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
Su, Yi; Blazey, Tyler M; Snyder, Abraham Z et al. (2015) Partial volume correction in quantitative amyloid imaging. Neuroimage 107:55-64
Shim, Yong Soo; Yang, Dong-Won; Roe, Catherine M et al. (2015) Pathological correlates of white matter hyperintensities on magnetic resonance imaging. Dement Geriatr Cogn Disord 39:92-104
Wang, Li-San; Naj, Adam C; Graham, Robert R et al. (2015) Rarity of the Alzheimer disease-protective APP A673T variant in the United States. JAMA Neurol 72:209-16
Ghoshal, Nupur; Perry, Arie; McKeel, Daniel et al. (2015) Variably Protease-sensitive Prionopathy in an Apparent Cognitively Normal 93-Year-Old. Alzheimer Dis Assoc Disord 29:173-6
Hurth, Kyle; Tarawneh, Rawan; Ghoshal, Nupur et al. (2015) Whipple's disease masquerades as dementia with Lewy bodies. Alzheimer Dis Assoc Disord 29:85-9
Aschenbrenner, Andrew J; Balota, David A; Tse, Chi-Shing et al. (2015) Alzheimer disease biomarkers, attentional control, and semantic memory retrieval: Synergistic and mediational effects of biomarkers on a sensitive cognitive measure in non-demented older adults. Neuropsychology 29:368-81
Lim, Miranda M; Gerstner, Jason R; Holtzman, David M (2014) The sleep-wake cycle and Alzheimer's disease: what do we know? Neurodegener Dis Manag 4:351-62
Pizzie, Rachel; Hindman, Halley; Roe, Catherine M et al. (2014) Physical activity and cognitive trajectories in cognitively normal adults: the adult children study. Alzheimer Dis Assoc Disord 28:50-7
Fagan, Anne M; Xiong, Chengjie; Jasielec, Mateusz S et al. (2014) Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease. Sci Transl Med 6:226ra30
Harari, Oscar; Cruchaga, Carlos; Kauwe, John S K et al. (2014) Phosphorylated tau-A?42 ratio as a continuous trait for biomarker discovery for early-stage Alzheimer's disease in multiplex immunoassay panels of cerebrospinal fluid. Biol Psychiatry 75:723-31

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