Associations of 24‐Hour Rest‐Activity Rhythm Fragmentation, Cognitive Decline, and Postmortem Locus Coeruleus Hypopigmentation in Alzheimer's Disease

Author:

Van Egroo Maxime1ORCID,van Someren Eus J.W.234,Grinberg Lea T.567,Bennett David A.89,Jacobs Heidi I.L.110ORCID

Affiliation:

1. Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience Alzheimer Centre Limburg, Maastricht University Maastricht The Netherlands

2. Department of Sleep and Cognition Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences Amsterdam The Netherlands

3. Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam The Netherlands

4. Department of Psychiatry, Amsterdam UMC, Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam The Netherlands

5. Department of Pathology, LIM‐22 University of São Paulo Medical School São Paulo Brazil

6. Memory and Aging Center, Department of Neurology, and Pathology University of California San Francisco California USA

7. Global Brain Health Institute University of California San Francisco California USA

8. Rush Alzheimer's Disease Center Rush University Medical Center Chicago Illinois USA

9. Department of Neurological Sciences Rush University Medical Center Chicago Illinois USA

10. Gordon Center for Medical Imaging, Department of Radiology Massachusetts General Hospital and Harvard Medical School Boston Massachusetts USA

Abstract

ObjectiveWhile 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.MethodsThis 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.ResultsAmong 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 [CI95%]: 1.16–1.84, pBONF = 0.004), particularly in individuals with cortical AD neuropathology (OR = 1.56, CI95%: 1.15–2.15, pBONF = 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, CI95%: ‐0.023–‐0.002, pBONF = 0.03).InterpretationThese 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

Funder

BrightFocus Foundation

Alzheimer Nederland

Alzheimer's Association

Rainwater Charitable Foundation

European Research Council

National Institutes of Health

Publisher

Wiley

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