title: Age and amyloid effects on human central nervous system amyloid-beta kinetics.
abstract: OBJECTIVE
  Age is the single greatest risk factor for Alzheimer's disease (AD), with the incidence doubling every 5 years after age 65. However, our understanding of the mechanistic relationship between increasing age and the risk for AD is currently limited. We therefore sought to determine the relationship between age, amyloidosis, and amyloid-beta (Aβ) kinetics in the central nervous system (CNS) of humans.
  
  
  METHODS
  Aβ kinetics were analyzed in 112 participants and compared to the ages of participants and the amount of amyloid deposition.
  
  
  RESULTS
  We found a highly significant correlation between increasing age and slowed Aβ turnover rates (2.5-fold longer half-life over five decades of age). In addition, we found independent effects on Aβ42 kinetics specifically in participants with amyloid deposition. Amyloidosis was associated with a higher (>50%) irreversible loss of soluble Aβ42 and a 10-fold higher Aβ42 reversible exchange rate.
  
  
  CONCLUSIONS
  These findings reveal a mechanistic link between human aging and the risk of amyloidosis, which may be owing to a dramatic slowing of Aβ turnover, increasing the likelihood of protein misfolding that leads to deposition. Alterations in Aβ kinetics associated with aging and amyloidosis suggest opportunities for diagnostic and therapeutic strategies. More generally, this study provides an example of how changes in protein turnover kinetics can be used to detect physiological and pathophysiological changes and may be applicable to other proteinopathies.
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, MO.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Patterson
authors.affiliation: Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Elbert
authors.affiliation: Department of Neurology, Washington University in St. Louis, St. Louis, MO.
authors.forename: Kwasi G
authors.initials: KG
authors.lastname: Mawuenyega
authors.affiliation: Department of Neurology, Washington University in St. Louis, St. Louis, MO.
authors.forename: Tom
authors.initials: T
authors.lastname: Kasten
authors.affiliation: Department of Neurology, Washington University in St. Louis, St. Louis, MO.
authors.forename: Vitaliy
authors.initials: V
authors.lastname: Ovod
authors.affiliation: Department of Biostatistics, Washington University in St. Louis, St. Louis, MO.
authors.forename: Shengmei
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Biostatistics, Washington University in St. Louis, St. Louis, MO.|Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University in St. Louis, St. Louis, MO.
authors.forename: Chengjie
authors.initials: C
authors.lastname: Xiong
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, MO.
authors.forename: Robert
authors.initials: R
authors.lastname: Chott
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, MO.
authors.forename: Kevin
authors.initials: K
authors.lastname: Yarasheski
authors.affiliation: Department of Neurology, Washington University in St. Louis, St. Louis, MO.|Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University in St. Louis, St. Louis, MO.
authors.forename: Wendy
authors.initials: W
authors.lastname: Sigurdson
authors.affiliation: Hope Center for Neurological Disorders, Department of Neurology, Washington University in St. Louis, St. Louis, MO.
authors.forename: Lily
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry, Washington University in St. Louis, St. Louis, MO.|Hope Center for Neurological Disorders, Department of Neurology, Washington University in St. Louis, St. Louis, MO.
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.affiliation: Department of Radiology, Washington University in St. Louis, St. Louis, MO.|Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University in St. Louis, St. Louis, MO.
authors.forename: Tammie
authors.initials: T
authors.lastname: Benzinger
authors.affiliation: Department of Neurology, Washington University in St. Louis, St. Louis, MO.|Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University in St. Louis, St. Louis, MO.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Department of Neurology, Washington University in St. Louis, St. Louis, MO.|Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University in St. Louis, St. Louis, MO.|Hope Center for Neurological Disorders, Department of Neurology, Washington University in St. Louis, St. Louis, MO.
authors.forename: David
authors.initials: D
authors.lastname: Holtzman
authors.affiliation: Department of Neurology, Washington University in St. Louis, St. Louis, MO.|Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University in St. Louis, St. Louis, MO.|Hope Center for Neurological Disorders, Department of Neurology, Washington University in St. Louis, St. Louis, MO.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Bateman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)