Disruption of normal circadian rhythms and sleep cycles are consequences of aging and can profoundly impact health. Accumulating evidence indicates that circadian and sleep disturbances, which have long been considered symptoms of many neurodegenerative conditions, may actually drive pathogenesis early in the course of these diseases. In this review we explore potential cellular and molecular mechanisms linking circadian dysfunction and sleep loss to neurodegenerative diseases, with a focus on Alzheimer’s Disease. We examine the interplay between central and peripheral circadian rhythms, circadian clock gene function, and sleep in maintaining brain homeostasis, and discuss therapeutic implications. The circadian clock and sleep can influence a number of key processes involved in neurodegeneration, suggesting that these systems might be manipulated to promote healthy brain aging.

The Amyloid Hypothesis, which has been the predominant framework for research in Alzheimer’s Disease (AD) over the past two decades, has also been the source of considerable controversy within the field. The Amyloid Hypothesis postulates that amyloid-beta peptide (Aβ) is the causative agent in AD, and is strongly supported by data from rare autosomal dominant forms of AD. However, the evidence that Aβ causes age-associated sporadic AD is more complex and less clear, prompting criticism of the hypothesis. Herein, we provide an overview of the major arguments for and against the Amyloid Hypothesis, and review key data supporting or refuting these arguments. We conclude that Aβ likely is the key initiator of a complex pathogenic cascade which causes AD, thus supporting the Amyloid Hypothesis in general. However, we argue that Aβ acts primarily as a trigger of other downstream processes, in particular tau aggregation, which mediate neurodegeneration. Thus, Aβ appears to be necessary but not sufficient to causes AD, and its major pathogenic effects may occur very early in the disease process. We discuss implications for therapeutic development and future research.

Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.

Dysfunction in 24-h circadian rhythms is a common occurrence in aging adults, however, circadian rhythm disruptions (CRD) are more severe in people with age-related neurodegenerative diseases, including Alzheimer's disease and related dementias (ADRD) and Parkinson's disease (PD). Manifestations of CRD differ according to type and severity of neurodegenerative disease, and importantly, could occur before onset of typical clinical symptoms of neurodegeneration. Evidence from preliminary studies suggest that-in addition to being a symptom of neurodegeneration-CRD might also be a potential risk factor for developing ADRD and PD, although large, longitudinal studies are needed to confirm this. The mechanistic link between *

Disturbances in the sleep–wake cycle and circadian rhythms are common symptoms of Alzheimer Disease (AD), and they have generally been considered as late consequences of the neurodegenerative processes. Recent evidence demonstrates that sleep–wake and circadian disruption often occur early in the course of the disease and may even precede the development of cognitive symptoms. Furthermore, the sleep–wake cycle appears to regulate levels of the pathogenic amyloid-beta peptide in the brain, and manipulating sleep can influence AD-related pathology in mouse models via multiple mechanisms. Finally, the circadian clock system, which controls the sleep–wake cycle and other diurnal oscillations in mice and humans, may also have a role in the neurodegenerative process. In this review, we examine the current literature related to the mechanisms by which sleep and circadian rhythms might impact AD pathogenesis, and we discuss potential therapeutic strategies targeting these systems for the prevention of AD.