Alzheimer?s disease (AD) is a devastating, progressive neurological disorder that selectively degrades the cognition of many older adults ? 6.1 million are living with AD in the US today and the estimated prevalence by 2050 is 12.7 million. Patients diagnosed with AD often live 8-10 years with the disease, but declines in memory and other cognitive abilities mean that patients face loss of independence and high costs of care (estimated to be $186 billion in 2018). Management of AD risk with targeted interventions is a needed part of our public health response, and genetic factors affecting AD risk will be essential to those efforts because they are present throughout the lifespan. Critically, it is possible that genetic AD risk factors may bias brain and cognitive development to increase vulnerability to AD later in life. A putative neurodevelopmental influence of genes on AD vulnerability would be consistent with 1) the predictive power of early cognitive ability for later AD risk, and 2) wide variability in how AD pathology (e.g., A? deposition) relates to AD symptomology (e.g., memory loss). Here, we hypothesize that genomic AD risk alters neurodevelopment of the brain systems most affected by AD in ways that increase AD vulnerability. If true, then properties of AD-affected brain structures and brain networks such as the hippocampus and functionally-coupled memory networks will vary with genetic AD risk even during youth. Measuring how genetic factors affect brain development will elucidate lifelong trends for AD risk while highlighting new opportunities for early intervention. The project lead is a new, early-stage investigator with a background in the cognitive neuroscience of memory and expertise in methods including neuroimaging and neuropsychology. In this study the investigators will apply these methods to the study of early polygenic effects on neurodevelopment that may affect the risk of late-onset neurodegenerative diseases including AD. Key preliminary data from large developmental datasets have provided important early support for this hypothesis, and the current proposal describes a new, tightly focused project designed to fill critical gaps in our existing knowledge.
The Specific Aims are: 1) Measure effects of AD-related genes on developmental differences in AD-vulnerable brain regions; 2) Quantify how genes affect development of functional brain networks that are later vulnerable to AD; 3) Test developmental differences in AD-vulnerable cognitive abilities attributable to AD-related genes. For these Aims, the research team will develop a new dataset from a large sample (N=270) of healthy youths aged 9, 11, or 13 years by combining neuroimaging (brain structure/function), neuropsychological tests (cognition), and genomic assays (AD-related genes) in a longitudinal design. These data will improve the field?s understanding of the pressing clinical problem of AD from a developmental risk perspective. While addressing AD by studying children appears counterintuitive, this approach may be a crucial step toward addressing a looming public health catastrophe: some of today?s children are primed to become tomorrow?s dementia patients.

Public Health Relevance

Public health agencies face a serious challenge in the growing prevalence of older adults with Alzheimer?s disease (AD), and vital insights about AD risk may be found in how genes drive childhood brain development. In this research project, the applicants will test the hypothesis that AD risk genes alter neurodevelopment of the brain systems most affected by AD in ways that increase AD vulnerability. By measuring brain and cognitive variables longitudinally in healthy children who have different genetic risk profiles for late-onset AD, this research project could identify opportunities for early intervention to reduce the risk of developing late- onset AD and thus promote the key NIH goal of 'understanding the complex interaction between genes and environment as it relates to Alzheimer?s risk.'

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG064247-01
Application #
9801726
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Anderson, Dallas
Project Start
2019-07-15
Project End
2024-04-30
Budget Start
2019-07-15
Budget End
2020-04-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Neurology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198