Genes, environments, interactions, and cognitive decline in the HRS Project Summary: Alzheimer's disease (AD) is a heterogeneous disease with a potentially wide range of contributing environmental and genetic risk factors. A long pre-clinical period of cognitive decline accompanies the accumulation of neuropathology and precedes the onset of AD. Navigating the many pathways to cognitive decline and dysfunction requires a multifaceted approach that incorporates both epidemiology and genetics. The role of epidemiology is crucial for identifying modifiable factors that may reduce AD risk; the role of genetics in AD has proven to be very complex. Early studies identified genes in the inflammatory pathways and genes associated with stress. Although some of these genes have shown evidence of environmental interactions, few have been investigated for interactions in AD and few have been replicated in genome wide association studies (GWAS). Instead, GWAS have yielded risk genes with relatively small effects, many of which have been tied to cognitive decline as well as AD. We propose to study interactions between AD risk genes, genes from the inflammatory pathway, environmental risk factors, and their combined influence on cognitive decline. Such interactions could explain a portion of AD prevalence that is currently unexplained. The Health and Retirement Study (HRS) longitudinal data coupled with newly released GWA data from over 11,000 participants age 65 and older provides an ideal opportunity to study these associations in a powerful way. Using latent trajectory models, we will define groups of individuals based on cognitive test performance over time. Using random forests, we will study the associations between cognitive trajectories and AD risk genes, inflammation genes, environmental factors, and their interactions. This approach, combining complex methods, will allow us to study in greater detail the interrelationships between genes, environments, and their interactions as they influence the rate of cognitive decline.

Public Health Relevance

There are significant genetic and environmental contributions to the risk of cognitive decline and Alzheimer's disease. To date, few studies have had the appropriate phenotypes, genotypes, and sufficient power to study gene-environment and gene-gene interactions in cognitive decline. These studies are crucial to the identification of factors that may modify cognitive trajectories and Alzheimer's disease risk. Elucidation of genetic and environmental interactions will contribute greatly to disease prevention strategies and the development of targeted and effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG042633-02
Application #
8928537
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Anderson, Dallas
Project Start
2014-09-30
Project End
2017-04-30
Budget Start
2015-07-15
Budget End
2016-04-30
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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