GLP‐1 receptor agonists in Alzheimer's disease and MCI: a meta‐analysis

Abstract INTRODUCTION Alzheimer's disease (AD) is the leading cause of dementia in older individuals and remains a major clinical and socioeconomic burden. Despite the success of anti‐amyloid therapies in reducing biomarker burden, more effective and safer treatments are still needed. Given the emerging evidence of a role for metabolic dysfunction and brain insulin resistance in AD pathophysiology, glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) have been proposed as potential disease‐modifying therapies.

Methods

We conducted a systematic review and meta‐analysis of PubMed, Embase, CENTRAL, and ClinicalTrials.gov from inception to April 22, 2026 to evaluate the efficacy and safety of GLP‐1 RAs in AD and mild cognitive impairment. Randomized controlled trials comparing GLP‐1 RAs with placebo, standard care, or non‐intervention across the Alzheimer's continuum were eligible; abstracts and studies with unavailable results were excluded. Random‐effects models were used. Risk ratios (RRs) were calculated for binary outcomes, and mean or standardized mean differences for continuous outcomes. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool.

Results

Seven studies comprising 4132 participants met the inclusion criteria. The mean age of the pooled studies was 72.1 years, while the mean baseline Clinical Dementia Rating—Sum of Boxes (CDR‐SB) varied from 2.71 to 3.8. GLP‐1 RAs were not associated with significant improvement in cognition (Alzheimer's Disease Assessment Scale–Cognitive Subscale: standard mean difference −0.05; 95% confidence interval [CI]: −0.12 to 0.02; p = 0.1928) or disease progression (CDR‐SB: mean difference: 0.09; 95% CI: −0.10 to 0.28; p = 0.362). They were associated with a higher frequency of adverse events (RR 1.07; 95% CI: 1.04 to 1.10; p < 0.0001) and weight loss (RR 5.01; 95% CI: 3.99 to 6.27; p < 0.0001). Biomarker and neuroimaging findings were inconsistent and failed to translate to clinical benefit.

Discussion

GLP‐1 RAs did not improve cognitive or functional outcomes in AD and were associated with adverse events. Their role may be better explored in biomarker‐enriched, metabolically selected populations or assessment of GLP‐1 RAs with greater brain penetrance.