Compartment-Specific Citrate Uncoupling as a Metabolic-Epigenetic Driver of Neurodegeneration: A Dual-Axis Hypothesis with Transcriptomic Evidence from GSE5281 and SEA-AD

Prevailing models of neurodegeneration center on amyloid-β and tau, yet metabolic dysfunction precedes proteinopathy by decades. We propose compartment-specific citrate uncoupling: opposing disturbances of citrate in neurons and astrocytes as a proteinopathy-independent driver of neurodegeneration. In neurons, a Warburg-like shift depletes cytosolic citrate, which starves ATP-citrate lyase (ACLY) and erodes the H3K27ac/H3K9ac marks that sustain synaptic gene expression, while loss of citrate-mediated PFK1 inhibition collapses the SLC13A5-dependent glycolytic gate. In surviving astrocytes, loss of ACO1, with SLC13A3 a weaker and less specific accompaniment, traps newly synthesized citrate intracellularly; ACLY then hyper-activates and STAT3 hyperacetylation drives an A1 identity. The intercellular citrate gradient inverts. We reanalyzed GSE5281 (161 postmortem samples across six brain regions). Core TCA-cycle enzymes were coherently downregulated in Alzheimer’s disease in five of six regions, more strongly in women, and not in the disease-spared visual cortex. The SLC13 transporter family instead shifted in opposite directions across regions. A cell-type-resolved reanalysis of the SEA-AD multiregion atlas placed the astrocytic arm on ACO1, which fell with pseudo-progression in all nine regions tested; SLC13A3 fell across most cortical cell types and is not compartment-specific. A four-proposition framework then combines PDK1 induction, Cryo-NanoSIMS, MALDI-TIMS-MSI, and spatial transcriptomics. If the model holds, neurodegeneration reads as a routing failure of a central metabolic hub.