Circadian fragmentation: a harbinger of Alzheimer's disease?
Authors: Erik S Musiek
Journal: The Lancet Healthy Longevity (2020)

The circadian system orchestrates 24-h rhythms in activity, physiology, and cellular function, which are aligned to the light–dark cycle of the earth. These circadian rhythms decline with age and are frequently disrupted in people with Alzheimer's dementia.1Coogan AN Schutova B Husung S et al.The circadian system in Alzheimer's disease: disturbances, mechanisms, and opportunities.Biol Psychiatry. 2013; 74: 333-339Summary Full Text Full Text PDF PubMed Scopus (109) Google Scholar Emerging evidence suggests that declines in circadian function can occur early in the course of Alzheimer's disease and might even contribute to the pathogenesis of the disease.2Musiek ES Bhimasani M Zangrilli MA Morris JC Holtzman DM Ju YE Circadian rest-activity pattern changes in aging and preclinical Alzheimer disease.JAMA Neurol. 2018; 75: 582-590Crossref PubMed Scopus (115) Google Scholar, 3Kress GJ Liao F Dimitry J et al.Regulation of amyloid-beta dynamics and pathology by the circadian clock.J Exp Med. 2018; 215: 1059-1068Crossref PubMed Scopus (49) Google Scholar However, the relation between specific circadian changes and disease progression and risk are not well understood. In The Lancet Healthy Longevity, Peng Li and colleagues address these issues by analysing longitudinal actigraphy data obtained from patients with normal cognition, mild cognitive impairment, and Alzheimer's dementia through the Rush Memory and Aging Project.4Li P Gao L Gaba A et al.Circadian disturbances in Alzheimer's disease progression: a prospective observational cohort study of community-based older adults.Lancet Healthy Longev. 2020; (published online Nov 12.)https://doi.org/10.1016/S2666-7568(20)30015-5Summary Full Text Full Text PDF Scopus (4) Google Scholar This study is remarkable for the large number of patients enrolled (n=1401), the longitudinal collection of actigraphy data over a long timeframe (up to 15 years), and the excellent cognitive phenotyping of all participants. Li and colleagues investigated four measures of circadian function: amplitude, which indicates the strength of circadian rhythm; acrophase, which marks the time of day of peak activity; intradaily variability, which quantifies fragmentation of activity rhythms over the course of the day; and interdaily stability, which shows consistency in the activity pattern from one day to the next. Obtaining actigraphy data in parallel with cognitive testing on an annual basis allowed longitudinal assessment of the relation between changes in circadian activity rhythms and the onset and progression of symptomatic Alzheimer's dementia. When assessing individuals without dementia (including those with normal cognition or mild cognitive impairment), Li and colleagues noted that lower amplitude and increased intradaily variability (showing a rise in rhythm fragmentation) were both associated with higher risk of progressing to Alzheimer's disease, even after controlling for amount of sleep, activity, and APOE ε4 genotype. They also noted that this effect was more pronounced in men, which accords with findings of a previous study.2Musiek ES Bhimasani M Zangrilli MA Morris JC Holtzman DM Ju YE Circadian rest-activity pattern changes in aging and preclinical Alzheimer disease.JAMA Neurol. 2018; 75: 582-590Crossref PubMed Scopus (115) Google Scholar When considering patients with mild cognitive impairment, worsening amplitude, interdaily stability, and intradaily variability were all associated with increased risk of progression to Alzheimer's disease. These observations support the notion that circadian dysfunction, particularly loss of amplitude and fragmentation of daily rhythms, accelerates during the early symptomatic phase of Alzheimer's disease and can predict impending Alzheimer's dementia. The findings of Li and colleagues provide strong support for the idea that the primary circadian deficit seen early in Alzheimer's disease is fragmentation of activity rhythms with subtle loss of the difference in activity between day and night. Although delayed acrophase (occurrence of peak activity later in the day) has been described in individuals with symptomatic Alzheimer's dementia,5Satlin A Volicer L Stopa EG Harper D Circadian locomotor activity and core-body temperature rhythms in Alzheimer's disease.Neurobiol Aging. 1995; 16: 765-771Crossref PubMed Scopus (175) Google Scholar, 6Ancoli-Israel S Klauber MR Jones DW et al.Variations in circadian rhythms of activity, sleep, and light exposure related to dementia in nursing-home patients.Sleep. 1997; 20: 18-23Crossref PubMed Scopus (224) Google Scholar altered acrophase did not predict progression to Alzheimer's disease in Li and colleagues' study, suggesting that phase delay is not an important part of early circadian changes in Alzheimer's disease. The findings of Li and colleagues accord with previous studies in patients with preclinical Alzheimer's disease. Because amyloid plaques and tau tangle pathology accumulate decades before cognitive symptom onset in Alzheimer's disease, biomarkers (eg, amyloid β and tau levels in cerebrospinal fluid, or amyloid PET) are needed to define the preclinical stage of Alzheimer's disease.7Jack Jr, CR Bennett DA Blennow K et al.NIA-AA research framework: toward a biological definition of Alzheimer's disease.Alzheimers Dement. 2018; 14: 535-562Summary Full Text Full Text PDF PubMed Scopus (2115) Google Scholar In previous studies, cognitively normal people with preclinical Alzheimer's disease (ie, those with biomarkers) had actigraphic evidence of increased daytime napping, decreased sleep efficiency at night, decreased circadian amplitude, and increased intradaily variability, but no change in acrophase.2Musiek ES Bhimasani M Zangrilli MA Morris JC Holtzman DM Ju YE Circadian rest-activity pattern changes in aging and preclinical Alzheimer disease.JAMA Neurol. 2018; 75: 582-590Crossref PubMed Scopus (115) Google Scholar, 8Ju YE McLeland JS Toedebusch CD et al.Sleep quality and preclinical Alzheimer disease.JAMA Neurol. 2013; 70: 587-593Crossref PubMed Scopus (362) Google Scholar When considered with these previous studies, the findings of Li and colleagues suggest that subtle fragmentation of circadian rhythms in activity and sleep occur very early in the disease course, perhaps before cognitive changes. Thus, further investigation is needed into the possibility that non-invasive measurements of circadian fragmentation (eg, intradaily variability) might be useful as biomarkers of early Alzheimer's disease. One shortcoming of the study by Li and colleagues is the absence of Alzheimer's disease biomarkers. As a result, it is impossible to know which participants in this study had preclinical Alzheimer's disease changes or how these changes might have affected circadian variables or future Alzheimer's disease progression. Because these pathological changes occur 15–20 years before the onset of cognitive symptoms in Alzheimer's disease, it likely that many participants who developed symptomatic Alzheimer's disease during the 15-year follow-up period had preclinical Alzheimer's disease at the start of the study. Thus, this study cannot prove that circadian disturbances cause Alzheimer's disease, only that circadian fragmentation is associated with the progression of disease. No circadian variables predicted progression to mild cognitive impairment in people who presented with normal cognition. Since only 42% of patients in this cohort with mild cognitive impairment went on to develop Alzheimer's disease, it is possible that the effect of presymptomatic Alzheimer's disease pathology on circadian function and progression to mild cognitive impairment might have been diluted by the high percentage of patients with mild cognitive impairment who did not actually have Alzheimer's disease neuropathology. Although Li and colleagues have made a large step forward in this area of research, future studies incorporating Alzheimer's disease biomarkers to define presymptomatic patients will be needed to establish whether circadian fragmentation causes Alzheimer's disease, or vice versa. ESM has worked as a consultant for Eisai Pharmaceuticals. Circadian disturbances in Alzheimer's disease progression: a prospective observational cohort study of community-based older adultsOur results indicate a link between circadian dysregulation and Alzheimer's progression, implying either a bidirectional relation or shared common underlying pathophysiological mechanisms. Full-Text PDF Open Access