Interleukin-1 Variants Linked to Alzheimer's - Brief Article

Applied Genetics News, March, 2000

Research groups in Italy and in the United States have demonstrated independently, and by different methods, that people who possess specific variations of the gene that produces interleukin-1 are predisposed to develop Alzheimer's, particularly at an early age.

Two polymorphisms, IL-1A2 and IL-1B2, from the gene for interleukin-1 (IL-1) were recently found to be linked to the development of Alzheimer's disease. Sue T. Griffin of the U.S. Department of Veterans Affairs' Central Arkansas Veterans Healthcare System and a multi-institutional team of scientists found that an individual who carries the IL-1A2 variant has a three-fold greater risk for developing Alzheimer's. A person with both variants (IL-1A2 and IL-1B2) carries a risk 11 times greater than that found in the general population. These data are reported in the March issue of the Annals of Neurology. The same issue of the Annals of Neurology also includes the Italian report (Grimaldi, et al.) of similar findings in clinically assessed Alzheimer's patients.

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 stimulated research on 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.

When neurons in the brain are injured as they are in Alzheimer's disease, they respond by making more b-amyloid precursor protein (BAPP). This normal protein is sometimes processed to form the substance that is deposited in the plaques found in the brain of Alzheimer's patients. The secreted protein then activates cells called microglia and stimulates them to produce IL-1, which is involved in the inflammation process. In normal circumstances, the production of IL-1 ceases when the repair is complete.

Griffin's study provides an explanation for why anti-inflammatory medication appears to protect against Alzheimer's disease and provides target IL-1, or its receptors, for therapeutic intervention. Future clinical trials may be aimed at specific patient populations determined by genetic polymorphism and other risk factors.

In the Italian study, led by Luigi Grimaldi, a neurologist at the San Raffaele Scientific Institute in Milan, the researchers enrolled living patients who had been diagnosed with Alzheimer's based on clinical evaluations. They extracted DNA from blood samples of 318 patients and compared it to that taken from 335 control subjects.

They found that people who carried only a certain polymorphism of the interleukin-1A gene had twice the risk of getting Alzheimer's as those who did not have this polymorphism.

"When we looked only at patients with Alzheimer's disease, we found that this particular configuration of interleukin-1A was associated five times more frequently with an onset of disease before 65 years of age," notes Grimaldi. Patients with the predisposing interleukin-1A polymorphism developed the disease an average of nine years earlier than patients who did not have that polymorphism.

Grimaldi would like to show that these particular gene polymorphisms with predisposition for Alzheimer's actually trigger more inflammation than other forms. He also hopes to introduce the various interleukin-1 polymorphisms into the genetic material of mice to see if he can generate the same kind of brain cell damage seen in humans with Alzheimer's.