Sleep, 24-Hour Activity Rhythms, and Subsequent Amyloid-ß Pathology.

Importance: Sleep disturbances are common among older adults and have been associated with the development of Alzheimer disease (AD), such as amyloid-ß (Aß) pathology. For effective AD prevention, it is essential to pinpoint the specific disturbances in sleep and the underlying 24-hour activity rhythms that confer the highest risk of Aß deposition. Objective: To determine the associations of 24-hour activity rhythms and sleep with Aß deposition in adults without dementia, to evaluate whether disrupted 24-hour activity and sleep may precede Aß deposition, and to assess the role of the apolipoprotein E ε4 (APOE4) genotype. Design, Setting, and Participants: This was an observational cohort study using data from the Rotterdam Study. Of 639 participants without dementia who underwent Aß positron emission tomography (PET) from September 2018 to November 2021, 319 were included in the current study. Exclusion criteria were no APOE genotyping and no valid actigraphy data at the baseline visits from 2004 to 2006 or from 2012 to 2014. The mean (SD) follow-up was 7.8 (2.4) years. Data were analyzed from March 2023 to April 2024. Exposures: Actigraphy (7 days and nights, objective sleep, and 24-hour activity rhythms), sleep diaries (self-reported sleep), Aß42/40, phosphorylated tau (p-tau)181 and p-tau217 plasma assays, 18F-florbetaben PET (mean standard uptake value ratio [SUVR] in a large cortical region of interest), and APOE4 genotype. Main Outcomes and Measures: Association of objective and self-reported sleep and 24-hour activity rhythms at baseline with brain Aß PET burden at follow-up. Results: The mean (range) age in the study population was 61.5 (48-80) years at baseline and 69.2 (60-88) years at follow-up; 150 (47%) were women. Higher intradaily variability at baseline, an indicator of fragmented 24-hour activity rhythms, was associated with higher Aß PET burden at follow-up (ß, 0.15; bootstrapped 95% CI, 0.04 to 0.26; bootstrapped P = .02, false discovery rate [FDR] P = .048). APOE genotype modified this association, which was stronger in APOE4 carriers (ß, 0.38; bootstrapped 95% CI, 0.05 to 0.64; bootstrapped P = .03) compared to noncarriers (ß, 0.07; bootstrapped 95% CI, -0.04 to 0.18; bootstrapped P = .19). The findings remained largely similar after excluding participants with AD pathology at baseline, suggesting that a fragmented 24-hour activity rhythm may have preceded Aß deposition. No other objective or self-reported measure of sleep was associated with Aß. Conclusions and Relevance: Among community-dwelling adults included in this study, higher fragmentation of the 24-hour activity rhythms was associated with greater subsequent Aß burden, especially in APOE4 carriers. These results suggest that rest-activity fragmentation could represent a modifiable risk factor for AD.

Pioneering a Multi-Phase Framework to Harmonize Self-Reported Sleep Data Across Cohorts.

STUDY OBJECTIVES: Harmonizing and aggregating data across studies enable pooled analyses that support external validation and enhance replicability and generalizability. However, the multidimensional nature of sleep poses challenges for data harmonization and aggregation. Here we describe and implement our process for harmonizing self-reported sleep data. METHODS: We established a multi-phase framework to harmonize self-reported sleep data: (1) compile items; (2) group items into domains; (3) harmonize items; and (4) evaluate harmonizability. We applied this process to produce a pooled multi-cohort sample of five United States cohorts plus a separate yet fully harmonized sample from Rotterdam, Netherlands. Sleep and sociodemographic data are described and compared to demonstrate the utility of harmonization and aggregation. RESULTS: We collected 190 unique self-reported sleep items and grouped them into 15 conceptual domains. Using these domains as guiderails, we developed 14 harmonized items measuring aspects of Satisfaction, Alertness/Sleepiness, Timing, Efficiency, Duration, Insomnia, and Sleep Apnea. External raters determined that 13 of these 14 items had moderate-to-high harmonizability. Alertness/Sleepiness items had lower harmonizability, while continuous, quantitative items (e.g., timing, total sleep time, efficiency) had higher harmonizability. Descriptive statistics identified features that are more consistent (e.g., wake-up time, duration) and more heterogeneous (e.g., time in bed, bedtime) across samples. CONCLUSIONS: Our process can guide researchers and cohort stewards towards effective sleep harmonization and provides a foundation for further methodological development in this expanding field. Broader national and international initiatives promoting common data elements across cohorts are needed to enhance future harmonization and aggregation efforts.

Sleep and 24-H Activity Rhythms and the Risk of Stroke: A Prospective Cohort Study.

INTRODUCTION: Short and long self-reported sleep durations are associated with a higher risk of stroke, but the association between objective estimates of sleep and 24-h activity rhythms is less clear. We studied the association of actigraphy-estimated sleep and 24-h activity rhythms with the risk of stroke in a population-based cohort of middle-aged and elderly. METHODS: We included 1,718 stroke-free participants (mean age 62.2 ± 9.3 years, 55.1% women) from the prospective, population-based Rotterdam Study. Actigraphy-estimated sleep (total sleep time, sleep efficiency, sleep onset latency, and wake after sleep onset) and 24-h activity rhythms (interdaily stability, intradaily variability, and onset of the least active 5 h) were measured during a median of 7 days (Q1-Q3: 6-7 days). The association of sleep and 24-h activity rhythms with risk of stroke was analyzed using Cox proportional hazards models. RESULTS: During a mean follow-up of 12.2 years (SD: 3.2), 105 participants developed a stroke, of whom 81 had an ischemic event. Although there was no clear association between actigraphy-estimated sleep and the risk of stroke, a more fragmented 24-h activity rhythm was associated with a higher risk of stroke (hazard ratio [HR] per SD increase 1.28, 95% confidence interval [CI] 1.07-1.53). A less stable (HR per SD increase in stability 0.78, 95% CI: 0.63-0.97) and more fragmented (HR 1.28, 95% CI: 1.04-1.58) 24-h activity rhythm was also associated with a higher risk of ischemic stroke. CONCLUSIONS: Disturbed 24-h activity rhythms, but not sleep, are associated with a higher risk of stroke in middle-aged and elderly persons. This suggests that unstable and fragmented activity rhythms may play a more prominent role in the risk of stroke than sleep per se.

Life stress and adiposity in mothers: A 14-year follow-up in the general population.

Exposure to specific stressors has been found to associate with higher adiposity in adulthood. However, the potential overlapping effects of stress domains have been overlooked, as well as the role of parenting-related stressors that mothers are widely exposed to in mid-adulthood. Therefore, we assessed the association of overlapping effects of stress domains, including parenting-related stress, with subsequent adiposity in mothers. In 3957 mothers from the population-based Generation R Study, life stress was assessed during the first 10 years of child-rearing and measured as a reflective latent variable of stress domains. Structural equation modelling was used to assess the association of life stress and its individual domains with body mass index (BMI) and waist circumference after 14 years of follow-up. Greater life stress over the course of 10 years was associated with a higher BMI (standardized adjusted difference: 0.57 kg/m2 [95% CI: 0.41-0.72]) and a larger waist circumference (1.15 cm [0.72-1.57]). When examining individual stress domains, we found that life events was independently associated with a higher BMI (0.16 kg/m2 ) and contextual stress was independently associated with a higher BMI (0.43 kg/m2 ) and larger waist circumference (1.04 cm). Parenting stress and interpersonal stress were not independently associated with adiposity at follow-up. The overlap of multiple domains of stress in mothers is associated with a higher risk of adiposity. This effect was stronger than for individual life stress domains, reiterating the need to consider overlapping effects of different life stress domains.

The Association of Life Stress with Subsequent Brain and Cognitive Reserve in Middle-Aged Women.

BACKGROUND: Cognitive and brain reserve refer to individual differences that allow some people to better withstand brain pathology than others. Although early life stress has been recognized as a risk factor for low reserve in late life, no research yet has studied this across midlife. OBJECTIVE: To examine the associations of life stress with brain and cognitive reserve in midlife. METHODS: We included 1,232 middle-aged women who participated in the ORACLE Study between 2002-2006). Life stress was calculated as the shared variance of four cumulative stress domains, created from items measured between pregnancy and 10 years after childbirth. Brain reserve was defined as healthy-appearing brain volume measured with MRI; cognitive reserve as better cognitive functioning than expected based on age, education, and brain MRI measures, using structural equation modelling. RESULTS: More life stress was associated with lower brain (standardized adjusted difference: -0.18 [95% CI 0.25,-0.12]) and cognitive reserve (-0.19 [-0.28,-0.10]). Although, effect sizes were typically smaller, cumulative stress domains were also associated with brain reserve (life events: -0.10 [-0.16,-0.04]; contextual stress: -0.13 [-0.19,-0.07]; parenting-related stress: -0.13[-0.19,-0.07]; interpersonal stress: -0.10 [-0.16,-0.04]) and cognitive reserve (life events: -0.18 [-0.25,-0.11]; contextual stress: -0.15 [-0.10,-0.02]; parenting-related stress: -0.10 [-0.18,-0.03]; interpersonal stress not significant). CONCLUSION: Women who experience more life stress in midlife were found to have lower reserve. Effects were primarily driven by shared variance across cumulative stress domains, suggesting that focusing on single domains may underestimate effects. The effect of life stress on lower reserve may make women with stress more prone to neurodegenerative disease later in life than women without stress.