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PROJECT SUMMARY

Late-onset Alzheimer’s disease (AD), the most common form of dementia, places a large economic and financial burden on families and society and can be emotionally devastating to loved ones. While we know several things can affect AD, it is an incredibly complex disease, and there are likely other risk factors of AD that we still don’t understand.

Over the past two decades cardiovascular disease (CVD) is being increasingly recognized as an important risk factor of AD. In this project, we are interested in seeing if there are specific changes to genes that are risk factors for CVD and risk factors for Alzheimer’s disease. If we can find genetic risk factors that overlap between CVD and AD, we could target these genes to prevent or delay the onset of Alzheimer’s disease.

One way to identify the genetic risk factors for CVD that are also risk factors in AD is through large-scale genome-wide association studies (GWAS). In GWAS, human genomes – typically ones without a disease and ones with a disease – are compared to see if there are specific changes (or ‘genetic variants’) in the genomes of individuals with a specific disease.

In this project, we plan to take GWAS a step further by using the genomes of patients with CVD to find new genetic risk factors for AD. By using this approach, we intend to identify a subset of genetic variants that are risk factors for dyslipidemia, inflammation (two CVD traits that can be treated and prevented) and AD. As a second step, to understand the role of these risk factors in AD, we will then investigate the relationship between each of these genes and known pathobiological markers of AD.

PROJECT GOALS

1) Identify and validate genetic variants associated with AD and CVD traits. We plan to use GWAS to identify genetic variants that are common to traits of CVD (dyslipidemia and inflammation) and AD.

2) Determine the effect that these common genetic variants have on clinical and neuropathological measures of AD. We will determine the relationship between AD/CVD genetic risk variants and the presence of markers known to be elevated in AD.

IMPORTANCE OF RESEARCH

Late-onset Alzheimer’s disease (AD), the most common form of dementia, effects an estimated 30 million people worldwide, a number that is expected to quadruple in the next 40 years. In the brain (or ‘neuropathologically’), AD is characterized by the presence of amyloid-beta plaques and tau-associated neurofibrillary tangles. Since there are no current disease-modifying therapies and there has been an increasing awareness that symptoms of AD develop over many years, there is a strong need to develop effective strategies to prevent AD. If we could even delay the onset of dementia by a modest 2 years, we could potentially lower the worldwide prevalence of AD by more than 22 million cases over the next 40 years.

Although previous studies have examined the association between AD and CVD traits, no study to date has fully identified the genetic and molecular basis of how dyslipidemia and inflammation influence AD. This project will provide us with a clearer understanding of how CVD and AD are related.

 Additionally, this study is the first step in research that is expected to lead to the development of novel strategies for preventing AD. Dyslipidemia and inflammation are effectively managed through current therapeutics; therefore, if we can identify an overlap between the genetic variants causing these CVD traits and AD, we could use drugs targeting dyslipidemia and inflammation to also treat, prevent, or delay AD. 

BUDGET

1. Project Resources - $0

There are no project resources required for this project.




2. Research Supplies - $10,000

Molecular and biochemical reagents: $5000 We will use molecular biology reagents and tissue culture reagents to generate constructs and to transiently express these constructs in cell lines to study APP and tau metabolism. This will cover site-directed mutagenesis kits, chemilluminescence kits, gels, membranes, protein ladders, and other western-blot reagents and cell culture supplies including plasticware, media and serum, Taq polymerase, primers, DNA ladders, kits for DNA purification, transfection, transformation, Sanger sequencing to confirm the sequence of the clones, RNA extraction kits, Taqman probes, antibodies for immunocytochemistry, and ELISAs. This will also include technician time to perform the experiments. Computer and software: $5000 We will budget for a computer, a high-resolution monitor and data analysis software (Matlab) that will be used solely for the purposes of the study including storage of genetic, CSF, neuropathological and MRI quantitative data, MRI image processing and all data analysis.




3. Salary Support - $0

There is no salary support needed for this project.




4. Indirect Costs - $0

There are no indirect costs associated with this project.




5. Other - $0

There are no other costs associated with this project.