Single-Nucleus Profiling Reveals Neuronal Metabolic Collapse During the Transition to Alzheimer's Disease Dementia

Current Alzheimer's disease (AD) neuropathological metrics, including Thal phasing, and Braak staging, often do not accurately predict cognitive status: many cognitively resilient individuals have substantial pathological burdens, whereas some patients with dementia show minimal classical AD pathology. Here, we addressed this discrepancy by investigating the molecular mechanisms underlying AD dementia using single-nucleus RNA-sequencing and single-nucleus multiome datasets. To eliminate cross-modality scaling artifacts and compositional biases inherent in neurodegenerative tissues, we normalized the datasets using our novel framework, bypassing scaling issues of conventional methods that may obscure critical biological signals of interest. We identified neuron-specific suppression of nuclear-encoded mitochondrial genes and their upstream mitochondrial biogenesis signaling (MBS) as primary drivers of clinical dementia. By integrating multi-omic quantitative trait loci, genome-wide association studies, and epigenomic profiles, we delineated genetic and epigenetic changes underlying MBS suppression. This study provides a systematic genomic framework for understanding the mechanisms of cognitive resilience.