Recent genetic studies of complex traits and diseases have focused on the identification of common variants associated with risk through genome-wide association studies (GWAS). Other aspects such as rate of progression, age at onset and the effect of rare variants are generally not investigated. These studies have been very successful in identifying novel loci associated with many complex diseases. The current proposal focuses on these understudied aspects of disease etiology, namely the role of common and rare genetic variation on quantitative diagnostic and prognostic endophenotypes of Alzheimer's disease (AD). We will use GWAS and exome-chip data to identify single variants, genes and pathways associated with cerebrospinal fluid (CSF) levels of known AD biomarkers (tau, ptau, A?, YKL40, VILIP1) and other AD-related proteins (CLU, APOE, TREM2). The integration of these endophenotypes will enable us to disentangle the genetic architecture of AD. With this insight, we will then determine whether those SNPs, genes or pathways are also associated with other AD phenotypes (risk, age at onset or progression), and whether we can use genetic information to increase the diagnostic or prognostic ability of these CSF biomarkers. Further, we will utilize Mendelian Randomization and a novel network-based approach to identify causal plasma and CSF proteins involved in AD and other complex traits. We will have access to a unique resource ? a large number of CSF and plasma protein levels ? allowing us to leverage unbiased approaches to reveal novel biomarkers and endophenotypes associated with AD and complex traits.

Public Health Relevance

Alzheimer's disease (AD) is a common neurodegenerative disease with devastating personal, familial, and societal burdens, and there is currently no effective means of prevention or treatment. We will use cerebrospinal fluid levels of known AD biomarkers (tau, ptau, A?, YKL40, VILIP1) and other AD-related proteins (CLU, APOE, TREM2), as endophenotypes for genetic studies to disentangle the genetic architecture of AD. If successful, our research will reveal novel intermediate traits and genetic variants involved in AD and other complex traits, potentially leading to prospective therapeutic targets, and will also provide guidelines for accurate and practical assessments of AD status, which will be invaluable for evaluations of effectiveness of experimental treatments in clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
3RF1AG053303-01S1
Application #
9655069
Study Section
Program Officer
Miller, Marilyn
Project Start
2016-09-15
Project End
2021-06-30
Budget Start
2018-06-01
Budget End
2021-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Deming, Yuetiva; Li, Zeran; Benitez, Bruno A et al. (2018) Triggering receptor expressed on myeloid cells 2 (TREM2): a potential therapeutic target for Alzheimer disease? Expert Opin Ther Targets 22:587-598
Maxwell, Taylor J; Corcoran, Chris; Del-Aguila, Jorge L et al. (2018) Genome-wide association study for variants that modulate relationships between cerebrospinal fluid amyloid-beta 42, tau, and p-tau levels. Alzheimers Res Ther 10:86
Yan, Qi; Nho, Kwangsik; Del-Aguila, Jorge L et al. (2018) Genome-wide association study of brain amyloid deposition as measured by Pittsburgh Compound-B (PiB)-PET imaging. Mol Psychiatry :
Deming, Yuetiva; Dumitrescu, Logan; Barnes, Lisa L et al. (2018) Sex-specific genetic predictors of Alzheimer's disease biomarkers. Acta Neuropathol 136:857-872
Li, Zeran; Del-Aguila, Jorge L; Dube, Umber et al. (2018) Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure. Genome Med 10:43
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
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
Cruchaga, Carlos; Del-Aguila, Jorge L; Saef, Benjamin et al. (2018) Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms. Alzheimers Dement 14:205-214
Fernández, Maria Victoria; Kim, Jong Hun; Budde, John P et al. (2017) Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease. PLoS Genet 13:e1007045
Ibanez, Laura; Dube, Umber; Saef, Benjamin et al. (2017) Parkinson disease polygenic risk score is associated with Parkinson disease status and age at onset but not with alpha-synuclein cerebrospinal fluid levels. BMC Neurol 17:198

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