Sleep and stress as modifiable drivers of Alzheimer's disease

Proper sleep and stress maintenance are essential for health and may contribute to disease progression when dysregulated. This review highlights the intricate links between sleep, stress, and Alzheimer's disease, including underlying neural circuitry and mechanisms that contribute to disease. Sleep is essential for protein clearance pathways including autophagy and the glymphatic system, which are impaired in neurodegenerative diseases. Similarly, chronic stress incites neuroinflammatory responses known to be elevated in brains of patients with neurodegeneration. As a result, it is perhaps unsurprising that tau pathology and neurodegeneration affect sleep and stress circuitry in the brain, including the Locus Coeruleus and Lateral Hypothalamus, beginning in prodromal phases of Alzheimer's disease. Though the precise mechanisms underscoring these vulnerabilities are incompletely understood, this provides a unique therapeutic opportunity for targeting these pathways in early Alzheimer's disease patients with concomitant sleep impairments and/or chronic stress. In this review, we offer insights into these relationships including specific brain region involvements, the contribution of molecular mechanisms of disease, and these translational opportunities which may arise.