Lifecourse sleep, cognitive decline and risk of Alzheimer's disease: a pooled cohort study.

PROJECT SUMMARY/ABSTRACT Mounting evidence from our team and others suggests a potential bi-directional relationship between sleep and Alzheimer's disease and related dementias (ADRD) in older adults, in which sleep disturbances precede clinical ADRD, in addition to commonly occurring after disease onset. This bi-directional relationship has important

implications for the early intervention of ADRD, yet it remains debatable whether sleep disturbance is a prodromal or modifiable risk factor of ADRD. Research to disentangle the role of sleep in ADRD requires the use of a life course approach to address the directionality of the association, particularly given the long neurodegenerative

processes leading to ADRD before symptoms onset and the large variations in sleep disturbances across the life course. Our long-term goal is to develop preventive strategies for ADRD by addressing the role of sleep disturbances across the life course. The objective of this proposal is to determine the effects of objective and

subjective sleep disturbances on age-related cognitive decline and risk of ADRD across the life course in diverse populations, and to elucidate mechanistic pathways contributing to this association at different stages of life. Our central hypothesis is that objective and subjective sleep disturbances over the life course are associated with

life-course cognitive trajectories and risk of ADRD, with varying magnitude and different underlying pathways for each stage of life. We have an unprecedented opportunity to leverage data from six well-characterized longitudinal cohorts, two with 40-50% Black or Mexican American participants, to create a synthesized diverse

cohort of ~35,000 (age 30-104) adults with objective (polysomnography and actigraphy) and subjective sleep measures, and cognition assessed regularly spanning up to 60-years. We will also perform replication analysis using data from the UK Biobank, a study of 500,000 UK adults aged 40-84-years. By applying an innovative life

course approach both in the synthesized and each individual cohort, we will address the following aims: 1) Identify age trends in objective and subjective sleep disturbances and cognition from early adulthood to the oldest old; 2) Evaluate the longitudinal association between sleep disturbances at different stages of life and

cognitive performance over the life course including incident ADRD; 3) Elucidate and compare novel pathways linking sleep disturbances to ADRD at different stages of life. The research is highly significant because it helps to address the timing of sleep disturbances in relation to cognitive aging over the life course and thus the

directionality of the relationship. The creation of the first-ever synthesized diverse cohort of sleep and cognition across the life course will also develop foundational resources for future research to disentangle the bi-directional link between sleep and ADRD. This work has a large impact as a critical step towards elucidating the role of life-

course sleep disturbance as a prodromal or modifiable risk factor for ADRD. This will directly inform the early detection of ADRD and the design of intervention trials, especially in establishing the optimal timing for sleep intervention to mitigate dementia risk, a topic with profound public health implications.