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.

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