Inheriting Gene Variants, Risk for Alzheimer's

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Embargoed by the Annals of Neurology
Until Wednesday, March 1, 2000 at 11:59 p.m. (CST)

Study Points to Genetic Marker as a New
Target for Alzheimer's Disease Treatment

LITTLE ROCK, Ark. -- Reporting in the March issue of the Annals of Neurology, researchers have discovered that inheriting certain genetic variants from both parents significantly increases the risk for developing Alzheimer's Disease. The multi-institutional team of scientists specifically looked at the variant of a gene that defines the function of the protein Interleukin-1, or IL-1.

These gene variants or polymorphisms are known technically as IL-1A2 and IL-1B2. Dr. Sue T. Griffin, of the U.S. Department of Veterans Affairs' Central Arkansas Veterans Healthcare System, along with Dr. James Nicoll, Glasgow, UK, and others found that an individual with the IL-1A2 variant has a three-fold risk for developing Alzheimer's, while someone with both variants (IL-1A2 and IL-1B2), carries a risk eleven times greater than that found in the general population.

"Now that we know what IL-1 can do in the brain, we can begin to study methods for targeting therapeutic intervention," said senior investigator Sue T. Griffin, Ph.D., Associate Director for Research, Geriatric Research, Education and Clinical Center, Central Arkansas Veterans Healthcare System. "In the future, early detection of this gene variant and targeted treatment may delay the onset of Alzheimer's Disease, allowing patients to live more normal lives."

Previous research reported by Griffin's group in 1989 indicated that IL-1 was over-expressed in individuals with Alzheimer's Disease and Down's Syndrome.

Those studies fueled the need to understand the function of IL-1 and its variants, and their impact on the neuropathological development of b-amyloid (beta-amyloid) plaques in brains of patients with Alzheimer's Disease and Down's Syndrome.

The same issue of the Annals of Neurology also includes another report of similar findings in clinically assessed Alzheimer's patients (Grimaldi et al, with Griffin as co-author).

When neurons in the brain are injured as in the case with Alzheimer's Disease, they respond by making more b-amyloid precursor protein (BAPP). This normal protein can be processed to form the substance that is deposited in the plaque found in the brain of Alzheimer patients. The secreted protein then activates cells called mycroglia and stimulates them to produce IL-1. In normal circumstances, the production of IL-1 ceases when the repair is complete. IL-1 is involved in the inflammation process, the response of the body's tissues to any type of injury or irritation.

However, for largely unknown reasons in conditions that favor Alzheimer's Disease, neurons chronically feel the need to repair and make more precursor protein. This results in the over-expression of IL-1, so there is more production and processing of BAPP, and more b-amyloid plaques. As the plaque deposits expand, the neurons experience further injury, and so the cycle continues. The unceasing stress on the neurons and plaque development ultimately interferes with normal brain activities, and thus leads to Alzheimer's Disease.

This research provides a specific target for the development of a therapeutic intervention that can be used in association with early detection of the disease. In addition, this study provides an explanation for why anti-inflammatory medication appears to protect against Alzheimer's Disease. Future clinical trials may be aimed at specific patient populations to determine the efficacy of a treatment based on age, genetics, and other risk factors.

In addition to Griffin and Nicoll, other authors of the paper include: Robert E. Mrak, M.D., Ph.D., Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences, Little Rock, Ark., United States; David I. Graham, M.D., Ph.D., and Janice Stewart, Southern General Hospital, Glasgow, Scotland:, Gordon Wilcock, D.M., and Sian MacGowan, D.M., University of Bristol, Bristol, England, UK; Margaret M. Esiri, D.M., Oxford University, Radcliffe Infirmary, Oxford, England, UK; Lilian S. Murray, Ph.D., University of Glasgow, Glasgow, Scotland; Deborah Dewar, Ph.D., Wellcome Surgical Institute, Glasgow, Scotland; Seth Love, Ph.D., and Tim Moss, Ph.D., University of Bristol, Frenchay Hospital, Bristol, England, UK.

This study was supported by the National Institute on Aging/National Institutes of Health, the Donald W. Reynolds Foundation, and the Friends of Psychiatry, the Medical Research Council, the Wellcome Trust, Bristol Research in Alzheimer's and Care of the Elderly, and the Marks and Spencer Charitable Foundation.

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