Circadian Rhythms in AD pathogenesis: A Critical Appraisal

Abstract

Purpose of the review: A wide array of sleep and circadian deficits have been observed in patients with Alzheimer's Disease (AD). However, the vast majority of these studies have focused on later-stage AD, and do not shed light on the possibility that circadian dysfunction contributes to AD pathogenesis. The goal of this review it to examine the evidence supporting or refuting the hypothesis that circadian dysfunction plays an important role in early AD pathogenesis or AD risk in humans.

Recent findings: Few studies have addressed the role of the circadian system in very early AD, or prior to AD diagnosis. AD appears to have a long presymtomatic phase during which pathology is present but cognition remains normal. Studies evaluating circadian function in cognitively-normal elderly or early-stage AD have thus far not incorporated AD biomarkers. Thus, the cause-and-effect relationship between circadian dysfunction and early-stage AD remains unclear.

Summary: Circadian dysfunction becomes apparent in AD as dementia progresses, but it is unknown at which point in the pathogenic process rhythms begin to deteriorate. Further, it is unknown if exposure to circadian disruption in middle age increases AD risk later in life. This review address gaps in current knowledge on this topic, and proposes several critical directions for future research which might help to clarify the potential pathogenic role of circadian clock dysfunction in AD.

Keywords: Alzheimer’s Disease; amyloid; circadian; clock genes; neurodegeneration.

Figure 1. Circadian dysfunction in the timecourse of AD pathogenesis

Theoretical curves showing the timecourse of amyloid plaque deposition (red line), tau aggregation (green line), and neuronal loss (black line) in relation to cognitive function in AD, modified from previous studies[72, 76, 77]. Blue dotted lines show possible positions for circadian dysfunction. Line A suggests a causal role, while B suggests that presymptomatic AD pathology leads to circadian disruption (which could then contribute to early disease). Line C suggests that circadian dysfunction is a late consequence of dementia.