Abstract

Alzheimer disease (AD) is the most common cause of dementia and is an increasing public health problem. Genetic, biochemical, and animal model studies suggest the accumulation and conformational change of amyloid-beta (A?) is a major contributor to the pathogenesis of AD. We propose to determine if A? production and clearance rates are altered in sporadic Alzheimer Disease versus controls. We will determine if the major genetic risk factor for AD is associated with decreased A? clearance. We will measure A? dynamic variations and correlate with any changes in A? clearance or production rates. Overall, this study will provide the first measurements of A? production and clearance in Alzheimer's disease and measure the effect of the major genetic risk factor in humans (APOE). This information will likely provide insights into the pathogenesis of AD by determining the contribution of overproduction or decreased clearance of A?. Eventually, this may lead to improved diagnostic or predictive testing for AD as well as aid in the evaluation of new disease modifying therapeutics.

Public Health Relevance

Alzheimer disease (AD) is the most common cause of dementia and is an increasing public health problem. Genetic, biochemical, and animal model studies suggest the accumulation and conformational change of amyloid-beta (A?) is a major contributor to the pathogenesis of AD. We propose to determine if A? production and clearance rates are altered in sporadic Alzheimer Disease versus controls. We will determine if the major genetic risk factor for AD is associated with decreased A? clearance. We will measure A? dynamic variations and correlate with any changes in A? clearance or production rates. Overall, this study will provide the first measurements of A? production and clearance in Alzheimer's disease and measure the effect of the major genetic risk factor in humans (APOE). This information will likely provide insights into the pathogenesis of AD by determining the contribution of overproduction or decreased clearance of A?. Eventually, this may lead to improved diagnostic or predictive testing for AD as well as aid in the evaluation of new disease modifying therapeutics.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065667-04
Application #
8104080
Study Section
Special Emphasis Panel (ZRG1-CND-E (90))
Program Officer
Corriveau, Roderick A
Project Start
2008-09-30
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$499,103
Indirect Cost

  Institution

Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Kinnunen, Kirsi M; Cash, David M; Poole, Teresa et al. (2018) Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study. Alzheimers Dement 14:43-53
Lucey, Brendan P; Hicks, Terry J; McLeland, Jennifer S et al. (2018) Effect of sleep on overnight cerebrospinal fluid amyloid ? kinetics. Ann Neurol 83:197-204
Bateman, Randall J; Benzinger, Tammie L; Berry, Scott et al. (2017) The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model. Alzheimers Dement 13:8-19
Yoon, Hyejin; Belmonte, Krystal C; Kasten, Tom et al. (2017) Intra- and Inter-individual Variability of microRNA Levels in Human Cerebrospinal Fluid: Critical Implications for Biomarker Discovery. Sci Rep 7:12720
Ovod, Vitaliy; Ramsey, Kara N; Mawuenyega, Kwasi G et al. (2017) Amyloid ? concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement 13:841-849
Lucey, Brendan P; Mawuenyega, Kwasi G; Patterson, Bruce W et al. (2017) Associations Between ?-Amyloid Kinetics and the ?-Amyloid Diurnal Pattern in the Central Nervous System. JAMA Neurol 74:207-215
Baker-Nigh, Alaina T; Mawuenyega, Kwasi G; Bollinger, James G et al. (2016) Human Central Nervous System (CNS) ApoE Isoforms Are Increased by Age, Differentially Altered by Amyloidosis, and Relative Amounts Reversed in the CNS Compared with Plasma. J Biol Chem 291:27204-27218
Lucey, Brendan P; Gonzales, Celedon; Das, Ujjwas et al. (2015) An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-? concentrations collected by lumbar puncture and indwelling lumbar catheter. Alzheimers Res Ther 7:53
Crisp, Matthew J; Mawuenyega, Kwasi G; Patterson, Bruce W et al. (2015) In vivo kinetic approach reveals slow SOD1 turnover in the CNS. J Clin Invest 125:2772-80
Elbert, Donald L; Patterson, Bruce W; Bateman, Randall J (2015) Analysis of a compartmental model of amyloid beta production, irreversible loss and exchange in humans. Math Biosci 261:48-61

Showing the most recent 10 out of 27 publications