Alzheimer’s disease (AD) researchers at the University of Pittsburgh have singled out a new genetic risk factor for the debilitating brain disease that affects four million Americans today and is expected to strike as many as 14 million during the next 50 years.

In a decade-long research study following more than 300 first-degree relatives of 189 Alzheimer’s patients, the Pitt researchers identified a small area of chromosome 10 that, when combined with the previously identified APOE E4 gene, significantly increases a person’s risk of developing the disease. This combination of genes produced a 16-fold increase in the risk of AD among first-degree relatives, said the researchers.

By comparison, this effect is greater than the increased risk of lung cancer caused by smoking. These new results are supported by independent studies of AD patients and controls from Pittsburgh, Boston, and Bonn, Germany.

The study results were published in the June issue of Molecular Psychiatry.

“Our findings may provide new opportunities for designing and evaluating treatments that prevent or delay the onset of AD,” said George S. Zubenko, M.D., professor of psychiatry in Pitt’s School of Medicine.

Zubenko and his colleagues studied normal individuals between the ages of 40 and 75 who were first-degree relatives of patients with AD. The subjects were given standard memory evaluation tests to be certain they had not suffered any cognitive decline prior to the start of the study, and then blood samples were drawn to identify genetic and biochemical risk factors for AD and related disorders. Eighteen people developed AD after 11.5 years of regular follow-up evaluations. Ongoing assessments of the remainder of the group and the continuing search for new risk factors is being supported by research grants from the National Institutes of Health, for which Zubenko serves as the principal investigator.

According to Zubenko, these findings may provide new molecular targets for therapeutic drug development and will help researchers design trials involving subjects who have the greatest likelihood of responding to therapy and for whom successful therapy would have the greatest impact. Furthermore, the newly discovered risk locus affects brain levels of dopamine, the neurotransmitter used by neurons that degenerate in Parkinson’s disease. As a result, the new findings may have relevance for both of these common neurodegenerative disorders.