We are synthesizing evidence on allosteric modulation across ionotropic receptors and GPCRs in Alzheimer’s disease—asking when “dial-like” modulators can safely rebalance pathways that govern memory and inflammation—focusing on muscarinic M1, mGluR5, and the calcium-sensing receptor, which show strong preclinical signals and instructive, mixed early clinical results to guide biomarker-anchored next steps. In parallel, our review of the orphan GPCR GPR149 highlights functions beyond reproduction: loss-of-function states resist diet-induced obesity and improve insulin sensitivity, while neural expression in glia and neurons links the receptor to myelination and neuroendocrine signaling, likely via MAPK/ERK. Because metabolism, inflammation, and myelin integrity sit at the core of neurodegeneration, defining GPR149’s ligands and signaling bias—alongside targeted allosteric strategies—could open convergent therapeutic avenues across metabolic and neurodegenerative disorders.