Page 9 - GPD-4-3

Gene & Protein in Disease

EDITORIAL
Circadian rhythms in Alzheimer’s disease: A

molecular clock worth watching

1,2
Bivek Singh *
1 Department of Neurology, Annapurna Neurological Institute and Allied Sciences, Kathmandu, Nepal
2 International Medical School and Postgraduate Centre, Management and Science University, Shah
Alam, Selangor, Malaysia

Alzheimer’s disease was first described in 1906 by Dr. Alois Alzheimer. Since then, there
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has been a compelling shift in our understanding of this and other neurodegenerative
disorders. While amyloid-β plaques and tau tangles remain pathological hallmarks
of Alzheimer’s disease, they do not fully account for the variability in disease onset,
progression, or therapeutic response. Among several emerging factors under
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investigation, circadian rhythm has gained recognition as a critical modulator of brain
health, aging, and neurodegeneration.
Circadian rhythm involves a central clock within the suprachiasmatic nucleus (SCN)
of the hypothalamus and peripheral clocks distributed across nearly all body tissues.
These clocks operate through transcriptional–translational feedback loops, comprising
core clock genes, such as BMAL1, CLOCK, PER, and CRY, which regulate essential cellular
processes including inflammation, redox balance, proteostasis, and mitochondrial
function. This pathway does not operate in isolation; it is tightly interconnected with
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hormonal, immune, and metabolic systems, forming a unified temporal network that
maintains neurobiological homeostasis across the lifespan.
*Corresponding author:
Bivek Singh Disruptions in circadian rhythms have been implicated in a wide range of systemic
(biveksingh123@gmail.com) disorders, including cardiovascular, metabolic, neurodegenerative, endocrine, and
immune-related conditions. These disturbances may arise from intrinsic factors, such as
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Citation: Singh B. Circadian
rhythms in Alzheimer’s disease: aging and genetic vulnerability, or extrinsic influences, such as shift work, jet lag, irregular
A molecular clock worth light exposure, and environmental misalignment. In individuals with Alzheimer’s disease,
watching. Gene Protein Dis.
2025;4(3):025160031. signs of circadian misalignment – such as altered sleep-wake cycles, sundowning behaviors,
doi: 10.36922/GPD025160031 and dysregulated hormonal patterns (e.g., cortisol and melatonin) – often emerge before
the onset of cognitive decline, reflecting core disruptions in molecular timing systems. 5
Received: April 14, 2025
Accepted: April 16, 2025 At the mechanistic level, circadian misalignment impairs proteostasis, reduces
the fidelity of DNA repair, and weakens glymphatic clearance of neurotoxic proteins,
Published online: May 19, 2025 such as amyloid-β and tau. Moreover, astrocytes and microglia exhibit circadian
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Copyright: © 2025 Author(s). oscillations, and dysfunction in these glial clocks can alter neuroinflammatory tone,
This is an Open-Access article impair synaptic pruning, and disrupt mitochondrial function. These desynchronized
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distributed under the terms of the
Creative Commons Attribution processes contribute to accelerated neurodegeneration and impaired synaptic plasticity,
License, permitting distribution, particularly in vulnerable regions, such as the hippocampus.
and reproduction in any medium,
provided the original work is The relationship between circadian disruption and Alzheimer’s disease is bidirectional:
properly cited. not only does circadian misalignment accelerate neuropathological processes, but the
Publisher’s Note: AccScience progression of Alzheimer’s disease also disrupts circadian output – particularly through
Publishing remains neutral with degeneration of the SCN. This feed-forward loop underscores the role of circadian
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regard to jurisdictional claims in
published maps and institutional rhythms not merely as biomarkers of the disease, but also as active drivers of its
affiliations. progression.

Volume 4 Issue 3 (2025) 1 doi: 10.36922/GPD025160031