Astrocytic lactate shuttle disruption and the energy-starved lysosome in Alzheimer's disease

Lysosomal dysfunction is central to Alzheimer’s disease (AD), yet why structurally intact vacuolar H⁺-ATPase (V-ATPase) proton pumps fail to maintain lysosomal pH remains unresolved. Because V-ATPase activity depends on continuous ATP supply, we hypothesized that disruption of the astrocyte–neuron lactate shuttle imposes a cross-cellular energy deficit—an “energy-starved lysosome” (ESL) state. Integrating single-nucleus transcriptomics (SEA-AD; 1.3 million nuclei, 84 donors) with cerebrospinal fluid proteomics (ADNI Emory; n = 1,105), we found that astrocytic lactate-export genes, led by MCT4 (− 43%), declined far faster than V-ATPase, and that astrocytic MCT4 was coupled to neuronal V-ATPase independently of disease stage (donor-level partial r = + 0.466). At the protein level, V-ATPase V1A abundance was preserved across diagnostic groups—consistent with structural pump integrity—while, at the individual level, glycolytic capacity (hexokinase-1, HK1) tracked Tau pathology; this glycolysis–Tau coupling reproduced on an independent proteomic platform and against immunoassay Tau, whereas an apparent CSF V1A–Tau correlation did not survive distribution-robust analysis or validation against immunoassay Tau and is not interpreted as an individual-level marker. These findings position cross-cellular metabolic decoupling, rather than structural pump loss, as a candidate upstream constraint on lysosomal acidification, defining a candidate intervention window.