SLEEP BEFORE DECLINE: INHIBITORY NETWORK CONTROL IN AGING AND ALZHEIMER’S DISEASE

Disturbances in sleep and memory are among the most common health concerns in older adults, substantially impacting their quality of life. Alzheimer’s disease (AD), the leading cause of dementia, affects over 7 million Americans aged 65 and older. Studies suggest that midlife sleep disturbances might increase the risk of later-life AD. Here, we used the AD-BXD mouse panel—a genetically diverse population carrying familial AD alleles—to examine the relationship between midlife sleep and late-life cognition. We find that reduced sleep during midlife predicts greater memory decline at old age. In AD-BXD strains susceptible to cognitive decline, AD neuropathology is pronounced in thalamic and hippocampal structures critical for sleep regulation and memory processing, respectively, and this pathology predicts the extent of cognitive impairment. Selective reduction in the apparent density of somatostatin-positive (SST⁺) interneurons is present in these regions in cognitively susceptible, but not resilient, AD-BXD mouse strains, and predicts memory performance in advanced age. In parallel experiments in aged wild-type mice, chemogenetic activation of hippocampal SST⁺ interneurons rescues age-related memory deficits in males, but not females. Together, these findings identify SST⁺ interneurons as a potential cellular link between midlife sleep disruption, network resilience, and memory decline in aging and Alzheimer’s disease.