Age and amyloid effects on human central nervous system amyloid-beta kinetics
Bruce W. Patterson PhD
Department of Medicine, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorDonald L. Elbert PhD
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorKwasi G. Mawuenyega PhD
Department of Neurology, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorTom Kasten PhD
Department of Neurology, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorVitaliy Ovod MS
Department of Neurology, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorShengmei Ma MS
Department of Biostatistics, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorChengjie Xiong PhD
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
Search for more papers by this authorRobert Chott BS
Department of Medicine, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorKevin Yarasheski PhD
Department of Medicine, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorWendy Sigurdson RN, MSN
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
Search for more papers by this authorLily Zhang BS
Hope Center for Neurological Disorders, Department of Neurology, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorAlison Goate D.Phil
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
Search for more papers by this authorTammie Benzinger MD, PhD
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
Search for more papers by this authorJohn C. Morris MD
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
Search for more papers by this authorDavid Holtzman MD
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
Search for more papers by this authorCorresponding Author
Randall J. Bateman MD
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
Address correspondence to Dr Randall Bateman, Department of Neurology, Washington University in St. Louis, 660 South Euclid Avenue, Box 8111, St. Louis, MO 63110. E-mail: [email protected]Search for more papers by this authorBruce W. Patterson PhD
Department of Medicine, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorDonald L. Elbert PhD
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorKwasi G. Mawuenyega PhD
Department of Neurology, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorTom Kasten PhD
Department of Neurology, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorVitaliy Ovod MS
Department of Neurology, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorShengmei Ma MS
Department of Biostatistics, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorChengjie Xiong PhD
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
Search for more papers by this authorRobert Chott BS
Department of Medicine, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorKevin Yarasheski PhD
Department of Medicine, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorWendy Sigurdson RN, MSN
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
Search for more papers by this authorLily Zhang BS
Hope Center for Neurological Disorders, Department of Neurology, Washington University in St. Louis, St. Louis, MO
Search for more papers by this authorAlison Goate D.Phil
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
Search for more papers by this authorTammie Benzinger MD, PhD
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
Search for more papers by this authorJohn C. Morris MD
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
Search for more papers by this authorDavid Holtzman MD
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
Search for more papers by this authorCorresponding Author
Randall J. Bateman MD
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
Address correspondence to Dr Randall Bateman, Department of Neurology, Washington University in St. Louis, 660 South Euclid Avenue, Box 8111, St. Louis, MO 63110. E-mail: [email protected]Search for more papers by this authorAbstract
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.
Interpretation
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. Ann Neurol 2015;78:439–453
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