Aging populations worldwide, particularly in developed countries, face an increasing burden of neurodegenerative diseases. The most common neurodegenerative disease is Alzheimer disease (AD), which is characterized by protein misfolding and aggregation. One intriguing characteristic is the broad spectrum of age at onset, even within specific risk groups (i.e, mutation carriers). Furthermore, the existence of resilient individuals (individuals who are positive for known biomarkers or have a high burden of genetic risk variants but do not exhibit symptoms), suggests that there are protective and disease-modifying genetic factors. The goal of this Project is to identify variants and genes that confer resilience as well as novel protective and modifying factors. We will use genetic data (GWAS, Exome-chip, Whole Exome Sequencing and Whole Genome Sequencing) from resilient individuals and compare them with matched affected individuals to identify protective and modifying genetic factors. The multi-factorial etiology and heterogeneity of AD may reveal itself in racial or ethnic differences in overall AD risk and in putative risk or protective factors or in the progression of neuropathology. For this reason, we will also determine if the modifier and protective variants, genes and pathways also play a role in other races, especially in African Americans.

Public Health Relevance

Aging populations worldwide, particularly in developed countries, face an increasing burden of neurodegenerative diseases, especially Alzheimer disease (AD). The goal of this study is to identify variants and genes that confer resilience as well as novel protective and modifying factors. Identifying protective variants, genes and pathways will be tremendously important for the neurodegenerative field; it will aid our understanding of the biology of the disease and, more importantly, to identify potential novel therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG003991-37
Application #
9914187
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
37
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Bussy, Aurélie; Snider, B Joy; Coble, Dean et al. (2018) Effect of apolipoprotein E4 on clinical, neuroimaging, and biomarker measures in noncarrier participants in the Dominantly Inherited Alzheimer Network. Neurobiol Aging 75:42-50
Besser, Lilah; Kukull, Walter; Knopman, David S et al. (2018) Version 3 of the National Alzheimer's Coordinating Center's Uniform Data Set. Alzheimer Dis Assoc Disord 32:351-358
Kawamura, Naoki; Yokota, Tatsuya; Hontani, Hidekata (2018) Super-Resolution of Magnetic Resonance Images via Convex Optimization with Local and Global Prior Regularization and Spectrum Fitting. Int J Biomed Imaging 2018:9262847
Su, Yi; Flores, Shaney; Hornbeck, Russ C et al. (2018) Utilizing the Centiloid scale in cross-sectional and longitudinal PiB PET studies. Neuroimage Clin 19:406-416
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
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
Brainstorm Consortium (see original citation for additional authors) (2018) Analysis of shared heritability in common disorders of the brain. Science 360:
Kinnunen, Kirsi M; Cash, David M; Poole, Teresa et al. (2018) Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study. Alzheimers Dement 14:43-53
Ibanez, Laura; Dube, Umber; Davis, Albert A et al. (2018) Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease. Front Neurosci 12:230
Schultz, Stephanie A; Gordon, Brian A; Mishra, Shruti et al. (2018) Widespread distribution of tauopathy in preclinical Alzheimer's disease. Neurobiol Aging 72:177-185

Showing the most recent 10 out of 911 publications