Alzheimer's Disease and the GLP-1 Receptor: Pathophysiology, Mechanisms and Therapeutic Evidence.

Abstract: Alzheimer's disease (AD) is a multifactorial, neurodegenerative disease characterized by the accumulation of amyloid-β, hyperphosphorylated tau, neuroinflammation, oxidative stress, mitochondrial dysfunction, loss of synapses and brain insulin resistance, and none of the available therapies are of much benefit in any way except as symptoms. The glucagon-like peptide-1 receptor (GLP-1R), a class B G protein-coupled receptor found broadly throughout the hippocampus, cortex, hypothalamus and brainstem, has been identified as a promising target due to its ability to influence restoration of brain insulin sensitivity, decrease amyloid-β and tau pathology, attenuate microglial and astrocytic inflammation, protect mitochondrial function and promote synaptic plasticity and neurogenesis through cAMP/PKA, PI3K/Akt, MAPK/ERK and CREB signaling. In preclinical studies, exenatide, liraglutide, and semaglutide were consistently demonstrated to have cognition and neuroprotective effects in transgenic AD models. However, evidence from clinical studies is mixed: Early-phase oral liraglutide studies demonstrated mild effects on cerebral glucose uptake and brain volume, but phase III oral semaglutide trials EVOKE and EVOKE+ showed a reduction in CSF tau biomarkers without slowing clinical cognitive decline. These data indicate that GLP-1R agonists have biological activity in AD that is measurable, but not clinically significant disease modification; continued research is needed to explore brain-penetrating formulations, patient selection, and combination therapies.