Alzheimer's disease develops over decades in humans, and still over months in the altogether more short-lived mouse. But the plaques that are the anatomical hallmark of the disease form, if not quite faster than a speeding bullet, then certainly faster than expected. They can arise within a day.

The time course "was really substantially different than what we had anticipated," senior author Bradley Hyman told BioWorld Today.

Hyman, a professor of neurology at Harvard Medical School, and his colleagues at Harvard and Washington University Medical School published their findings in the Feb. 7, 2008, issue of Nature.

By using a novel imaging technique to repeatedly look at the same regions of the brains of living mice, the researchers were able to watch plaques as they formed, determining their exact birthday. They first took images at intervals of a week in a mouse model of aggressive Alzheimer's disease. After realizing that the speed of plaque formation was much greater than they had anticipated, they moved to daily imaging in a less aggressive model to see whether plaques would form as rapidly there.

They did. Though plaque formation was rare overall in both mouse models, when it happened, it happened quickly. Plaques generally formed within a day, and grew for only about five days before stabilizing in size.

The scientists also investigated the relationship between blood vessels and plaques. Some scientists believe that problems in blood flow either lies at the root of Alzheimer's disease, or contributes much more strongly than currently is realized. (See BioWorld Today, Jan. 25, 2007, and Jan. 28, 2008.)

Hyman said that the studies published in Nature did not investigate blood flow directly. But they did test "the relationship of plaques to capillaries," and specifically whether capillaries appear to give rise to plaques. Hyman said that in the plaques they observed, that did not appear to be the case, though he cautioned that just because his group did not see such a phenomenon does not mean that it does not happen. Still, after a statistical analysis, the authors concluded in their paper that "new plaques . . . do not form any closer to vessels than would be expected by chance."

Earlier investigations have shown that microglia - neuronal support cells that react to inflammation and other damage - often are found in the vicinity of plaques. Hyman and his team showed that once a plaque formed, microglia also tended to show up at the same site within a day.

Although there was no evidence that microglia were actively removing the plaques, the investigators think that they may help restrict plaque growth, which may be why the plaques stop growing in less than a week.

Given that they don't appear to prefer real estate near blood vessels, how the plaques do decide where to settle down remains a mystery. Hyman said that his group plans next to investigate the factors that cause plaque to form in a particular place, and whether those factors can be targeted therapeutically.

He also said that his group's data validated the approach of trying to get rid of the plaques, a strategy that has received much attention but also has been called into question by some newer research suggesting that intermediate aggregates of amyloid-beta may do more damage to neurons than the plaques themselves.

Hyman said that his team's work does not investigate the relative toxicities of intermediates vs. plaques, but noted that the changes he and his colleagues observed amounted to what he termed a "toxic halo" around the plaques, a finding that suggested the efforts that biotech and pharma companies have directed at plaque-busting drugs are on the right track. "Even though other things might also be toxic, plaques themselves are certainly not directly protective," he said.