Largescale multiomic modelling of human brain reveals metabolic adaptation that precedes bioenergetic collapse in Alzheimer’s disease

Proteopathy and synaptic dysfunction accumulates over decades in Alzheimer’s disease (AD), accompanied by marked mitochondrial changes and oxidative stress. Adaptive metabolic programs may oppose degeneration, such as the pentose phosphate pathway (PPP), a major source of NADPH required for antioxidant defence. But the PPP, and upper-glycolytic pathways in general are poorly characterised in extant AD metabolomic workflows, because phosphorylated metabolites (characteristic of upper glycolysis metabolites) have low volatility, hydrophilicity, and ionization efficiency. Phosphate groups also interfere with the protonation or deprotonation of metabolites during the ionisation process in MS, leading to poor sensitivity and resolution, resulting in deficient metabolic profiling of the AD brain. To address this, we performed the largest integrated (phospho)metabolomic and proteomic analyses in human brain tissue spanning the AD clinicopathological spectrum (n = 625) accompanied with proteomics to reconstruct the molecular natural history of AD. We identified the PPP as the metabolomic pathway most strongly associated with AD, alongside enrichment of the Warburg effect and fructose and mannose catabolism. Discriminative Events-Based Modelling revealed that metabolites capable of being diverted into the PPP transitioned to abnormal states at an early event stage in AD, proximal to amyloid accumulation and synaptic dysregulation. Decreased mitochondrial oxidative phosphorylation represented the final event stage, most proximal to iron accumulation glutathione depletion and evidence of oxidative stress. Therefore, the molecular natural history of AD is characterized by early preservation of the PPP that supports redox homeostasis but may occur at the cost of progressive N-glycosylation loss in aggregation-prone synaptic proteins. Prolonged central carbon flux diversion into the PPP later manifests in mitochondrial protein loss and oxidative stress in the degenerative phase of the disease.