Human brains typically grow through development, then remain the same size in adulthood, and often shrink through age-related degeneration that induces cognitive decline and impaired functionality. In most cases, however, the neural and organismal changes that accompany shrinkage, especially early in the process, remain unknown. Paralleling neurodegenerative phenotypes, the Eurasian common shrew Sorex araneus, shrinks its brain in autumn through winter, but then reverses this process by rapidly regrowing the brain come spring. To identify the molecular underpinnings and parallels to human neurodegeneration of this unique brain size change, we analyzed multi-organ, season-specific transcriptomics and metabolomic data. Simultaneous with brain shrinkage, we discovered system-wide metabolic shifts from lipid to glucose metabolism, as well as neuroprotection of brain metabolic homeostasis through reduced cholesterol efflux. These mechanisms rely on a finely tuned brain-liver crosstalk that results in changes in expression of human markers of aging and neurodegeneration in Parkinson’s disease and Huntington’s disease. We propose metabolic shifts with signals that cross the brain blood barrier are central to seasonal brain size changes in S. araneus, with potential implications for therapeutic treatment of human neurodegeneration.