Alzheimer’s Discovery Could Spur Drug Development

The enzyme beta-secretase seems to be a culprit in early-onset Alzheimer’s. Now it appears to be one in late-onset Alzheimer’s as well.

The finding comes from Hiroaki Fukumoto, Ph.D., a research associate in neurology at Harvard Medical School; Michael Irizarry, M.D., an assistant professor of neurology at Harvard Medical School; and colleagues and is reported in the September Archives of Neurology.

In an accompanying editorial, Roger Rosenberg, M.D., editor of the journal, declared that the finding is “of critical importance as it provides a consistent and uniform view and linkage with the autosomal dominant, early-onset forms of Alzheimer’s.”

For some time, the case has been building that early-onset Alzheimer’s is due to the buildup of senile plaques in the brain; that these plaques are composed of beta-amyloid protein; that beta-amyloid in turn derives from the amyloid precursor protein; and that beta-amyloid is split from the amyloid precursor protein by the enzymes gamma-secretase and beta-secretase. However, a number of Alzheimer’s investigators were skeptical that gamma-secretase and beta-secretase might play a role in late-onset Alzheimer’s, which is the kind that most people develop. The evidence now published by Fukumoto and his colleagues may well change their minds, at least as far as beta-secretase is concerned.

Fukumoto and his coworkers collected brain material from 61 persons who had died from late-onset Alzheimer’s and from 31 persons who had died from causes other than Alzheimer’s and who served as controls for the study. They exposed various areas of Alzheimer’s brains to new assays they had developed that measure both the amount and activity of beta-secretase. They also exposed the same areas of control brains to the same assays. They then compared the amount of beta-secretase in various areas of Alzheimer’s brains with the amount of beta-secretase in the same areas of control brains. They also compared the amount of beta-secretase activity in various areas of Alzheimer’s brains with that in the same areas of control brains.

And as they reported, there was considerably more beta-secretase and beta-secretase activity in areas of the Alzheimer’s brains that are known to be afflicted with beta-amyloid plaques compared with the same areas in the control brains. The difference was highly significant statistically.

In contrast, there was not more beta-secretase and beta-secretase activity in areas of the Alzheimer’s patients’ brains that are known not to be afflicted with plaques as compared with the same areas in the control subjects’ brains.

These findings thus suggest that beta-secretase might be a major player in late-onset Alzheimer’s, just as it seems to be in the early-onset variety.

And, as Rosenberg asserted in his editorial, “Clearly, their data support beta-secretase activity as an important target for therapeutic intervention in Alzheimer’s. . . .” Indeed, some drug companies are searching for a compound that can counter beta-secretase activity and that might prove to be an effective and safe Alzheimer’s treatment (Psychiatric News, September 8).

The study was supported by grants from the National Institutes of Health, the Walters Family Foundation in New York City, and Takeda Chemical Industries in Osaka, Japan.

An abstract of the study, “Beta-secretase Protein and Activity Are Increased in the Neocortex in Alzheimer’s Disease,” is posted on the Web at http://archneur.ama-assn.org/issues/current/abs/noc20210.html. ▪

Arch Neurol 2002 59 1381