Carbonyl stress primes the metastable aging brain for Alzheimer’s disease
Alzheimer’s disease (AD) is defined by amyloid-β (Aβ) plaques and tau tangles, yet the inflammation that comes with it is only partly localized where those lesions accumulate. Using spatial transcriptomics on 16 human hippocampal sections containing adjacent cortex, we found that plaques concentrated in grey matter, especially cortex. In contrast, the strongest inflammatory response occupied white matter and increased with distance from Aβ-positive spots. This inflammatory signature increased with Braak stage in an independent 31-subject hippocampal bulk proteomic cohort. The white-matter environment revealed a distinct chemistry, with lipidomics showing cortical white matter gaining cholesteryl esters, lysosomal storage lipids and peroxidation-prone polyunsaturated species while losing myelin lipids, alongside carbonyl, glycation and iron-handling signatures. In an external single-nucleus cohort, an oligodendrocyte lipid-droplet program tracked cognitive decline after adjustment for amyloid and tangles, and the same reactive-glia chemistry recurred above expression-matched nulls across seven neurodegenerative datasets. We propose that this lipid-rich glial environment is a metastable, primed state, and that Aβ and tau act as catalysts that tip it toward a self-sustaining inflammatory reaction. Highlights Plaques concentrate in grey matter, whereas inflammatory programs increase with distance and peak in glial/myelin-rich white matter. The white-matter response strengthens with Braak stage and is characterized by carbonyl stress, lipid storage, and myelin loss. An oligodendrocyte lipid-droplet program tracks cognitive decline after adjustment for Aβ and tau. A lipid-droplet reactive-glial state recurs across neurodegenerative diseases with distinct triggers and vulnerable cells. Aβ and pTau may tip a metastable tissue environment already primed by lipid and carbonyl stress. Graphical abstract