Bruce W Patterson1, Donald L Elbert2, Kwasi G Mawuenyega3, Tom Kasten3, Vitaliy Ovod3, Shengmei Ma4, Chengjie Xiong4,5, Robert Chott1, Kevin Yarasheski1, Wendy Sigurdson3,5, Lily Zhang6, Alison Goate7,6, Tammie Benzinger8,5, John C Morris3,5, David Holtzman3,5,6, Randall J Bateman3,5,6. 1. Department of Medicine, Washington University in St. Louis, St. Louis, MO. 2. Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO. 3. Department of Neurology, Washington University in St. Louis, St. Louis, MO. 4. Department of Biostatistics, Washington University in St. Louis, St. Louis, MO. 5. Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University in St. Louis, St. Louis, MO. 6. Hope Center for Neurological Disorders, Department of Neurology, Washington University in St. Louis, St. Louis, MO. 7. Department of Psychiatry, Washington University in St. Louis, St. Louis, MO. 8. Department of Radiology, Washington University in St. Louis, St. Louis, MO.
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. 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.
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.
Authors: M A Mintun; G N Larossa; Y I Sheline; C S Dence; S Y Lee; R H Mach; W E Klunk; C A Mathis; S T DeKosky; J C Morris Journal: Neurology Date: 2006-08-08 Impact factor: 9.910
Authors: Randall J Bateman; Ling Y Munsell; John C Morris; Robert Swarm; Kevin E Yarasheski; David M Holtzman Journal: Nat Med Date: 2006-06-25 Impact factor: 53.440
Authors: Davis C Ryman; Natalia Acosta-Baena; Paul S Aisen; Thomas Bird; Adrian Danek; Nick C Fox; Alison Goate; Peter Frommelt; Bernardino Ghetti; Jessica B S Langbaum; Francisco Lopera; Ralph Martins; Colin L Masters; Richard P Mayeux; Eric McDade; Sonia Moreno; Eric M Reiman; John M Ringman; Steve Salloway; Peter R Schofield; Reisa Sperling; Pierre N Tariot; Chengjie Xiong; John C Morris; Randall J Bateman Journal: Neurology Date: 2014-06-13 Impact factor: 9.910
Authors: Dominic N Reeds; W Todd Cade; Bruce W Patterson; William G Powderly; Samuel Klein; Kevin E Yarasheski Journal: Diabetes Date: 2006-10 Impact factor: 9.461
Authors: Kaleigh Filisa Roberts; Donald L Elbert; Tom P Kasten; Bruce W Patterson; Wendy C Sigurdson; Rose E Connors; Vitaliy Ovod; Ling Y Munsell; Kwasi G Mawuenyega; Michelle M Miller-Thomas; Christopher J Moran; Dewitte T Cross; Colin P Derdeyn; Randall J Bateman Journal: Ann Neurol Date: 2014-10-24 Impact factor: 10.422
Authors: Benjamin T Kress; Jeffrey J Iliff; Maosheng Xia; Minghuan Wang; Helen S Wei; Douglas Zeppenfeld; Lulu Xie; Hongyi Kang; Qiwu Xu; Jason A Liew; Benjamin A Plog; Fengfei Ding; Rashid Deane; Maiken Nedergaard Journal: Ann Neurol Date: 2014-09-26 Impact factor: 10.422
Authors: H Lewis; D Beher; N Cookson; A Oakley; M Piggott; C M Morris; E Jaros; R Perry; P Ince; R A Kenny; C G Ballard; M S Shearman; R N Kalaria Journal: Neuropathol Appl Neurobiol Date: 2006-04 Impact factor: 8.090
Authors: Ross W Paterson; Audrey Gabelle; Brendan P Lucey; Nicolas R Barthélemy; Claire A Leckey; Christophe Hirtz; Sylvain Lehmann; Chihiro Sato; Bruce W Patterson; Tim West; Kevin Yarasheski; Jonathan D Rohrer; Norelle C Wildburger; Jonathan M Schott; Celeste M Karch; Selina Wray; Timothy M Miller; Donald L Elbert; Henrik Zetterberg; Nick C Fox; Randall J Bateman Journal: Nat Rev Neurol Date: 2019-06-20 Impact factor: 42.937
Authors: Vitaliy Ovod; Kara N Ramsey; Kwasi G Mawuenyega; Jim G Bollinger; Terry Hicks; Theresa Schneider; Melissa Sullivan; Katrina Paumier; David M Holtzman; John C Morris; Tammie Benzinger; Anne M Fagan; Bruce W Patterson; Randall J Bateman Journal: Alzheimers Dement Date: 2017-07-19 Impact factor: 21.566
Authors: Nicolas R Barthélemy; Yan Li; Nelly Joseph-Mathurin; Brian A Gordon; Jason Hassenstab; Tammie L S Benzinger; Virginia Buckles; Anne M Fagan; Richard J Perrin; Alison M Goate; John C Morris; Celeste M Karch; Chengjie Xiong; Ricardo Allegri; Patricio Chrem Mendez; Sarah B Berman; Takeshi Ikeuchi; Hiroshi Mori; Hiroyuki Shimada; Mikio Shoji; Kazushi Suzuki; James Noble; Martin Farlow; Jasmeer Chhatwal; Neill R Graff-Radford; Stephen Salloway; Peter R Schofield; Colin L Masters; Ralph N Martins; Antoinette O'Connor; Nick C Fox; Johannes Levin; Mathias Jucker; Audrey Gabelle; Sylvain Lehmann; Chihiro Sato; Randall J Bateman; Eric McDade Journal: Nat Med Date: 2020-03-11 Impact factor: 53.440