Peripheral amylin modulation rebalances brain glycolysis and Tau-Ser214 phosphorylation via cAMP-PKA signaling.

Brain glucose dysregulation is shared by Alzheimer's disease (AD) and diabetes, but whether it arises from central or peripheral mechanisms remains unclear. Amylin, a pancreatic hormone, normally supports CNS cAMP-PKA signaling, metabolism and memory; however, prediabetes-associated hypersecretion disrupts this balance. Using human amylin-inducible mice, we show that toggling amylin secretion during metabolic stress bidirectionally regulates brain glycolysis and function. Excess amylin overactivates cAMP-PKA signaling, suppressing glycolysis and inducing Tau-Ser214 phosphorylation, two core features of AD pathology. This state is accompanied by activation of the amino acid starvation response, Tau-T231 hyperphosphorylation, pTau-Aβ coupling, neuroinflammation and memory deficit. In contrast, reducing amylin in prediabetes preserves glycolysis, ATF4-dependent proteostasis and cognition. Astrocytes emerge as primary targets, as amylin receptor blockade prevents glycolytic deficits ex vivo, and amylin accumulates in GFAP-enriched regions in vivo. Together, these results define prediabetic hyperamylinemia as an upstream, modifiable driver of PKA-mediated tau pathology linking metabolic dysfunction to AD.