Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease

Abstract

Importance: Circadian rhythm disturbances occur in symptomatic Alzheimer disease (AD) and have been hypothesized to contribute to disease pathogenesis. However, it is unknown whether circadian changes occur during the presymptomatic phase of the disease.

Objective: To examine the associations between circadian function, aging, and preclinical AD pathology in cognitively normal adults.

Design, setting, and participants: This cross-sectional study was conducted using community volunteers from the Knight Alzheimer's Disease Research Center at Washington University in St Louis. Cognitively normal participants (n = 205) underwent 7 to 14 days of actigraphy in their home environment between 2010 and 2012, in addition to clinical assessment, amyloid imaging with Pittsburgh Compound B (PiB), and cerebrospinal fluid biomarker collection. Data collected from 3 years before to 6 months after actigraphy were included. Sixteen participants were excluded owing to incomplete data collection.

Main outcomes and measures: Circadian rhythm analysis was performed on actigraphy data using 3 methods: cosinor, nonparametric, and empirical mode decomposition. Preclinical AD was assessed by longitudinal clinical assessment, amyloid imaging with PiB, and cerebrospinal fluid biomarker collection.

Results: Data from 189 participants were included in the analyses. The mean (SD) age was 66.6 (8.3) years, and 121 participants (64%) were women. Older age (β = .247; P = .003) and male sex (β = .170; P = .04), in the absence of amyloid pathology, were associated with a significant increase in intradaily variability, a nonparametric measure of rest-activity rhythm fragmentation, as well as decreased amplitude by several measures. After correction for age and sex, the presence of preclinical amyloid plaque pathology, assessed by positive PiB imaging (mean [SD], 0.804 [0.187] for PiB negative vs 0.875 [0.178] for PiB positive; P = .05) or increasing cerebrospinal fluid phosphorylated-tau to amyloid β 42 ratio (β = .231; P = .008), was associated with increased intradaily variability, indicating rest-activity rhythm fragmentation.

Conclusions and relevance: Preclinical AD is associated with rest-activity rhythm fragmentation, independent of age or sex. Aging was also associated with circadian dysfunction independently of preclinical AD pathology, particularly in men. The presence of circadian rhythm abnormalities in the preclinical phase of AD suggests that circadian dysfunction could contribute to early disease pathogenesis or serve as a biomarker of preclinical disease.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Musiek is a consultant for Eisai Pharmaceuticals. Dr Holtzman serves on the scientific advisory boards of C2N Diagnostics and Proclara Biosciences and is a consultant for Eli Lilly, AbbVie, Genentech, and GlaxosmithKline. No other disclosures were reported.

Figures

Figure 1.. Association Between Age, Sex, and Circadian Variables in Amyloid-Negative Individuals

A-C, Circadian amplitude (Mesor, alphacount, and EMD amplitude) declines with age. Circadian fragmentation, as measured by intradaily variability (IV) (D), and day-to-day consistency, as measured by interdaily stability (E), increase with age, while acrophase does not change (F). Men are indicated by dark blue circles and the dashed gray line, women by orange triangles and the blue line, and the dark blue line indicates linear trendline for all participants. Magnitudes and P values of age effects are listed in Table 2. Magnitudes (in standardized β format) and P values for the effect of female sex on circadian variables (adjusting for age) are mesor, β = .292, P < .001; alphacount, β = .287, P = .001; empirical mode decomposition (EMD) amplitude, β = .226, P = .04; fragmentation, β = −.170, P = .04; interdaily stability, β = .320, P < .001; acrophase, β = .048, P = .16; cosinor F (goodness of fit, not shown), β = .233, P = .007; and EMD period (not shown), β = .035, P = .67. aAge is a significant predictor of a circadian variable. bSex is a significant predictor of a circadian variable after adjusting for age.

Figure 2.. Association Between Phosphorylated Tau181 (pTau) to Amyloid β 42 (Aβ42) Ratio and Circadian Fragmentation Intradaily Variability (IV)

Scatterplot showing a significant positive association (P = .008) between the pTau to Aβ42 ratio (indicating increasing Alzheimer disease–related pathology) and circadian fragmentation (IV) for all participants with available cerebrospinal fluid biomarkers (n = 148), adjusted for age and sex.