Efficacy and safety of GLP-1 receptor agonists in the treatment or prevention of cognitive decline

Glucagon-like peptide-1 (GLP-1) receptor agonists, initially developed for the treatment of type 2 diabetes mellitus and, subsequently, obesity, have been investigated for their potential effect on cognitive decline, motivated by preclinical evidence of neuroprotection and epidemiological observations of a lower incidence of dementia among users of these medications (Yang; Liang, 2026). An exploratory analysis of the REWIND trial demonstrated that dulaglutide was associated with a 14% reduction in the risk of substantive cognitive impairment in patients with type 2 diabetes, with a hazard ratio of 0.86 (Cukierman-Yaffe et al., 2020). The phase 2b randomized clinical trial ELAD, with liraglutide in patients with mild to moderate Alzheimer's disease, did not meet its primary endpoint of cerebral glucose metabolism, but identified less decline in the executive domain and less brain volume loss in secondary and exploratory analyses (Edison et al., 2026). In contrast, the phase 3 trials EVOKE and EVOKE+, which evaluated oral semaglutide in more than 3.800 patients with early-stage symptomatic Alzheimer's disease, did not demonstrate superiority over placebo in reducing the clinical progression of the disease (Cummings et al., 2026). Real-world observational studies, in turn, have suggested a reduction in the risk of Alzheimer's disease among users of GLP-1 receptor agonists compared with other classes of antidiabetic drugs (Zhang et al., 2025). The safety profile of these agents is generally favorable, dominated by gastrointestinal adverse events, with rarer signals related to cholelithiasis and medullary thyroid carcinoma (Jalleh et al., 2026). This chapter critically reviews the evidence on the efficacy and safety of GLP-1 receptor agonists in the context of cognitive decline, discussing the proposed mechanisms, the discordant results across different agents and trials, and the future prospects for this line of investigation.