Circadian Rhythms in AD Pathogenesis: a Critical Appraisal

Purpose of Review: A wide array of sleep and circadian deficits has 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 is 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 presymptomatic 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 addresses 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.