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Bulk rhythm amplitude differences may reflect changes in the amplitude of the underlying cellular oscillators or changes in their temporal coherence. To resolve this fundamental ambiguity, we developed ORPHEUS (\n                  <jats:bold>O<\/jats:bold>\n                  scillatory\n                  <jats:bold>R<\/jats:bold>\n                  hythm\n                  <jats:bold>P<\/jats:bold>\n                  hase\n                  <jats:bold>H<\/jats:bold>\n                  eterogeneity\n                  <jats:bold>E<\/jats:bold>\n                  stimated\n                  <jats:bold>U<\/jats:bold>\n                  sing\n                  <jats:bold>S<\/jats:bold>\n                  tatistical-moments), an analytical method that quantifies cellular desynchrony by leveraging the unique 12hr rhythmic signature it imparts on intercellular expression variance. 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. Most critically, we observed a dramatic loss of cellular synchrony in excitatory neurons from subjects with Alzheimer\u2019s Disease (AD) dementia. By decoupling the influence of cellular amplitude and synchrony, ORPHEUS introduces a new, interpretable tool for analyzing circadian coordination in time-course single-cell data.\n                <\/jats:p>","DOI":"10.64898\/2026.03.23.713759","type":"posted-content","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T04:27:42Z","timestamp":1774499262000},"source":"Crossref","is-referenced-by-count":0,"title":["Single-cell Transcriptomic Variance Analysis Reveals Intercellular Circadian Desynchrony in the Alzheimer\u2019s Affected Human Brain"],"prefix":"10.64898","author":[{"given":"Henry C.","family":"Hollis","sequence":"first","affiliation":[{"name":"School of Biomedical Engineering and Health Systems, Drexel University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Veltri","sequence":"additional","affiliation":[{"name":"University of Wisconsin Biotechnology Center, Bioinformatics Resource Center, University of Wisconsin, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ksenija","family":"Korac","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vilas","family":"Menon","sequence":"additional","affiliation":[{"name":"Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6664-996X","authenticated-orcid":false,"given":"Sean M.","family":"Ronnekleiv-Kelly","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"},{"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7726-8246","authenticated-orcid":false,"given":"Junhyong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Computer and Information Science, University of Pennsylvania, Philadelphia, USA"},{"name":"Department of Biology, University of Pennsylvania, Philadelphia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron C.","family":"Anafi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026032804400772000_2026.03.23.713759v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80566-8"},{"key":"2026032804400772000_2026.03.23.713759v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2430"},{"key":"2026032804400772000_2026.03.23.713759v1.3","doi-asserted-by":"publisher","DOI":"10.1126\/science.2305266"},{"key":"2026032804400772000_2026.03.23.713759v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-0586-x"},{"key":"2026032804400772000_2026.03.23.713759v1.5","doi-asserted-by":"crossref","unstructured":"A. Zulfiqar , Z. A. Myers , A. Menon , K. Greenham , Single-Nucleus Transcriptomics Reveals How Tissue Context Shapes the Circadian Transcriptome of the Arabidopsis Leaf. [Preprint] (2025). 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