Circadian Rhythm Dysfunction in Neurodegenerative Diseases: A Bidirectional Perspective and Therapeutic Potential

Abstract: Disruption of circadian rhythms is a recognized hallmark of age-related neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Emerging evidence suggests these disruptions are not merely symptoms but potential causal factors that, in some cases, manifest prior to clinical onset. This points to a bidirectional relationship in which neurodegenerative processes and circadian dysfunction mutually exacerbate each other. Core clock genes, including BMAL1, PER , and CRY , regulate critical processes such as redox balance, mitochondrial function, and neuroinflammation, which are commonly disrupted in neurodegenerative conditions. Although molecular pathways involving altered protein homeostasis, immune dysregulation, and inflammatory processes are proposed, the precise mechanisms linking circadian rhythm disruptions to neurodegeneration remain unclear. This review provides an integrated overview of shared circadian rhythm disruptions observed in major neurodegenerative diseases and evidence on the underlying molecular mechanisms including oxidative stress and clock gene perturbation, and evaluates the temporal dynamics of circadian disruption relative to disease onset and progression. Furthermore, we discuss the translational potential of circadian-oriented interventions and highlight the limitations of current evidence. Understanding these interactions may help identify novel therapeutic strategies for stabilizing circadian rhythm to mitigate disease progression in neurodegenerative diseases. Keywords: circadian rhythm, neurodegenerative diseases, suprachiasmatic nucleus, Circadian-oriented interventions