Environmental causes of Alzheimer's disease, Marshfield Clinic researchers launch study

(2005-06-19)

Marshfield Clinic researchers have begun searching for genetic and environmental links to Alzheimer's disease as a first step toward developing diagnostic markers to identify people at risk before they develop the disease.

Researchers will study the DNA of Alzheimer's patients from its database of more than 18,000 voluntarily-donated DNA samples. The Marshfield Clinic Research Foundation (MCRF) created the database as part of its landmark Personalized Medicine Research Project (PMRP).* Marshfield Clinic also has a complete electronic medical record on each of the individuals to be studied.

"We know exactly the medication they have been taking and what diseases they have been diagnosed for. We also know some environmental factors," said Principal Investigator Nader Ghebranious, Ph.D., director of the Molecular Diagnostics Laboratory, Marshfield Laboratories. "Now we can do genetic analysis and examine the DNA together with phenotypes and relevant environmental factors."

"It's exciting because we're not looking at just environmental risk factors, or just genetics, but the two together," said Marshfield Clinic Epidemiologist Catherine McCarty, Ph.D., principal investigator of the Personalized Medicine Research Project and co-investigator of the Alzheimer's study. "We are the first that I know of to look at the interaction between genetics and environment on the risk of disease." The study requires 150 people with Alzheimer's disease and about 300 people of similar age who do not have the disease. "Association studies like this require us to match people who have the illness with those who do not," Ghebranious said.

Because the disease is extremely complex, researchers believe that more than one genetic anomaly and perhaps environmental factor leads to Alzheimer's disease. Marshfield Clinic researchers are studying four specific genes and their connection to the disease process.

"It is important to consider more than one factor because one gene variant by itself may not confer a detectable risk of getting the disease," he said. "It is when multiple gene variants act together synergistically that probability for disease increases."

A person with even the most probable genetic link, APOE4, a gene variant of the protein APOE that functions in the transport of cholesterol and phospholipids, is estimated to have five times higher risk of developing Alzheimer's disease.

A second gene, Cytochrome P46, which modifies cholesterol, may be associated with Alzheimer's disease and the way the body removes cholesterol from the brain.

The other two genes, Oxidized LDL receptor 1 and Angiotensin 1-converting enzyme, are tied to the way the brain cells bind to APOE and reduce buildup of harmful proteins, known as plaques, in the brain, respectively.

Environmental factors likely contribute to Alzheimer's disease as well. Two specific potentially protecting factors - cigarette smoking and use of cholesterol-lowering drugs called statins - will be considered in this study.

"There are controversial findings in previous studies on smoking," Ghebranious said. "Some earlier research has suggested nicotine decreases the brain plaque associated with Alzheimer's disease. Results of a new mouse study point to the opposite conclusion. More studies are needed."

Other studies have indicated that people who use statins have less risk of Alzheimer's disease than those who do not, but no studies have proven it conclusively. Other environmental factors (e.g., infections, metals, industrial or other toxins) may trigger oxidation, inflammation and the disease process, particularly in people with genetic susceptibility to Alzheimer's disease.

It is known that a "heart healthy" diet and exercise also lower risk of Alzheimer's disease, probably by lowering cholesterol.

The Marshfield Clinic study is unique because other researchers do not have access to complete medical histories as researchers at Marshfield Clinic do, Ghebranious said. Having the history of medications people have taken, their illnesses and health status are important to linking genetics, environment and resulting disease.

The study, funded by donors to Marshfield Clinic, is expected to take two years to complete.

*Marshfield Clinic's Personalized Medicine Research Project (PMRP) collected DNA from more than 18,000 people who live in central and northern Wisconsin and who receive all or most of their health care from Marshfield Clinic. Using the electronic medical record developed by Marshfield Clinic more than a decade ago, researchers will be able to link anonymous health histories with genetic information to understand the role specific genes play in disease.

Contact: Chris Schellpfeffer
cschell@lsb.com
608-251-7070
Marshfield Clinic