Incretin-based therapies and dementia: Reconciling epidemiological prevention signals with negative disease-modifying trials in early symptomatic alzheimer's disease

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonism have been proposed as candidate interventions against cognitive decline. This structured critical review appraises clinical, epidemiological, pharmacological and biomarker evidence through 23 September 2026 and examines why favourable prevention signals diverge from negative disease-modification trials. Pooled cardiovascular-trial data and a later, partly overlapping randomized-trial meta-analysis suggest fewer dementia events, recorded as secondary or safety outcomes, with GLP-1RAs, whereas target-trial emulations remain vulnerable to channelling, surveillance and residual confounding. A quantitative E-value sensitivity analysis shows marked variation in robustness across key observational estimates, from weak confidence-bound robustness in several comparisons to effect estimates so large as to be causally implausible and compatible with structural bias. In EVOKE and EVOKE+ (n=3,808), oral semaglutide did not slow Clinical Dementia Rating-Sum of Boxes progression at 104 weeks despite modest changes in cerebrospinal-fluid Alzheimer-related biomarkers. The phase 2b liraglutide trial in AD and the phase 3 exenatide trial in Parkinson's disease were also negative on their primary outcomes. We compare four competing explanations (disease stage, insufficient central exposure, confounded epidemiology and indirect vascular mediation) and specify evidence capable of discriminating among them. We further formalize a hypothesis-generating, stage-dependent Metabolic Window Hypothesis with explicit predictions and refutation conditions, and propose a Precision Incretin-Neurodegeneration Framework as a provisional operational scaffold for biomarker-stratified research. Neither semaglutide nor tirzepatide is an established therapy for preventing or treating Alzheimer's disease or dementia.