Stable neuronal representations to repeated stimulation underlie cognitive resilience in Alzheimer's disease...

While Alzheimer's Disease (AD) typically triggers cognitive decline, some individuals with significant AD pathology maintain normal cognition into late life. Understanding the neuronal underpinnings of such cognitive resilience would propel the development of interventions for delaying dementia. To this end, we used cognitive testing to identify a subset of cognitively resilient 13-month-old TgF344-AD rats (established AD) and their non-transgenic littermates, followed by Neuropixels recording from 8500 neurons during repeated somatosensory stimulation. Cognitively resilient TgF344-AD rats recruited fewer neurons yet displayed more stable neuronal representations during repeated stimulations in cortical excitatory and hippocampal inhibitory ensembles, with reduced excitatory spike burstiness during network activation and a distinct pattern of functional synaptic connectivity. These associations existed independently of amyloid and tau levels. For the first time, our study revealed neuronal population-level hallmarks of maintained cognition that may serve as a novel neurophysiological biomarker of cognitive resilience and a target for stabilizing cognition.