Elevated endogenous glucagon‐like peptide‐1 as a novel Alzheimer's disease biomarker associated with neuroinflammation and Aβ pathology

Vollständiger Abstract

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ABSTRACT Background Alzheimer's disease (AD), a neurodegenerative disorder, is pathologically defined by the accumulation of amyloid‐β (Aβ) plaques, hyperphosphorylated tau tangles and sustained neuroinflammation. Glucagon‐like peptide‐1 (GLP‐1), originally characterised as an incretin hormone, is also expressed endogenously in the brain. Although GLP‐1 receptor agonists (GLP‐1RAs) have demonstrated compelling neuroprotective effects in preclinical AD models, their efficacy in human clinical trials has, thus far, been inconsistent and limited. Moreover, the physiological role and dynamics of endogenous GLP‐1 during AD progression remain poorly understood, with studies reporting conflicting findings across different patient cohorts. Aims This study aimed to characterise serum GLP‐1 levels across the Alzheimer's disease cognitive continuum and to examine their associations with neuroinflammation, Aβ pathology, tau pathology, brain atrophy and cognitive decline. Methods We analysed two independent cohorts (Renji: n = 123; SheMountain: n = 127), including participants with cognitive unimpairment, mild cognitive impairment and AD dementia. Serum biomarkers (GLP‐1, glial fibrillary acidic protein [GFAP], Aβ40, Aβ42 and tau phosphorylated at threonine 217 [pTau217]) were quantified, along with APOE genotyping, neuropsychological assessments, brain magnetic resonance imaging and Aβ‐PET imaging. Postmortem brain tissue GLP‐1 expression was analysed in the prefrontal cortex (PFC) and hippocampus (HP). Statistical analyses included partial correlations, mediation analysis and machine learning models. Results GLP‐1 levels were significantly elevated in both brain tissue and serum of patients with AD compared to controls, with concentrations increasing progressively from cognitively normal individuals through mild cognitive impairment (MCI) to AD dementia. Serum GLP‐1 negatively correlated with Montreal Cognitive Assessment (MoCA) cognitive performance and positively correlated with GFAP, pTau217 and brain amyloid burden. Serial mediation analysis suggested that GLP‐1 and GFAP were statistically positioned along the association between amyloid burden and tau pathology. Machine learning models combining GLP‐1 with other biomarkers achieved diagnostic performance (area under the curve = 0.896). Conclusions The elevation of endogenous GLP‐1 in Alzheimer's disease likely represents a compensatory yet ultimately insufficient response to the underlying pathology. It functions as a multidimensional biomarker, reflecting the integrated neuroinflammatory burden, amyloid deposition and clinical disease severity, and may have potential utility in diagnostic applications.