Alzheimer's Disease Education and Referral Center

NIA expands genetics research: Families with multiple AD cases sought

December 1, 2002

The National Institute on Aging (NIA) is accelerating the pace of Alzheimer's disease genetics research with a major new initiative to speed the process of creating a large repository of DNA and cell lines from families with multiple AD cases. The NIA's AD Genetics Initiative will intensify sample collection and encourage data sharing by providing access to the repository to qualified investigators. This new initiative is the result of a series of recommendations made by a team of AD geneticists during a spring 2002 workshop, to speed discovery of risk factor genes that may contribute to late-onset AD. Discovery of these genes is essential for understanding the causes of late-onset AD and for developing appropriate treatments and prevention strategies.

One Late-Onset Risk Factor Gene

Late-onset AD is the most common form of the disease, accounting for 90-95 percent of all cases. It usually strikes people 65 years of age and older. Late-onset AD shows no obvious inheritance pattern. However, researchers have identified an increased risk of developing late-onset AD related to the apolipoprotein E (apoE) gene found on chromosome 19. This gene comes in several different forms, or alleles, but three occur most frequently: apoE2 (E2), apoE3 (E3), and apoE4 (E4).

People inherit one apoE allele from each parent. Having one or two copies of the E4 allele increases a person's risk of getting AD, but it does not mean that AD is certain. Some people with two copies of the E4 allele (the highest risk group) do not develop the disease, and others with no E4s do. The rarer E2 allele appears to be associated with a lower risk of AD. The E3 allele is the most common form found in the general population and may play a neutral role in AD. Scientists cannot determine the exact degree of risk of AD for any given person based on their apoE status.

Early-Onset Genes

Early-onset AD, or familial AD, is much rarer and has been conclusively linked to mutations in three genes--the APP gene on chromosome 21, the PS1 gene on chromosome 14, and PS2 on chromosome 1. If only one mutation on one of these genes is present, early-onset AD will almost certainly occur. Early-onset AD is the result of an autosomal dominant inheritance pattern, meaning that all offspring in the same generation have a 50/50 chance of developing AD if one of their parents had the genetic mutation. Early-onset AD strikes people as young as age 30.

Late-Onset Gene Search

Scientists have made great progress in the 10 years since apoE4 was identified as a risk factor gene, in narrowing the search for other risk factor genes that may have links to late-onset AD. They have drawn significantly closer to identifying at least four regions of chromosomes where other risk factor genes might be. Intriguing evidence has been uncovered during recent studies, but further analysis of larger sample sets is needed.

Genetics Experts Meet

Recognizing that much larger sets of AD samples is key to continuing the progress made to date and speeding up late-onset AD genetics research, science administrators in the NIA's Neuroscience and Neuropsychology of Aging Program (NNA) brought together leading experts for a workshop. Their discussions centered on how to expand DNA sample collection, standardize data collection, improve access to that data for funded and commercial researchers, and how to rapidly share data to identify and corroborate new risk factor genes.

Workshop participants agreed that an important component of the NIA's genetics initiative will be a new emphasis on recruiting large families with two or (preferably) more members - known as multiplex families - who have late-onset AD. Collecting blood samples from affected and unaffected family members, to create and maintain cell lines for DNA analysis will aid in the hunt for new genes. This will allow researchers to spend more time on experiments, and less time on the expensive and arduous task of collecting appropriate samples.

"This is extremely important research and we are very pleased to be in a position to recruit subjects to organize sample collection, and to offer well-characterized samples to many of the world's leading AD genetics experts. If the search for risk factor genes is successful, then there are broad implications for future treatments," said Dr. Richard Hodes, NIA Director.

National Cell Repository

A centralized repository at Indiana University - the National Cell Repository for AD (NCRAD) - is expanding its collection facilities as part of this new initiative. Ten Alzheimer's Disease Centers (ADCs) have been provided with supplemental funding to recruit new individuals for genetics research and deposit their blood samples with NCRAD. NIA hopes to gather between 1,000 and 2,000 samples for study.

NCRAD has been banking DNA and cells and building a database of family histories and medical records for qualified researchers since 1989. The Repository was established to provide genetic researchers with cell lines and/or DNA samples from people with well-documented AD and from controls. Many researchers working to identify genetic defects associated with AD have used genetic material stored in the Repository.

Because supplies of DNA are finite and cannot be regenerated, NCRAD makes "immortalized" cell lines - cells continuously regenerated in the laboratory from the blood samples - in order to provide samples for the exhaustive studies needed to identify risk factor genes. NNA Associate Director Marcelle Morrison-Bogorad, PhD, commented, "The process of identifying these risk factor genes is incredibly complicated and time consuming. This new initiative on genetics research has great potential to revolutionize early diagnosis and target better drug treatments. It is an important component of the NIA's AD research efforts."

National Case/Control Samples Set

In 2003, AD genetics researchers are planning a national case-control sample set, in which the genes of individuals with AD (case) are compared to those who have no symptoms of the disease (control). Workshop participants arrived at consensus that creating such a sample set, against which potential candidates for risk factor genes for late-onset AD can be evaluated, is also essential.

Population Studies also Useful

Existing population-based datasets, such as the Framingham study, the Honolulu Heart study, the Nurses study, and the Baltimore Longitudinal Study of Aging, could also help scientists evaluate gene-environment interactions. In addition, researchers have access to the valuable AD genetics database maintained by the National Institute of Mental Health.

New Data Sharing Policy

To enhance diversity of analysis, promote new research, and permit creation of new datasets from previously collected data, the National Institutes of Health is adopting a scientific data sharing policy. This policy encourages a freer flow of information among NIH-supported researchers and will help in exchange of information. Further information on the draft policy can be found at:

Informed Consent in Genetic Research

Genetic research is often the only way scientists can pin down the root causes of a disease, but genetic research also presents unique problems for obtaining informed consent. Informed consent is the process by which a fully informed patient or research subject can make choices related to participation in health care and/or medical research. In genetics research, benefits and risks of the research may affect the individual, his/her family, or the community in which the individual lives. Therefore, potential research participants should be given sufficient information about the implications and limitations of the research to allow them to make an informed choice of whether to participate or not.

Using plain language they understand, they should be told the purpose of the research, procedures to be used, possible outcomes, potential benefits to the participants and others, any discomfort expected from participation, how the resulting information will be communicated, and how confidentiality will be maintained. Subjects should be informed about the collection and disposition of blood and tissue samples, storage of data and samples, sharing with other investigators, and potential commercial implications. For genetics research there are risks that disclosure of results could influence life choices, affecting the individual directly, disrupting family dynamics and leading to social stigmatization and possible discrimination that may influence insurability. Therefore, protection from disclosure is very important and "firewalls" should be established to guard against disclosure. These procedures should be outlined during the consent process. Since participation in research is voluntary, subjects should be given the opportunity to withdraw at any time.

Samples From Minority Populations

Of particular interest to genetics researchers is the collection of samples from ethnic/minority populations and other special populations, including African Americans, the Amish, Hispanics, Asians, Japanese-Americans, and Africans. NIA staff plan to develop community outreach programs and collaborate with institutions and investigators who have close ties to minority communities, professional societies and institutions.

Dr. Richard Mayeux, Co-Director, Columbia University ADC, has investigated AD genetic risk factors in specific populations in New York and the Caribbean and has been appointed as the Genetics Initiative Study Coordinator. He commented, "We're very pleased by the extent to which NIA is supporting genetics research. We're looking forward to working with the ADCs and the Alzheimer's Association to educate the public on the value of participating in sample collection. We hope that people with AD will want to share their blood and data to help in the search for causes, treatment, and prevention."

Families interested in participating can contact the National Cell Repository for Alzheimer’s Disease at 1-800-526-2839 or 1-317-274-7360. Jamalynne Stuck, MS, is the Genetic Counselor and Research Coordinator, and she can be reached via e-mail at Their Internet address is

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