Circadian rhythm, metabolic stress, and Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Beyond hereditary factors related to an individual's genetics, acquired traits are becoming increasingly common, including lifestyle changes such as diet and pathogenic infections. This brings about the involvement of metabolic stress and gut-brain axis dysfunction in the progression of AD. Recent studies have revealed that circadian rhythms not only regulate brain energy metabolism but also orchestrate changes in gut microbiota, inducing neurological modulations. Gut-derived metabolites and microbial signals can modulate host circadian gene expression, thereby influencing neuroinflammation. Metabolic stresses, characterized by impaired glucose utilization, mitochondrial dysfunction, and oxidative stress, exacerbate this cycle through systemic inflammation and gut dysbiosis. Additionally, dietary patterns and timing, such as time-restricted feeding, have been known to benefit both the circadian clock and gut-brain axes, thereby reducing neuroinflammation and improving cognitive outcomes. Therefore, this chapter synthesizes the emerging evidence on the interconnected roles of circadian rhythm, gut microbiota, and metabolic stresses in AD pathogenesis. It highlights the mechanistic insights into how chronobiology and nutrition can be leveraged to restore gut-brain metabolic homeostasis, offering innovative strategies for early intervention of Alzheimer's disease.