Associations of 24-hour rest-activity rhythm fragmentation, cognitive decline, and postmortem locus coeruleus hypopigmentation in Alzheimer's disease
Open accessAbstract
Objective: While studies suggested that locus coeruleus (LC) neurodegeneration contributes to sleep–wake dysregulation in Alzheimer's disease (AD), the association between LC integrity and circadian rest‐activity patterns remains unknown. Here, we investigated the relationships between 24‐hour rest‐activity rhythms, cognitive trajectories, and autopsy‐derived LC integrity in older adults with and without cortical AD neuropathology. Methods: This retrospective study leveraged multi‐modal data from participants of the longitudinal clinical‐pathological Rush Memory and Aging Project. Indices of 24‐hour rest‐activity rhythm fragmentation (intradaily variability) and stability (interdaily stability) were extracted from annual actigraphic recordings, and cognitive trajectories were computed from annual cognitive evaluations. At autopsy, LC neurodegeneration was determined by the presence of hypopigmentation, and cortical AD neuropathology was assessed. Contributions of comorbid pathologies (Lewy bodies, cerebrovascular pathology) were evaluated. Results: Among the 388 cases included in the study sample (age at death = 92.1 ± 5.9 years; 273 women), 98 (25.3%) displayed LC hypopigmentation, and 251 (64.7%) exhibited cortical AD neuropathology. Logistic regression models showed that higher rest‐activity rhythm fragmentation, measured up to ~7.1 years before death, was associated with increased risk to display LC neurodegeneration at autopsy (odds ratio [OR] = 1.46, 95% confidence interval [CI 95% ]: 1.16–1.84, p BONF = 0.004), particularly in individuals with cortical AD neuropathology (OR = 1.56, CI 95% : 1.15–2.15, p BONF = 0.03) and independently of comorbid pathologies. In addition, longitudinal increases in rest‐activity rhythm fragmentation partially mediated the association between LC neurodegeneration and cognitive decline (estimate = ‐0.011, CI 95% : ‐0.023–‐0.002, p BONF = 0.03). Interpretation: These findings highlight the LC as a neurobiological correlate of sleep–wake dysregulation in AD, and further underscore the clinical relevance of monitoring rest‐activity patterns for improved detection of at‐risk individuals. ANN NEUROL 2024;95:653–664
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Newer methods create high-dimensional embeddings from audio or text that capture complex patterns, giving a more holistic view than individual features but reducing transparency.
“Additionally, recent approaches have generated high-dimensional representations—known as embeddings—that capture nuanced relationships within audio (e.g., wav2vec2) or text (e.g., BERT) to extract complex patterns,102–104 enabling a more holistic approach to speech analysis than using individual features, yet at the cost of transparency.”
From Review of Artificial Intelligence for Clinical Use in Alzheimer's Disease and Related Dementias (2026) · cites this paper as [102]
The Methods (page unavailable) describe actigraphy, cognitive evaluations, and neuropathology, while the statistical analyses concern rest-activity rhythms and cognitive decline. Searches for embeddings, wav2vec2, BERT, audio, text, and speech analysis found no passage addressing the attributed claim. (LLM, conf=0.78)
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Paget‐Blanc, A., Thurston, R. C., Smagula, S. F., Chang, Y.-F., & Maki, P. M. (2025) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.70105 · Cited by 3 · see citing works
Mortazavi, N., Zubkov, M. A., Chylinski, D., Collette, F., Bastin, C., Maquet, P., Vandewalle, G., & Talwar, P. (2026) · SLEEP · doi:10.1093/sleep/zsag143 · Cited by 2 · see citing works
Sleep Disorders in Neurodegenerative Diseases: Pathological Correlations and Underlying Mechanisms
Wang, Z., He, F., Li, L., Wang, W., Zhang, L., Tang, J., & Le, W. (2026) · Neuroscience Bulletin · doi:10.1007/s12264-026-01609-2 · Cited by 1 · see citing works
Zhang, Y., Ren, R., Feng, X., Wang, M., Huang, J., Shi, J., Lu, L., Sanford, L. D., Vitiello, M. V., & Tang, X. (2026) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2026.102289 · Cited by 1 · see citing works
Mulvey, B., Divecha, H. R., Tippani, M., Bach, S. V., Bharadwaj, R. A., Rosario, I. D., Maguire, S. E., Miller, R. A., Salisbury, A. J., Chandra, A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.29.685354 · Cited by 1 · see citing works
Control vs. salience: a new axis of circadian brain-body organization
Demers, O., Ghaffari, S., Li, C., & Butler, R. (2026) · npj Biological Timing and Sleep · doi:10.1038/s44323-025-00065-x
Rae, R. J., Alberhasky, J. M. H., Baillet, M., Bangasser, D. A., Belloy, M. E., Berry, A. S., Berteotti, C., Bow, H., Buckley, R. F., Caldwell, J. K., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71291 · Cited by 1 · see citing works
Self-citationThe brainstem in neurodegenerative diseases
Grinberg, L. T. (2026) · Handbook of clinical neurology · doi:10.1016/b978-0-443-15736-3.00017-2
Self-citationThe Peripheral Immune-Sleep- Cognition Axis Across Diagnostic Stages of Alzheimer’s DiseasePreprint
Krix, S., Falgàs, N., Hücker, S. M., Pérez‐Millan, A., Antonell, A., Ruiz‐García, R., Lorca‐Arce, D., Stadler, C., Proske, J., Braiman, S., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-9574288/v1
Zhao, B., Shang, S., Zhang, M., Guo, X., Zhou, R., Qu, Q., & Cao, H. (2026) · Sleep Medicine · doi:10.1016/j.sleep.2026.109140
Клінічна нейросомнологія на перетині з ангіоневрологією, цефалгіями та епілептологією
(2026) · Український медичний часопис · doi:10.32471/umj.1680-3051.279952
Molecular programs in human locus coeruleus link APOE and neuromelanin to Alzheimer’s vulnerability
Mulvey, B., Divecha, H. R., Tippani, M., Bach, S. V., Bharadwaj, R. A., Rosario, I. D., Maguire, S. E., Miller, R. A., Salisbury, A. J., Chandra, A., et al. (2026) · Acta Neuropathologica · doi:10.1007/s00401-026-03073-8 · Cited by 1 · see citing works
- Authors
- Van Egroo, M., van Someren, E. J. W., Grinberg, L. T., Bennett, D. A., & Jacobs, H. I. L.
- Affiliations
- Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience Alzheimer Centre Limburg, Maastricht University Maastricht The Netherlands
- Department of Sleep and Cognition Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences Amsterdam The Netherlands
- Universidade de São Paulo (BR)
- Rush University Medical Center (US)
- Harvard University (US)
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2024-02-26
- Volume
- 95
- Issue
- 4
- Pages
- 653-664
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC11875531
- OpenAlex
- W4392168605
- Cited by
- 28
- References
- 60
- Citations by year
- 2026: 14 · 2025: 11 · 2024: 3
- FWCI
- 6.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of Neurology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- VU Research Portal (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, cc-by-nc-nd)
- Funders
- BrightFocus Foundation (A20211016F)
- Alzheimer Nederland (WE.03‐2019‐02)
- Alzheimer's Association (AARG‐22‐920434)
- Rainwater Charitable Foundation
- European Research Council (AdG 2021 101055383 OVERNIGHT)
- National Institutes of Health (K24AG053435, P30AG010161, P30AG10161, R01AG056573, R01AG060477, R01AG062559, R01AG064314, R01AG068062, R01AG070826, R01AG15819, R01AG17917, R21AG074220)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
- Keywords
- Alzheimer's disease, circadian rhythm, cognitive decline, actigraphy, intradaily variability, interdaily stability, Lewy bodies, cerebrovascular pathology, older adults, Rush Memory and Aging Project
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Autopsy, Circadian Rhythm, Female, Humans, Locus Coeruleus, Retrospective Studies, Hypopigmentation, Cognitive Dysfunction
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