Recent advances of GPR40 agonists as potential anti-Alzheimer's agents

Alzheimer's disease (AD) is a progressive and multifactorial neurodegenerative disorder involving metabolic dysfunction, neuroinflammation, mitochondrial impairment, synaptic failure, and neuronal loss. Although amyloid-beta deposition and neurofibrillary tangles composed of hyperphosphorylated tau remain central pathological hallmarks, interconnected mechanisms contribute to disease progression and limit the effectiveness of single-target therapies. Current small-molecule drugs mainly provide symptomatic relief, whereas recently approved monoclonal antibodies have broadened the therapeutic landscape but still show modest clinical benefits, high treatment costs, and relevant safety concerns. GPR40/FFAR1, a transmembrane lipid-sensing G protein-coupled receptor, has emerged as a promising target because its activation may modulate neurotrophic signaling, neurogenesis, inflammatory regulation, neuronal survival, mitochondrial protection, autophagy, and synaptic plasticity. Preclinical studies suggest that GPR40/FFAR1 activation improves cognitive performance and attenuates AD-related pathological events through CREB activation, increased neurotrophic factor expression, reduced oxidative stress, restoration of autophagic flux, and inhibition of neuroinflammatory pathways, including NLRP3 inflammasome signaling. This review discusses the biological basis, pharmacological evidence, and medicinal chemistry advances supporting GPR40/FFAR1 as a potential therapeutic target for AD, while highlighting translational challenges related to selectivity, brain penetration, long-term safety, and target engagement.