events per 1,000 person-years. Scale Information: Not applicable (this is a time-to-event diagnostic outcome, not a rating scale).

Time frame: Up to 10 years (from index date of medication initiation to date of first AD diagnosis, death, or end of follow-up, whichever occurs first).

Secondary Outcomes

Incidence of All-Cause Dementia.

Measurement Tool: ICD-10 codes for any dementia diagnosis, including Alzheimer's disease (G30), vascular dementia (F01), and unspecified dementia (F03), extracted from EHR and hospitalization records. Unit of Measure: Time to first diagnosis, expressed as Hazard Ratio (HR) with 95% CI. Scale Information: Not applicable (diagnostic outcome).

Time frame: Up to 10 years

Rate of Progression from Mild Cognitive Impairment (MCI) to Alzheimer's Disease

Measurement Name: Rate of Progression from MCI to AD. Measurement Tool: ICD-10 code G31.84 (Mild cognitive impairment) at baseline, followed by subsequent ICD-10 code G30 (Alzheimer's disease) during follow-up, extracted from EHR. Unit of Measure: Time to progression, expressed as Hazard Ratio (HR) with 95% CI, specifically analyzed within the EVOKE-eligible patient subgroup (those with baseline cognitive impairment). Scale Information: Not applicable (diagnostic progression outcome).

Time frame: Up to 10 years

Rate of All-Cause Mortality.

Measurement Tool: Death records linked from national or regional death registries (e.g., Hong Kong Death Registry, Swedish National Death Registry, UK Office for National Statistics). Unit of Measure: Time to death, expressed as Hazard Ratio (HR) with 95% CI, analyzed using Fine-Gray subdistribution hazard models to account for competing risks. Scale Information: Not applicable (mortality outcome).

Time frame: Up to 10 years.