Johns Hopkins researchers have received a $25 million grant from the National Institute on Aging, a part of the National Institutes of Health, for a study that will determine whether sustained use of non-steroidal anti-inflammatory drugs, or NSAIDs--some of which are now available over-the-counter--can delay or prevent the onset of Alzheimer's disease in people at high genetic risk. Earlier studies in twins by the same researchers had found that onset of AD appeared to be delayed in the twin who had taken NSAIDs for prolonged periods--mostly as treatment for arthritis--as compared with the other twin who had not taken NSAIDs.

According to principal investigator John Breitner, a professor in the Department of Mental Hygiene in the School of Public Health, "It is increasingly clear that the neurodegenerative process of Alzheimer's disease evolves over a period of decades. If we can intervene with protective drugs at the early stages, we may be able to delay or even prevent the disease."

The Hopkins scientists also had previously shown that people with a certain inherited variant--E4 allele--of the apolipoprotein-E gene, known as APOE, are predisposed to earlier onset of AD: The more E4 alleles one inherits, the earlier the onset is likely to be.

The seven-year study will consider NSAIDs to protect against AD if their use reduces the incidence of Alzheimer's disease by at least 30 percent in a sample population. As a secondary goal, the researchers will assess whether NSAIDs reduce normal age-related cognitive decline, which may have mechanisms in common with Alzheimer's disease. A parallel trial of a new cyclooxygenase-2 inhibitor will also be conducted. COX-2 inhibitors have anti-inflammatory actions similar to conventional NSAIDs, but they may be safer.

The study population will consist of 2,625 people aged 72 to 88 who are free of dementia but who are related to someone with Alzheimer's dementia. The participants will be grouped by age and by their numbers of E4 variants of the APOE gene. They will then be randomly assigned to subgroups who receive either a conventional NSAID, a COX-2 inhibitor or a placebo. Throughout the trial period, the participants will undergo quarterly medical monitoring and annual cognitive screening so that any cognitive decline can be detected.

As soon as the last person enrolled in the study has completed 30 months, the researchers will perform an interim analysis of the data. The trial would probably be stopped if there was a 50 percent reduction in new cases of AD in either the NSAIDs or COX-2-inhibitor groups. The study also would be stopped at that time if there was no apparent treatment benefit.

The work will be performed at sites in four states through the Johns Hopkins schools of Medicine and Public Health; Sun Health Research Institute in Sun City, Ariz.; the University of Rochester; and Boston University.

Local sites will include The Johns Hopkins Hospital in East Baltimore; the Johns Hopkins Assessment Clinic in Sykesville; and Cedar Lane Psychotherapy Services in Bethesda.

In the United States, Alzheimer's disease is the third most costly disease after heart disease and cancer, with current annual expenditures that exceed $90 billion. Three to four million Americans have the disease today, and that number is expected to climb to 10 to 14 million by 2050. A treatment that reduced the occurrence of AD by 30 percent could result in 3 to 4 million fewer cases in 2050 and a savings of more than $100 billion annually.