Multiomic Evidence for a Unified Model of Alzheimer's Disease Etiology Linking Astrocyte‐Neuron Lactate Shuttle Impairment and Microglial Flux Capacity

Neurodegeneration in AD is driven by the brain's failure to process excess cholesterol from neuronal debris, resulting in widespread lipidomic, metabolic, and proteomic disruptions. Disruptions in lipid homeostasis occur upstream of both amyloid and tau pathology, as excess cholesterol accumulation enhances APP translocation to γ-secretase, accelerating amyloid production, while also impairing astrocytic metabolic support, leading to ATP deficits, elevated intracellular Ca²⁺, and aberrant tau phosphorylation. This breakdown in cholesterol homeostasis offers a comprehensive explanation for the observed multi-omic alterations in AD, positioning lipid dysregulation as a primary driver of disease progression. Our unified hypothesis enables us to leverage large omics data to learn new biology, and identify and evaluate novel therapeutic targets for both the prevention and treatment of AD.