Potential Neuroprotective Role of GLP-2 in Alzheimer’s Disease: Clinical Observations, Mechanistic Insights, and Comparison with GLP-1

Alzheimer’s disease (AD) is the most common cause of dementia and is characterized by progressive cognitive decline, β-amyloid accumulation, tau pathology, oxidative stress, and neuroinflammation. Increasing evidence suggests that metabolic dysregulation may contribute to AD pathogenesis. Glucagon-like peptide-2 (GLP-2), an intestinal peptide hormone, has demonstrated neuroprotective effects in preclinical models, potentially through anti-inflammatory and anti-apoptotic mechanisms. However, its role in human neurodegenerative disorders remains insufficiently understood. This study aimed to compare plasma GLP-2 concentrations between individuals with AD and cognitively healthy controls and to examine associations between GLP-2 levels, cognitive impairment severity, and metabolic parameters. Sixty-one patients with clinically diagnosed AD and twenty-three cognitively unimpaired controls were recruited. Plasma total GLP-2 concentrations were assessed at baseline in all participants and additionally at 6 and 12 months in a subgroup of 34 AD patients. Cognitive function was evaluated using the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) scale. Group comparisons, subgroup analyses based on AD severity, repeated-measures analyses, Spearman correlations, and multivariable linear regression models (including age and clinical group) were performed. Plasma GLP-2 concentrations were significantly higher in AD patients than in controls, with a moderate effect size (Cohen’s d ≈ 0.60). In severity-based subgroup analyses, both the mild and moderate-to-severe AD groups showed significantly higher GLP-2 levels than controls. Longitudinal analyses in AD patients (n = 34) showed no significant changes in GLP-2 concentrations over 12 months. Cognitive performance declined over time, with a significant reduction in MMSE from baseline to 6 months, whereas GLP-2 levels were not correlated with MMSE or CDR at any time point. GLP-2 levels correlated positively with body mass index (BMI), body weight, insulin, and HOMA-IR. In multivariable regression analysis, neither age nor clinical group independently predicted GLP-2 concentrations (both p > 0.05). Plasma GLP-2 concentrations were higher in patients with AD than in cognitively healthy controls; however, GLP-2 levels were not associated with cognitive performance or its progression over 12 months. GLP-2 was positively related to markers of adiposity and insulin resistance, suggesting stronger links to metabolic status than to cognitive severity. Further studies are needed to clarify whether GLP-2 alterations in AD reflect compensatory mechanisms, metabolic factors, or disease-related pathophysiology.