Mitochondrial bioenergetic signatures differentiate asymptomatic from symptomatic Alzheimer's disease.

Asymptomatic Alzheimer's disease (AsymAD) refers to individuals who, despite exhibiting amyloid-β plaques and tau pathology comparable to Alzheimer's disease (AD), maintain cognitive performance similar to cognitively normal individuals. The resilience mechanism in AsymAD individuals remains understudied. We performed a systematic analysis comparing AsymAD and AD across multiple cohorts (ROSMAP, Banner and Mount Sinai), brain regions (BA6, BA9, BA36 and BA37) and neuronal and glial cell types using proteomics and transcriptomics data. AsymAD brains exhibited preserved mitochondrial bioenergetics, characterized by enhanced oxidative phosphorylation, electron transport chain activity, fatty acid and lipid metabolism, and branched-chain amino acid utilization. Pathways regulating mitochondrial complex biogenesis and calcium homeostasis were also upregulated. Key mitochondrial proteins such as MRPL47, CPT2, BCAT2, and IDH2, were consistently upregulated in AsymAD. At the cellular level, excitatory neurons, including superficial, mid-layer, and deep-layer subtypes, exhibited the most preserved mitochondrial function, whereas vulnerable inhibitory subtypes, including PVALB and SST neurons, showed increased cellular abundance and bioenergetic activity. In contrast, microglia and oligodendrocytes proportions were reduced in AsymAD relative to AD. Our findings identify preserved mitochondrial bioenergetics in AsymAD and suggest that enhancing NADH metabolism via NAD+ precursor-based interventions may potentially help in maintaining cognitive function despite amyloid and tau pathology.