Evaluating the clinical effects of GLP-1 receptor agonists for Alzheimer's and Parkinson's diseases using minimal clinically important difference: systematic review and meta-analysis.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are promising candidates for Alzheimer's disease (AD) and Parkinson's disease (PD). However, their effects in non-diabetic populations, independent of metabolic confounding, remain unclear. We evaluated the effects of GLP-1RAs on cognition, clinical outcomes, biomarkers, and safety in non-diabetic individuals with PD, AD, and mild cognitive impairment. We assessed the clinical meaningfulness of these effects using minimal clinically important difference thresholds. Relevant studies were retrieved from PubMed, Embase, and Web of Science from inception to November 2025. A random-effects meta-analysis was applied to calculate standardized mean differences (SMDs), mean differences (MDs), and risk ratios with 95% confidence intervals (CIs). The protocol was registered in PROSPERO (CRD420261277032). Fourteen randomized controlled trials enrolling 1260 participants were included. GLP-1RAs showed a small statistically significant improvement in global cognition (SMD 0.14, 95% CI 0.01 to 0.27; I² = 7%), supported by high-certainty evidence. Despite statistical significance, findings suggest only a trivial probability (1%) of a clinically important benefit. Conversely, GLP-1RAs were associated with poorer verbal fluency (SMD - 0.43, 95% CI - 0.79 to - 0.08; I² = 0%), supported by high-certainty evidence. For clinical severity, function, depression, and PD-related outcomes, pooled estimates generally favored GLP-1RAs, but none reached statistical significance. A significant between-disease subgroup difference was observed for function. In the PD subgroup, GLP-1RAs significantly improved depression symptoms relative to control (MD - 2.09, 95% CI - 3.99 to - 0.20; I² = 0%). Nevertheless, this magnitude of improvement remained below the threshold for clinically important benefit. Biomarker findings were inconsistent across trials. GLP-1RAs significantly reduced weight and were associated with poorer tolerability and increased gastrointestinal adverse events. Current evidence provides no convincing support for a clinically meaningful or disease-modifying effect of GLP-1RAs, and adverse effects may limit their clinical utility. Large-scale trials are needed to definitively weigh potential benefits against associated risks.