Sleep, 24-Hour Activity Rhythms, and Subsequent Amyloid-β Pathology

Abstract

Importance: Sleep disturbances are common among older adults and have been associated with the development of Alzheimer disease (AD), such as amyloid-β (Aβ) 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 Aβ deposition.

Objective: To determine the associations of 24-hour activity rhythms and sleep with Aβ deposition in adults without dementia, to evaluate whether disrupted 24-hour activity and sleep may precede Aβ 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 Aβ 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), Aβ42/40, 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 Aβ 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 Aβ PET burden at follow-up (β, 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 (β, 0.38; bootstrapped 95% CI, 0.05 to 0.64; bootstrapped P = .03) compared to noncarriers (β, 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 Aβ deposition. No other objective or self-reported measure of sleep was associated with Aβ.

Conclusions and relevance: Among community-dwelling adults included in this study, higher fragmentation of the 24-hour activity rhythms was associated with greater subsequent Aβ burden, especially in APOE4 carriers. These results suggest that rest-activity fragmentation could represent a modifiable risk factor for AD.

Figure 1.. Study Design and Participant Selection

A, Diagram of the relevant measurements in the Rotterdam Study (RS). The current study included participants from the second and third RS cohort (RS-II, RS-III). Participants are reexamined on average every 4 years.^, Actigraphy and sleep diary were collected in the visits from 2004 to 2007 (RS-II-2 and RS-III-1) and from 2011 to 2014 (RS-II-3 and RS-III-2). Alzheimer disease plasma markers were measured in blood samples collected between 2012 to 2015. A subgroup of RS-II and RS-III participants were invited to undergo amyloid positron emission tomography (PET) during an extra visit from 2018 to 2021.^, B, Of 2068 eligible individuals for PET, 1697 were invited, 645 (response rate 38%) made an appointment, and 639 amyloid PET scans were acquired. A total of 340 participants had APOE genotyping and actigraphy data. Twenty-one had to be excluded due to invalid actigraphy measurements, including malfunctioning, measurements taken during the change to or from daylight savings time, and less than 96 hours of consecutive recording. The final sample included 319 participants. If participants had 2 valid actigraphy measurements, we included the most recent one (n = 42 from 2004-2007; n = 277 from 2011-2014).

Figure 2.. Examples of High and Low Interdaily Stability and Intradaily Variability

Four examples of 24-hour rest and activity rhythms are shown. The x-axis represents time (0:00, midnight; 12:00, noon), and the y-axis represents activity counts per 30 seconds. Participants started wearing the actigraph unit at 18:00 hours on day 1. These activity counts are scaled relative to the individual means and cannot be compared easily across persons. A, Rhythm with high interdaily stability and low intradaily variability. B, Rhythm with low interdaily stability and low intradaily variability. C, Rhythm with high interdaily stability and high intradaily variability. D, Rhythm with low interdaily stability and high intradaily variability.

Figure 3.. Association Between Fragmented 24-Hour Activity Rhythms at Baseline and Amyloid-β (Aβ) Positron Emission Tomography (PET) Burden at Follow-Up

A, The scatterplot shows the association between intradaily variability (x-axis) and Aβ PET burden (y-axis) a mean (SD) 7.8 (2.4) years later measured as the mean cortical standard uptake value ratio (SUVR). The solid black line represents the linear regression line, with shaded areas indicating 95% CIs. B, The scatterplot displays the same association as in A separately for APOE4 carriers (orange) vs noncarriers (gray). C, The scatterplots show the association between intradaily variability (x-axis) and residuals of Aβ PET SUVR (y-axis) after statistically controlling for (continuous values of) Aβ42/40, phosphorylated tau (p-tau)₁₈₁, and p-tau₂₁₇ at baseline. D, The graphs show the standardized β coefficients and bootstrapped 95% CIs (y-axis) of the main effect of intradaily variability (left graph) and the intradaily variability by APOE4 interaction (right graph) on Aβ PET burden. To evaluate whether a fragmented 24-hour activity rhythm preceded Aβ deposition, we compared the effect size in the whole sample to those computed after excluding participants with the most abnormal Aβ42/40, p-tau₁₈₁, or p-tau₂₁₇ plasma levels at baseline (x-axis). We used 3 cut points for participant exclusion (color-coded). Note that 15% is a conservative threshold given that the prevalence of a positive Aβ PET scan at follow-up was 15.4%. Alternatively, we used an established p-tau₂₁₇ cut point of >0.63 pg/mL.