Abstract

Over 7 million Americans, approximately 1 in 9 individuals aged 65 and older are currently living with Alzheimer's disease (AD), a number projected to nearly double by 2060. AD is characterized by the accumulation of misfolded proteins, amyloid-β and tau, leading to progressive brain atrophy and memory loss. Despite decades of clinical trials targeting these proteins, therapeutic success has not translated into cognitive benefit. Recent large-scale human studies have identified a distinct group of individuals, termed asymptomatic or resilient AD (AsymAD), who exhibit significant amyloid and tau pathology yet remain cognitively intact. To uncover the mechanisms of resilience in AsymAD, we analyzed single-nucleus RNA sequencing data from over 1.9 million cells in the DLPFC (ROSMAP cohort) and validated findings using proteomics data from four brain regions (DLPFC, premotor cortex, hippocampus, temporal cortex) across independent cohorts (ROSMAP, Banner, and MSBB). Machine learning models were used to identify key protein features distinguishing AsymAD from AD. Our findings reveal mitochondrial bioenergetics as a central differentiator between AsymAD and AD. AsymAD brains showed enhanced oxidative phosphorylation (OXPHOS), electron transport chain (ETC) activity, fatty acid and lipid metabolism, and branched-chain amino acid (BCAA) utilization. Key mitochondrial proteins such as MRPL47, CPT2, BCAT2, and IDH2 were consistently upregulated in AsymAD. At the cellular level, excitatory and inhibitory neurons exhibited preserved bioenergetics, while inflammatory microglia and astrocytes were reduced in AsymAD. These results highlight preserved mitochondrial function as a hallmark of resilience and support the potential for NAD⁺-based metabolic interventions in early-stage AD.