Midlife short sleep with and without obesity, and the risk of future dementia: a prospective cohort study

Short sleep duraiton is a putative risk for dementia, whereas midlife obesity is an well-known risk factor. Midlife short sleep and obesity share some biological changes such as inflammations or metabolic changes, but their combined impact is not yet fully understood. Our aim is to investigate the associations of short leep obesity with cognitive decline and dementia risk, and to investigate whether these associations are mediated by blood markers. This is an analysis of prospective cohort study of adults who were free of dementia, had data on sleep duration and BMI at baseline in 1997-1999, and were tracked for dementia diagnoses until 2023 via linkage to electronic health records. Participants will be divided into four groups: (1) the reference group (2) short sleep (2) short sleep (≤6 hours) and non-obese weight; (3) normal sleep and obesity (≥30kg/m ²); (4) short sleep and obesity, the main exposure group. Baseline blood-based biomarkers include chitinase-3-like protein (YKL-40), triggering receptor expressed on myeloid cells 2 (TREM2), neurofilament-light chain (NfL), and brain-derived neurotrophic factor (BDNF), interleukin (IL)-1(, IL-6, C-reactive protein (CRP), transforming growth factor (TGF)-(3, adiponectin, insulin, ghrelin, and leptin. Cognitive status, measured using tests of executive function, memory, phonemic fluency and semantic fluency, was repeatedly assessed. We will use linear mixed-effects models and Cox proportional hazard models to examine the associations of short sleep and obesity with change in cognitive functioning and risk of dementia, respectively. To examine whether blood-based biomarkers partially mediate these associations, formal mediation analyses will be performed, estimating the proportion of excess dementia risk mediated by the biomarkers individually and in combination. The results of this study may provide an additional insight whether co-occurring short sleep and obesity is a risk factor for dementia and the biological changes associated with these factors..