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The substantial associations between sleep and dementia continue to mount, with considerable evidence suggesting that deficits in sleep duration may be linked to a greater risk for dementia. Results of a large observational study recently published in Neurology indicate that sleep irregularity, independent of duration, may also be a risk factor.
The data from this study was extracted from the UK Biobank database, including information regarding sleep regularity and dementia incidence from over 88,000 individuals living in the UK. The median age was 62, and participants were followed for an average of 7.2 years (during which 480 people were diagnosed with dementia). Sleep was assessed during a 7-day period of wearing a wrist accelerometer and quantified by the sleep regularity index (SRI). The SRI is calculated as the probability of being in the same state (asleep or awake) at any two time points 24 hours apart (averaged over 1 week), with a score of 100 representing perfect regularity and zero indicating waking and sleeping at entirely random times.
After multivariate adjustment, a U-shaped associated with dementia was observed, but only irregular sleepers had a significant increase in risk for dementia (i.e. perfectly regular sleepers also had a higher risk, but this was not significant). Relative to the average SRI (an SRI of 61), people in the 5th percentile (SRI of 41) had a 53% greater risk of developing dementia during the study period. Additionally, in a subset of participants that also had MRI data, gray matter and hippocampal volume were reduced among people at the extremes of the SRI.
It’s worth noting that the SRI was previously found to be inversely associated with mortality using data from this same population. Relative to the median, the most irregular sleepers (5th percentile) had a 53% higher mortality rate, while sleepers in the 95th percentile (SRI of 75) had a 10% lower mortality rate, with similar findings for overall mortality, cardiovascular mortality, and cancer mortality. Additionally, these associations were independent of sleep duration, fragmentation, and quality, suggesting that some aspect of regularity is driving the mortality and dementia risks.
Associations between sleep duration and the subsequent risk of dementia have also been observed previously, with recent data suggesting potential mechanisms. Sleep disruption resulting from dementia is clearly established, but whether poor sleep during mid-life contributes to the development of dementia is not so clear. One of the largest and longest-spanning studies to suggest that insufficient sleep precedes dementia was the Whitehall II cohort study, which provided data from nearly 8,000 participants with a median follow-up of 25 years, published in Nature Communications. In this study, compared to “normal” sleep (defined as 7 hours), sleeping 6 hours or less at age 50, 60, or 70 was associated with between a 22 to 37% increase in the risk of developing dementia, and no increase in risk was observed for longer sleep duration. These longer-term studies help to rule out reverse causation, as poor sleep clearly comes long before established dementia.
Another step made toward establishing the direction of causation was research published in JAMA Network Open. In this cross-sectional study, over 4400 cognitively healthy adults who had had PET scans (showing the degree of amyloid β (Aβ) deposition) also self-reported day and nighttime sleep duration. In this group of healthy older adults (aged 65-85), people reporting longer total nighttime sleep had reduced levels of Aβ brain deposition. This association was also significant in the early stages of Aβ accumulation, even without abnormal elevations in Aβ. In contrast, daytime sleep was associated with an increase in the risk for deposition in sites known to be targeted early. There was no apparent upper limit to the protective effect of nighttime sleep; each additional hour of nighttime sleep was associated with a 6% decreased risk for Aβ deposition. In the range of 4 to 10 hours of sleep per night (the range of duration reported in this study), there was an inverse linear relationship between sleep and amyloid deposits.
Data from this same study of cognitively healthy participants also found associations between sleep duration, as well as physical activity, on cognitive performance, evaluated using the Preclinical Alzheimer Cognitive Composite. Additionally, these associations appeared to be mediated by specific but independent mechanisms, as determined by MRI. For example, longer sleep reduced the Aβ burden in specific areas of the brain known for early accumulation (precuneus, and the medial orbitofrontal, anterior cingulate, and posterior cingulate cortices). Physical activity, on the other hand, was associated with larger volumes in parts of the brain associated with episodic and long-term memory (e.g., the hippocampus, parahippocampal and entorhinal cortices, and the fusiform gyrus). In sum, both sleep and physical activity were associated with better cognitive function, through different mechanisms, and the imaging data helps to provide physical links for these associations.
It is possible that Aβ itself disrupts sleep, and causation is in the opposite direction. This is extremely difficult to determine, because randomized clinical trials with sufficient power and that occur over decades, in which the primary variable requires altering sleep patterns, have essentially no chance of happening. It may be that the types of studies reported here are the best we will ever have. They make a strong case that improving the various aspects of sleep is likely to be one of the most important actions we can take to prevent cognitive decline.
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