3rd Edition of Dementia World Conference 2026

Abstract

Alzheimer’s disease (AD) is associated not only with progressive cognitive decline but also with profound circadian dysregulation, which correlates with worsening neurological function and diminished quality of life. Degeneration within brain regions involved in timekeeping disrupts sleep–wake cycling and physiological rhythms, further exacerbating disease burden. This study establishes a cross-species translational framework connecting human neuroimaging biomarkers with Caenorhabditis elegans molecular assays to identify candidates capable of restoring circadian function in AD. Magnetic resonance imaging (MRI) and clinical data from 660 individuals with AD (Alzheimer’s Disease Neuroimaging Initiative; ADNI) were used to construct a Circadian Dysfunction Index (CDI) integrating hypothalamic and ventricular volumes with caregiver-reported changes in sleep and appetite. Lower hypothalamic volumes and ventricular enlargement were associated with greater circadian impairment, supporting a structural–functional link between hypothalamic integrity and rhythmic disruption. To interrogate conserved molecular mechanisms, C. elegans were treated with the CK1δ/ε inhibitor SR-3029 to perturb the LIN-42/KIN-20 pathway, an analog of the mammalian PER/CLOCK system. Four therapeutic candidates—curcumin, resveratrol, epigallocatechin gallate (EGCG), and melatonin—were screened for their ability to rescue rhythmic molting behavior as a proxy for circadian function. EGCG produced the most robust improvement, reducing molting periodicity from 840–920 minutes to approximately 640 minutes, while resveratrol and melatonin also demonstrated measurable restoration. Cross-species integration indicated that compounds effective in C. elegans correspond to pathways implicated in human circadian disruption. Collectively, these findings present a scalable, mechanism-driven platform for circadian-targeted therapeutic discovery in Alzheimer’s disease and identify conserved kinase-dependent pathways as promising intervention points for restoring biological rhythm in neurodegeneration.