Dissertation
Transcriptomic analysis of circadian rhythm disruption and intercellular desynchrony in the human brain with Alzheimer's disease
Doctor of Philosophy (Ph.D.), Drexel University
May 2026
DOI:
https://doi.org/10.17918/00011366
Abstract
Disrupted behavioral circadian rhythms are a hallmark of neurodegenerative diseases like Alzheimer's disease (AD), yet the precise transcriptional mechanisms driving this dysregulation remain poorly understood. To address this, we re-analyzed single-nucleus RNA-sequencing from 409 post-mortem cortical samples to informatically reconstruct cell-type-specific circadian phases in individuals with and without AD dementia. While core clock rhythms remained largely preserved, critical metabolic output pathways, specifically ribosomal biogenesis and oxidative phosphorylation, exhibited severe dampening. These transcriptional changes were experimentally validated in APP/PS1 mouse models. Protein-level and polysome analyses revealed a step-wise reduction in active translation and ribosomal abundance in response to combined amyloid pathology and environmental circadian insult. Furthermore, stochastic mathematical modeling of the core molecular clock demonstrated that altered translation can decrease circadian precision. This suggested the possibility that reduced translational capacity in AD could affect the core clock, further altering circadian transcriptional rhythms. Dampened tissue-level rhythms that we observed in AD samples underscore a fundamental ambiguity in modern molecular circadian biology: dampened bulk rhythms can be produced by either a loss of individual cellular amplitude or an increase in intercellular phase dispersion (cells drifting out of sync). To resolve the true nature of the dampened rhythms observed in AD, we developed a novel analytical framework: ORPHEUS (Oscillatory Rhythm Phase Heterogeneity Estimated Using Statistical-moments). After validating ORPHEUS in silico and on data from the mouse suprachiasmatic nucleus (SCN), we applied it to data from the mouse liver and human brain to uncover disease- and pathway-related differences in intercellular synchrony. In both tissues, we found that circadian synchrony is higher in cells and samples with higher MTORC activity. Applying this framework to the human brain data revealed an overall reduction in intercellular synchrony in AD excitatory neurons. ORPHEUS demonstrated that the genes in pathways dampened in AD (oxidative phosphorylation and ribosome) exhibit lower cellular synchrony in AD. This offers a nuanced resolution to the bulk-rhythm ambiguity, indicating that phase dispersion contributes to the dampened metabolic rhythms observed in the disease. Ultimately, this work contributes to a more detailed understanding of circadian disruption in neurodegeneration and establishes a powerful computational tool for analyzing the true nature of complex tissue rhythms.
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Details
- Title
- Transcriptomic analysis of circadian rhythm disruption and intercellular desynchrony in the human brain with Alzheimer's disease
- Creators
- Henry C. A. Hollis
- Contributors
- Ron C. Anafi (Advisor)Andres Kriete (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University
- Number of pages
- x, 125 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 991022182375304721