# Short sleep and obesity in midlife and the risk of cognitive decline and incident dementia in later life: the Whitehall II cohort study

## TL;DR

This study explores how short sleep and obesity in midlife may increase dementia risk later in life, possibly through brain inflammation and metabolic issues.

## Contribution

The novel aspect is examining the combined effect of short sleep and obesity on dementia risk and investigating potential biological mechanisms like neuroinflammation.

## Key findings

- Short sleep and obesity may jointly increase dementia risk.
- Neuroinflammatory biomarkers like GFAP and YKL-40 could mediate this risk.
- Cognitive decline is tracked over decades to link midlife factors to later dementia.

## Abstract

Obesity and short sleep duration have both been associated with an increased risk of dementia, but their combined impact and the underlying mechanisms are not yet fully understood. Our aim is to investigate the separate and combined associations of short sleep and obesity with cognitive decline and dementia risk, and to investigate whether these associations are mediated by neuroinflammatory responses and metabolic disturbances, as indicated by blood-based biomarkers. This is a 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 glial fibrillary acidic protein (GFAP), chitinase-3-like protein (YKL-40), triggering receptor expressed on myeloid cells 2 (TREM2), neurofilament-light chain (NfL), and brain-derived neurotrophic factor (BDNF), measured from EDTA plasma, as well as insulin resistance measured from fasting serum samples. Cognitive status, measured using tests of executive function, memory, phonemic fluency and semantic fluency, was assessed in 1997-1999, 2002-2004, 2007-2009, 2012-2013, and 2015-2016. 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 shed light on the pathomechanisms of sleep and obesity for dementia in terms of neuroinflammation.

It has been known for some time that a considerable proportion of dementia can theoretically be prevented through controlling of modifiable risk factors, particularly in midlife. There are many postulated risk factors, including short sleep duration and obesity. We will investigate whether short sleep combined with obesity is associated with an increased risk of cognitive impairment in terms of memory, reasoning and fluency, and clinical dementia. If so, we will test what biomarker changes in the body may contribute this as it is unknown. We will use information from an observational cohort study of British civil servants, the Whitehall II study, with a nearly 30 years of follow-up. We will then look at whether inflammation in the brain, as indicated by circulating proteins, is part of the cause. The results of this study may help us understand the importance of normal sleep and weight in terms of brain health.