Circadian changes in Alzheimer's disease: Neurobiology, clinical problems, and therapeutic opportunities

The understanding of Alzheimer's disease (AD) pathophysiology is an active area of research, and the traditional focus on hippocampus, amyloid and tau protein, and memory impairment has been expanded with components like neuroinflammation, insulin resistance, and circadian rhythm alterations. The bidirectional vicious cycle of neuroinflammation and neurodegeneration on a molecular level may cause functional deficits already long before the appearance of overt clinical symptoms. Located at the crossroads of metabolic, circadian, and hormonal signaling, the hypothalamus has been identified as another brain region affected by AD pathophysiology. Current findings on hypothalamic dysfunction open a broader horizon for studying AD pathogenesis and offer new opportunities for diagnosis and therapy. While treatments with cholinomimetics and memantine form a first line of pharmacological treatment, additional innovative research is pursued toward the development of antiinflammatory, growth factor, or antidiabetic types of medication. Following recent epidemiological data showing associations of AD incidence with modern societal and "life-style"-related risk factors, also nonpharmacological interventions, including sleep optimization, are being developed and some have been shown to be beneficial. Circadian aspects in AD are relevant from a pathophysiological standpoint, but they can also have an important role in pharmacologic and nonpharmacologic interventions, and appropriate timing of sleep, meals, and medication may boost therapeutic efficacy.