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Basic Science and Pathogenesis.

Hyun Woong Roh1, Sunwoo Yoon1, Homin Song1

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Cellular circadian rhythm disruptions in Alzheimer's disease (AD) patients correlate with neurodegeneration and cognitive decline. These cellular period deviations may serve as early biomarkers for AD and aging-related neurodegenerative changes.

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Area of Science:

  • Neuroscience
  • Chronobiology
  • Biomarker Discovery

Background:

  • Circadian rhythm alterations are common in Alzheimer's disease (AD) and other neurodegenerative conditions.
  • The role of ex-vivo cellular circadian periods and their deviation from 24 hours in patient-derived fibroblasts is not well understood.

Purpose of the Study:

  • To investigate the association between cellular circadian period metrics (period length and deviation from 24 hours) and AD biomarkers.
  • To explore the relationship between cellular circadian rhythm and neurodegenerative changes, cognitive status, and clinical progression in individuals with cognitive complaints.

Main Methods:

  • Analysis of 135 older adults with cognitive complaints from the BICWALZS cohort.
  • Measurement of cellular circadian periods in patient-derived fibroblasts using Bmal1-luciferase assays.
  • Assessment of AD biomarkers (plasma pTau-217, NfL, GFAP) and neuroimaging (MRI), alongside cognitive tests and survival analysis.

Main Results:

  • Cellular circadian period correlated with tauopathy, neural injury, and inflammation biomarkers.
  • Longer periods were linked to reduced grey matter density in AD-relevant brain regions.
  • Period deviation from 24 hours associated with age, neurodegeneration, cognitive decline, and memory/language impairments.
  • Longer cellular circadian periods predicted faster clinical progression in AD.

Conclusions:

  • Cellular circadian period deviation reflects aging-related neurodegeneration and cognitive impairment.
  • Cellular circadian metrics show potential as biomarkers for AD and aging-related neurodegeneration.
  • Further research is warranted to validate these findings and explore clinical applications.