The Proteomic Signature of Sleep and its implication for Alzheimer's Disease

Alzheimer's Disease (AD) is characterized by progressive cognitive decline leading to mortality and is a leading cause of death among older adults. The disease involves the formation of plaques and tangles in the brain, which hinder cognitive functioning. Alzheimer's Disease is also associated with sleep architecture, including evidence that alterations in sleep architecture is a predisposing factor for Alzheimer's Disease. There is, indeed, an established relationship between sleep, neurocognition, and brain maintenance, exemplified by the glymphatic system. Research suggests that the glymphatic system helps to clear detrimental proteins from the brain primary during sleep and thus disrupted sleep may hinder this process. Still, we lack a complete understanding of the underlying risk factors and mechanisms for Alzheimer's Disease, which could be improved by the establishment of a network map that connects neurocognitive dimensions, sleep endophenotypes and molecular markers. To address these gaps in knowledge, the proposed project aims to (1) investigate polysomnographic (PSG) sleep biomarkers, proteomic blood biomarkers, and neurocognition in a large longitudinal sample of adults; (2) disentangle the relationship between sleep, neurocognitive function, and circulating proteins using an experimental approach in humans designed to identify proteins that are modulated only by sleep and that are associated with cognitive function, and (3) build a knowledge graph highlighting the three-way relationship between inter-individual variation on circulating proteins, sleep endophenotypes, and changes in cognitive function before and after sleep. The primary hypothesis is that there will be a set of biomolecules associated with neuronal pathways that modulate the relationship between sleep and cognitive decline. A second hypothesis is that this molecular set will significantly share components with biomarkers associated with cognitive decline and dementia. The project includes two distinct studies. The first capitalizes on existing samples and data from a longitudinal study in Brazil, the Baependi Heart Study (BHS) (1R01HL141881) where blood samples were collected before and after a night of sleep recorded via PSG in 2020-2023. We propose to repeat PSG, blood sampling and add new neurocognitive evaluations and AD biomarker in 450 adults who were at least 40 years old at the first PSG recording to provide longitudinal data. We will also repeat the neurocognitive testing 3 years later in these participants. The second study is an experimental study in 50-65 year olds designed to identify sleep-related changes in protein biomarkers that are associated with cognitive function. This experiment involves four controlled 8-hour periods: 8-hour nocturnal sleep opportunity, 8-hour nocturnal wake, 8-hour daytime wake, 8-hour daytime sleep opportunity. Cognitive tests are performed before and after these periods and sleep is recorded with PSG. The results of this study will provide novel mechanistic data linking sleep disruption to the development of Alzheimer's Disease. Further, these protein biomarkers could help identify those at risk of developing neurodegeneration. Project Number: 1R01AG089354-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Kristen Knutson (+1 co-PI) | Institution: NORTHWESTERN UNIVERSITY, CHICAGO, IL | Award Amount: $691,009 | Activity Code: R01 | Study Section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH] View on NIH RePORTER: https://reporter.nih.gov/project-details/11131818