Until the mid-1980s, little was known about why the Alzheimer’s plaques and tangles form or who is most likely to be afflicted—and why some people never are, no matter how long they live. Part of the reason seems to involve lifestyle and mental activity.

?Those who eat heart-healthy diets, remain physically and intellectually active, and stay socially connected may be less likely than others to develop Alzheimer’s. But researchers have long suspected that genetics also has a part to play, and in 1987 they isolated the first gene thought to be associated with early-onset familial Alzheimer’s disease. Then in 1991, mutations in that gene were discovered and found to be responsible for fewer than 1% of Alzheimer’s cases, most often striking people under age 50. Rudolph Tanzi, director of the Massachusetts General Hospital’s (MGH) genetics and aging research unit in Charlestown, had a key role in finding that initial gene and two others now linked to early-onset familial Alzheimer’s. He also uncovered several of those genes’ nearly 200 mutations—all of which guarantee the development of early-onset disease and increase production of A-beta 42. Discovering these genetic links and understanding that the offending genes increased production of A-beta 42 was a major breakthrough, says Tanzi. "Finally we had a valid biological target instead of just having to guess which protein was causing the disease," he says.

Because A-beta 42 triggers the cascade of destruction, many pharmaceutical companies have tried to develop drugs that can either prevent the neurotoxic form of A-beta 42 from clumping, so it can be cleared from the brain by enzymes, or block production of A-beta 42 by inhibiting the enzyme that cleaves it from the long APP. Alzhemed, the first antiamyloid compound to be tested in a Phase III trial—normally the final hurdle before FDA approval—keeps A-beta 42 fibrils from aggregating. Promising results from earlier testing showed that the drug reduced levels of A-beta 42 in the cerebral spinal fluid of trial participants—and, presumably, in their brains as well. (When A-beta 42 is removed from the brain, it appears in spinal fluid, which can be sampled through a lumbar puncture. A low level in the spinal fluid is thought to also indicate a low level in the brain.)

Another medication in Phase III trials is Flurizan, a drug that reduces production of A-beta 42. Todd Golde, chair of neuroscience at Mayo Clinic in Jacksonville, Fla., and Eddie Koo, professor of neurosciences at the University of California, San Diego, followed a lead from epidemiological studies showing that people who take a nonaspirin nonsteroidal anti-inflammatory drug (NSAID) for more than two years reduce their Alzheimer’s risk by an average of 60%. Golde and Koo determined that compounds such as ibuprofen can prevent an enzyme from clipping APP into A-beta 42, but could pose such dangers as ulcers and kidney dysfunction. The trick, they decided, was to find a compound that could reduce A-beta 42 but which lacked the risky anti-inflammatory properties of an NSAID. They hit upon Flurizan, which may hold promise because it was proved safe in a trial in which it was tested as a prostate cancer therapy.

Other researchers have taken a different tack, attempting to bolster or even instigate an immune response that would clear A-beta 42 from the brain. In 1995, Dale Schenk, chief scientific officer of the Elan Corp., proposed testing a vaccine for that purpose in a genetically engineered “Alzheimer’s mouse” created to mimic symptoms of the disease. But Elan researchers had to compete for a limited supply of the special mice, and Schenk’s colleagues at the biotechnology company’s South San Francisco facility ranked his proposal dead last in priority.

“There were two very good reasons the vaccine shouldn’t have worked,” says Schenk. The first was that the blood-brain barrier, the tightly packed layer of cells that protect the brain from foreign chemicals, would lock out the antibodies the vaccine would stimulate. The second was that Alzheimer’s plaques, then considered rocklike and immutable, were thought to be forever lodged in the brain. Still, Schenk was convinced some antibodies could reach the brain, attach to plaques and stimulate their clearance. So scientists at Elan immunized a few mice that hadn’t been doled out for other experiments, and about a year later, when the brains of other mice the same age were riddled with plaques, the immunized mice had hardly any.

“Everyone, including me, thought we had mixed up the mice,” Schenk says. They tried again, this time waiting until the mice developed plaques before immunizing them. The treatment not only prevented new plaques from forming but also eliminated some that were already there.

However, human trials of the vaccine, conducted by Elan and Wyeth Pharmaceuticals, were halted in January 2002 after 18 of 300 participants with mild to moderate Alzheimer’s developed encephalitis. The kind of immunization being tried—known as active immunization because it spurs the body to produce its own antibodies—also causes the body to marshal white blood cells against foreign pathogens, and that led to the brain inflammation, Schenk says. Moreover, the success of the vaccine was limited, with only one-sixth of participants making sufficient levels of antibodies against A-beta 42, probably because they were mostly in their seventies and eighties, and the immune system loses effectiveness with age. Subjects who generated the most antibodies, however, cleared plaques from their brains and showed improvement in memory and the ability to perform daily functions.