Objective:

To systematically evaluate the clinical efficacy, biomarker effects, and real-world dementia risk reduction associated with GLP-1 receptor agonists in Alzheimer’s disease, integrating trial and population data through a living systematic review and Efficacy–Feasibility Matrix to assess their translational readiness for scalable, disease-modifying intervention.

Background:

GLP-1 receptor agonists (GLP-1 RAs), developed for diabetes and obesity, cross the blood-brain barrier and modulate insulin signaling, neuroinflammation, and amyloid-tau pathways. Their dual metabolic and neuroprotective actions position them as leading repurposed candidates for Alzheimer’s disease (AD).

Design/Methods:

This living systematic review synthesized phase 2/3 trials and large real-world studies of liraglutide, semaglutide, and exenatide in MCI and AD (2000–2025). Data on cognition, biomarkers, safety, delivery, and accessibility were analyzed to compare efficacy with population-level dementia risk reduction. Translational readiness was mapped using an Efficacy–Feasibility Matrix.

Results:

Across > 2,000 participants, liraglutide (daily SC, 12 mo) slowed FDG-PET decline and hippocampal atrophy (standardized Δ ≈ 0.25 SD; p ≈ 0.04) despite a neutral primary outcome. Semaglutide (oral daily; EVOKE / EVOKE+) has the highest statistical power (N ≈ 1,800 each); results are expected in 2025. Exenatide (weekly SC) remained underpowered and neutral. Real-world diabetic cohorts (N > 2 million) consistently demonstrated ~20–35 % lower dementia incidence among GLP-1 users, strongest for semaglutide, compared with DPP-4 or SGLT2 users. Translational mapping positioned GLP-1 RAs as high-efficacy, moderate-feasibility interventions: biologically robust yet limited by cost and injectable delivery. Safety mirrored metabolic indications (GI symptoms > 10 %, no CNS toxicity).

Conclusions:

GLP-1 RAs currently represent the most mature, mechanistically coherent repurposed strategy for AD. Integrating trial and real-world evidence underscores consistent neuroprotective trends across settings. Pending phase 3 readouts will clarify disease-modifying potential. The Efficacy–Feasibility Matrix highlights semaglutide’s translational edge through oral dosing and scalability, supporting near-term pragmatic deployment if efficacy is confirmed.