Sleep and circadian rhythm disruption and stress intersect in Alzheimer's disease

Alzheimer's disease (AD) was discovered and the pathological hallmarks were revealed more than a century ago. Subsequently, many remarkable discoveries and breakthroughs provided us with mechanistic insights into the pathogenesis of AD. The identification of the molecular underpinning of the disease not only provided the framework of AD pathogenesis but also targets for therapeutic inventions. Despite all the initial successes, no effective treatment for AD has emerged yet as all the late stages of clinical trials have failed. Many factors ranging from genetic to environmental factors have been critically appraised as the potential causes of AD. In particular, the role of stress on AD has been intensively studied while the relationship between sleep and circadian rhythm disruption (SCRD) and AD have recently emerged. SCRD has always been thought to be a corollary of AD pathologies until recently, multiple lines of evidence converge on the notion that SCRD might be a contributing factor in AD pathogenesis. More importantly, how stress and SCRD intersect and make their concerted contributions to AD phenotypes has not been reviewed. The goal of this literature review is to examine at multiple levels - molecular, cellular (e.g. microglia, gut microbiota) and holistic - how the interaction between stress and SCRD bi-directionally and synergistically exacerbate AD pathologies and cognitive impairment. AD, in turn, worsens stress and SCRD and forms the vicious cycle that perpetuates and amplifies AD.