Abstract

Human CNS-Apolipoprotein E Isoform Production and Clearance A.
Specific Aims : Alzheimer's disease (AD) is a common, devastating disease. 5 million Americans are suffering from AD, and it is currently estimated that by 2050 this number will triple. The only major and wellvalidated genetic risk factor for AD is one's Apolipoprotein E (ApoE) genotype. One ApoE4 allele increases the risk of developing AD by 3-fold, while two copies of ApoE4 increase this risk by 12-fold. A reduced risk for AD is associated with the ApoE2 allele. The metabolism and function of ApoE is partially understood in the periphery, however very little is known about ApoE in the central nervous system (CNS). Because ApoE plays such an important role in the CNS, and because its metabolism in the CNS is not well understood, we propose to determine the physiology and possible isoform pathophysiology as it relates to AD. Isoform dependent changes in ApoE metabolism and amount (and subsequently transport of AP) may underiie the increased risk of AD in humans. Hypothesis 1: ApoE4 amount is less in the brain and CSF vs. ApoE3. Hypothesis 2: ApoE4 clearance rate or turn-over rate if faster in the CNS compared to ApoE3.
Specific Aim : Utilizing a recently developed mass spectrometry assay to measure ApoE isoforms independently, we will measure ApoE4 and ApoE3 in the human brain and CSF. In addition, the in vivo metabolism of human ApoE will be measured using stable isotope-labeling and mass spectrometry in 60 cognitively normal or dementia of the Alzheimer's type (DAT) participants with E2, E3 or E4 ApoE alleles. These participants will be recruited from the Washington University ADRC. B. Relevance to Alzheimer's Disease: ApoE is the strongest genetic risk factor for Alzheimer's disease, and is a potential target for disease-modifying therapies. Our data will provide an important link regarding how ApoE4 may be involved in the pathophysiology of Alzheimer's disease, and may lead to improved therapeutics, which target the major genetic risk factor of Alzheimer's disease, ApoE4.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
2P50AG005681-27
Application #
8014518
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (J2))
Project Start
Project End
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
27
Fiscal Year
2010
Total Cost
$187,181
Indirect Cost

  Institution

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

  Publications

Vlassenko, Andrei G; Gordon, Brian A; Goyal, Manu S et al. (2018) Aerobic glycolysis and tau deposition in preclinical Alzheimer's disease. Neurobiol Aging 67:95-98
Javaherian, Kavon; Newman, Brianne M; Weng, Hua et al. (2018) Examining the Complicated Relationship Between Depressive Symptoms and Cognitive Impairment in Preclinical Alzheimer Disease. Alzheimer Dis Assoc Disord :
Wildburger, Norelle C; Gyngard, Frank; Guillermier, Christelle et al. (2018) Amyloid-? Plaques in Clinical Alzheimer's Disease Brain Incorporate Stable Isotope Tracer In Vivo and Exhibit Nanoscale Heterogeneity. Front Neurol 9:169
Lin, Ming; Gong, Pinghua; Yang, Tao et al. (2018) Big Data Analytical Approaches to the NACC Dataset: Aiding Preclinical Trial Enrichment. Alzheimer Dis Assoc Disord 32:18-27
Qiu, Shangran; Chang, Gary H; Panagia, Marcello et al. (2018) Fusion of deep learning models of MRI scans, Mini-Mental State Examination, and logical memory test enhances diagnosis of mild cognitive impairment. Alzheimers Dement (Amst) 10:737-749
Pehlivanova, Marieta; Wolf, Daniel H; Sotiras, Aristeidis et al. (2018) Diminished Cortical Thickness is Associated with Impulsive Choice in Adolescence. J Neurosci :
Gordon, Brian A; Blazey, Tyler M; Su, Yi et al. (2018) Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study. Lancet Neurol 17:241-250
Jansen, Willemijn J; Ossenkoppele, Rik; Tijms, Betty M et al. (2018) Association of Cerebral Amyloid-? Aggregation With Cognitive Functioning in Persons Without Dementia. JAMA Psychiatry 75:84-95
Allison, Samantha; Babulal, Ganesh M; Stout, Sarah H et al. (2018) Alzheimer Disease Biomarkers and Driving in Clinically Normal Older Adults: Role of Spatial Navigation Abilities. Alzheimer Dis Assoc Disord 32:101-106
Stout, Sarah H; Babulal, Ganesh M; Ma, Chunyu et al. (2018) Driving cessation over a 24-year period: Dementia severity and cerebrospinal fluid biomarkers. Alzheimers Dement 14:610-616

Showing the most recent 10 out of 952 publications