Stable neuronal representations underlie cognitive resilience to Alzheimer's disease pathology.

INTRODUCTION

While Alzheimer's disease (AD) typically elicits progressive cognitive decline, some individuals with significant AD pathology maintain cognition. Understanding the neuronal underpinnings of such cognitive resilience would propel the development of interventions for delaying dementia.

METHODS

We used Barnes Maze testing to identify 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, and culminating in post mortem tau and amyloid load quantifications.

RESULTS

Cognitively resilient TgF344-AD rats recruited fewer neurons and displayed more stable neuronal representations during repeated stimulations in cortical excitatory and hippocampal inhibitory ensembles, with reduced excitatory spike burstiness and a distinct pattern of functional synaptic connectivity. These associations existed independently of amyloid levels.

DISCUSSION: 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.