Patterns of biological, cognitive, and physical aging in cancer survivors and controls and the role of sleep health: Relevance for Alzheimer's Disease and Related Dementias

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Abstract We use a geroscience framework to advance Alzheimer’s disease-related dementias (ADRD) research by establishing how biological aging affects cognitive and physical decline and defining the role of sleep in these relationships. We use the interface of aging and breast cancer in older women for this purpose because of their unique bi-directional relationships. Biological aging processes increase the risk of developing cancer, so that newly diagnosed breast cancer patients may have accelerated aging prior to therapy. Cancer treatments can further accelerate aging processes. Despite possible inverse relationships between cancer and ADRD, breast cancer therapy is associated with short-term cognitive decline and this may be due to the effects of accelerated biological aging on underlying early ADRD or damage to similar systems as involved in ADRD. As we age, sleep is fundamental to repairing damage to maintain system regulation and homeostasis, including clearance of waste products seen in Alzheimer’s disease (AD). Poor sleep is common in cancer survivors and sleep has been associated with biological aging and/or physical decline and cognitive problems and increased risk for ADRD in non-cancer settings. However, there is very limited longitudinal research testing these relationships in older survivors with control groups to inform research into cognitive aging and early ADRD. Our transdisciplinary team of nationally recognized leaders in aging and cancer, biological aging, sleep, neuroscience, Alzheimer’s disease and geriatrics are uniquely placed to fill this gap. The proposed study leverages an extant cohort to efficiently conduct a novel new study of the effects of biological aging on health. Our primary research questions are: 1) Do breast cancer survivors have more biological aging before systemic treatment than concurrent frequency- matched non-cancer controls?, 2) Do systemic treatments drive further biological aging and lower cognitive and physical function in survivors beyond that seen in non-cancer controls over time? and 3) Does poor sleep lead to more aging and lower function? To address these questions, we begin with breast cancer survivors (N=368) aged 60+ and contemporaneously evaluated non-cancer controls (N=354) frequency-matched to survivors on age, racial group, education level and recruitment site. These women have rich pre-treatment/enrollment neurocognitive, physical and sleep data and blood obtained and banked to specifically test aging markers. We will conduct follow-up out to 48-months and perform assays of several hallmarks of biological aging (epigenetic age, DNA damage, cellular senescence, SASP, and leukocyte telomere length). While accelerated biological aging has been postulated to explain cognitive and functional decline among people with and without cancer, this rigorous project will be the first to our knowledge to definitively evaluate this theory. The population and questions proposed are significant and will only become more important with the aging of the population. This clinical translational project addresses key NIA priority areas and will provide important data to inform future ADRD studies and interventions to improve health and resilience of our aging population.