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Yafei Huang, PhD; Rachel Potter, BA; Wendy Sigurdson, MSN; Anna Santacruz, BSN; Shirley Shih, BA; Yo-El Ju, MD; Tom Kasten, PhD; John C. Morris, MD; Mark Mintun, MD; Stephen Duntley, MD; Randall J. Bateman, MD

Arch Neurol. 2012;69(1):51-58. doi:10.1001/archneurol.2011.235

Background  The amyloid hypothesis predicts that increased production or decreased clearance of β-amyloid (Aβ) leads to amyloidosis, which ultimately culminates in Alzheimer disease (AD).

Objective  To investigate whether dynamic changes in Aβ levels in the human central nervous system may be altered by aging or by the pathology of AD and thus contribute to the risk of AD.

Design  Repeated-measures case-control study.

Setting  Washington University School of Medicine in St Louis, Missouri.

Participants  Participants with amyloid deposition, participants without amyloid deposition, and younger normal control participants.

Main Outcome Measures  In this study, hourly cerebrospinal fluid (CSF) Aβ concentrations were compared with age, status of amyloid deposition, electroencephalography, and video recording data.

Results  Linear increases were observed over time in the Aβ levels in CSF samples obtained from the younger normal control participants and the older participants without amyloid deposition, but not from the older participants with amyloid deposition. Significant circadian patterns were observed in the Aβ levels in CSF samples obtained from the younger control participants; however, circadian amplitudes decreased in both older participants without amyloid deposition and older participants with amyloid deposition. Aβ diurnal concentrations were correlated with the amount of sleep but not with the various activities that the participants participated in while awake.

Conclusions  A reduction in the linear increase in the Aβ levels in CSF samples that is associated with amyloid deposition and a decreased CSF Aβ diurnal pattern associated with increasing age disrupt the normal physiology of Aβ dynamics and may contribute to AD.

Author Affiliations: Departments of Neurology (Drs Huang, Ju, Kasten, Morris, Duntley, and Bateman and Mss Potter, Sigurdson, and Santacruz), Internal Medicine (Ms Shih), Pathology and Immunology (Dr Morris), and Radiology (Dr Mintun), Charles F. and Joanne Knight Alzheimer's Disease Research Center (Drs Morris and Bateman), and Hope Center for Neurological Disorders (Dr Bateman), Washington University School of Medicine, St Louis, Missouri. Dr Mintun is now with Avid Radiopharmaceuticals, Philadelphia, Pennsylvania.

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