The effects of GLP-1 receptor agonists on Alzheimer's pathophysiology: A systematic review.

BACKGROUND: The incidence of Alzheimer's disease (AD) is increasing globally but there are limited effective therapies available. Recently, evidence has demonstrated a role of GLP-1 receptor (GLP-1R) agonists, commonly used in the treatment of type 2 diabetes, may have therapeutic potential in AD. GLP-1R agonists have exhibited their neuroprotective role by targeting tau hyperphosphorylation and the accumulation of beta-amyloid (Aβ) plaques. This systematic review aims to evaluate the effectiveness of liraglutide, semaglutide, exenatide and dulaglutide on AD pathology with a focus on the key biomarkers: hyperphosphorylated tau and Aβ. METHODS: A systematic literature search was conducted using PubMed, Embase and Cochrane Library. Inclusion criteria involved pre-clinical and clinical studies investigating the effects of GLP-1 agonists dulaglutide, liraglutide, semaglutide or exenatide on Aβ and tau pathology. Randomised and non-randomised studies were included. Exclusion criteria involved studies evaluating GLP-1R agonists other than those specified. RESULTS: This review examined thirty preclinical studies investigating the effects of four GLP-1 receptor agonists on Alzheimer's disease pathology, particularly Aβ plaque accumulation and tau hyperphosphorylation. Most studies focused on liraglutide, which consistently reduced both Aβ and tau pathology in animal and cell models. Dulaglutide, although studied less frequently, consistently reduced tau phosphorylation and Aβ accumulation in mouse models while also improving cognitive outcomes. Semaglutide also showed largely positive effects with four studies reporting reduced Aβ or tau pathology, though one study reported no benefit. Two clinical studies were also reviewed. A phase II trial of Exenatide showed reduced plasma Aβ42 in extracellular vesicles but not cognitive benefit. A smaller liraglutide trial demonstrated no reduction in Aβ burden or cognitive change though it preserved brain glucose metabolism. An EXSCEL trial showed significant changes in systemic inflammatory markers. While pre-clinical data has been encouraging, clinical evidence remains limited. CONCLUSIONS: There is consistent preclinical evidence that GLP-1R agonists are effective in reducing Aβ levels and hyperphosphorylated tau. While the neuroprotective effect in preclinical studies is clear, clinical findings have so far failed to demonstrate an arresting effect on cognitive. REGISTRATION: PROSPERO CRD420251029748.