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

Neuron-specific suppression of nuclear-encoded mitochondrial genes and upstream mitochondrial biogenesis signaling (MBS) is linked to clinical dementia during the transition to Alzheimer’s disease.

• Why it matters: Classical AD neuropathological metrics can fail to predict cognitive status, motivating molecular mechanisms that explain why some individuals remain resilient while others develop dementia.
• What they did: The study used single-nucleus RNA-sequencing and single-nucleus multiome datasets, normalized with a novel framework to bypass scaling artifacts and compositional biases, then integrated multi-omic QTL, GWAS, and epigenomic profiles.
• The result: Genetic and epigenetic changes underlying MBS suppression were delineated, providing a systematic genomic framework for understanding mechanisms of cognitive resilience.