Alzheimer's disease (AD) is the most common neurodegenerative disease with no effective means of prevention or treatment. Most of the recent published genetic studies for AD have focused on the identification of genetic variants associated with risk for disease. Other aspects of AD, such as age at onset, disease duration or rate of disease progression are less well studied. It is very likely that different genetic variants and genes will influence these different aspects of disease. The goal of this study is to identify novel genetic variants and genes associated with rate of disease progression and other informative endophenotypes for AD, such as amyloid imaging (Pittsburgh compound B or florbetapir) and hippocampal volume. We will use innovative genomic and statistical methods, to analyze not only the effect of common variants but also rare coding variants on endophenotype levels by incorporating genome-wide association data, whole-genome sequencing and exome-chip data into our analyses. We will also test whether the variants associated with rate of progression, amyloid imaging and hippocampal volume are also associated with risk for disease, cerebrospinal fluid tau and A? levels and other AD phenotypes. The broad, long-term goal of this research is to dissect the complex genetic architecture of Alzheimer's disease, which will lead to better prediction and treatment of this devastating disease. By studying several AD endophenotypes we expect to identify genetic variants, genes and pathways affecting different aspects of the disease. These findings will help to identify novel and key proteins involved in disease pathogenesis and potential therapeutic targets.

Public Health Relevance

As instructed by the funding opportunity announcement for this application (PAR-13-329), only the Overall component contains a project narrative. Cores and projects were instructed not to include this section.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG003991-31A1
Application #
8739017
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (M1))
Project Start
Project End
2019-04-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
31
Fiscal Year
2014
Total Cost
$153,142
Indirect Cost
$52,721
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Joseph-Mathurin, Nelly; Su, Yi; Blazey, Tyler M et al. (2018) Utility of perfusion PET measures to assess neuronal injury in Alzheimer's disease. Alzheimers Dement (Amst) 10:669-677
Pottier, Cyril; Zhou, Xiaolai; Perkerson 3rd, Ralph B et al. (2018) Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. Lancet Neurol 17:548-558
Oxtoby, Neil P; Young, Alexandra L; Cash, David M et al. (2018) Data-driven models of dominantly-inherited Alzheimer's disease progression. Brain 141:1529-1544
Del-Aguila, Jorge L; Fernández, Maria Victoria; Schindler, Suzanne et al. (2018) Assessment of the Genetic Architecture of Alzheimer's Disease Risk in Rate of Memory Decline. J Alzheimers Dis 62:745-756
Bonham, Luke W; Karch, Celeste M; Fan, Chun C et al. (2018) CXCR4 involvement in neurodegenerative diseases. Transl Psychiatry 8:73
Mishra, Shruti; Blazey, Tyler M; Holtzman, David M et al. (2018) Longitudinal brain imaging in preclinical Alzheimer disease: impact of APOE ?4 genotype. Brain 141:1828-1839
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
Schindler, Suzanne E; Gray, Julia D; Gordon, Brian A et al. (2018) Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging. Alzheimers Dement 14:1460-1469
Pehlivanova, Marieta; Wolf, Daniel H; Sotiras, Aristeidis et al. (2018) Diminished Cortical Thickness is Associated with Impulsive Choice in Adolescence. J Neurosci :
Weintraub, Sandra; Besser, Lilah; Dodge, Hiroko H et al. (2018) Version 3 of the Alzheimer Disease Centers' Neuropsychological Test Battery in the Uniform Data Set (UDS). Alzheimer Dis Assoc Disord 32:10-17

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