Circadian clocks, cognition, and Alzheimer's disease: synaptic mechanisms, signaling effectors, and chronotherapeutics
Open accessAbstract
Modulation of basic biochemical and physiological processes by the circadian timing system is now recognized as a fundamental feature of all mammalian organ systems. Within the central nervous system, these clock-modulating effects are reflected in some of the most complex behavioral states including learning, memory, and mood. How the clock shapes these behavioral processes is only now beginning to be realized. In this review we describe recent findings regarding the complex set of cellular signaling events, including kinase pathways, gene networks, and synaptic circuits that are under the influence of the clock timing system and how this, in turn, shapes cognitive capacity over the circadian cycle. Further, we discuss the functional roles of the master circadian clock located in the suprachiasmatic nucleus, and peripheral oscillator populations within cortical and limbic circuits, in the gating of synaptic plasticity and memory over the circadian cycle. These findings are then used as the basis to discuss the connection between clock dysregulation and cognitive impairments resulting from Alzheimer’s disease (AD). In addition, we discuss the conceptually novel idea that in AD, there is a selective disruption of circadian timing within cortical and limbic circuits, and that it is the disruption/desynchronization of these regions from the phase-entraining effects of the SCN that underlies aspects of the early- and mid-stage cognitive deficits in AD. Further, we discuss the prospect that the disruption of circadian timing in AD could produce a self-reinforcing feedback loop, where disruption of timing accelerates AD pathogenesis (e.g., amyloid deposition, oxidative stress and cell death) that in turn leads to a further disruption of the circadian timing system. Lastly, we address potential therapeutic approaches that could be used to strengthen cellular timing networks and, in turn, how these approaches could be used to improve cognitive capacity in Alzheimer’s patients.
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Disruption of the circadian system is a common comorbidity in ASD and is implicated in exacerbating sleep disturbances, behavioral rhythm abnormalities, and emotional dysregulation, potentially by dysregulating the temporal coordination of neuronal and synaptic processes.
“Disruption of this system is a common comorbidity in ASD and is implicated in exacerbating sleep disturbances, behavioral rhythm abnormalities, and emotional dysregulation, potentially by dysregulating the temporal coordination of neuronal and synaptic processes”
From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Hoyt and Obrietan, 2022
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- Authors
- Hoyt, K. R., & Obrietan, K.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Hoyt, Kari R.
- Obrietan, Karl
- Venue
- Molecular Neurodegeneration
- Published
- 2022-05-07
- Volume
- 17
- Issue
- 1
- Pages
- 35-35
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC9078023
- OpenAlex
- W4229016791
- Cited by
- 77
- References
- 200
- Citations by year
- 2026: 21 · 2025: 18 · 2024: 16 · 2023: 18 · 2022: 4
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Foundation for the National Institutes of Health (GM133032, AG065830, and MH103361)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- circadian clock, Alzheimer's disease, cognition, suprachiasmatic nucleus, peripheral oscillators, synaptic plasticity, memory, kinase signaling pathways, gene networks, circadian desynchrony, amyloid deposition, oxidative stress, chronotherapy
- MeSH terms
- Alzheimer Disease, Animals, Circadian Rhythm, Cognition, Humans, Mammals, Drug Chronotherapy, Circadian Clocks
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