By David N. Leff

Two smoking guns put the finger on Alzheimer's Disease (AD), setting its guilt apart from other senile dementias. These telltale hallmarks are neuritic amyloid plaques, wrapped around AD neurons in the brain, and fibrillary tangles inside those nerve cells. The grim Catch-22 is that they can only be seen as confirming a diagnosis of the disease by post-mortem examination of the deceased patient's brain. (See BioWorld Today, June 24, 1999, p. 1.)

And it's a wide open question whether those plaques cause AD, or, conversely, that disease generates the brain-degrading amyloid peptide.

In fact, it's a much larger molecule in the brain, amyloid precursor protein (APP), that gives rise to the stubby, amyloid-beta (Ab) peptide. A protein-chopping protease enzyme cleaves that short, plaque-forming sequence off its APP mother-lode molecule. Ab's complicity in creating the tangles is less clear, but strongly suspect.

Current and experimental AD therapies focus on slowing and softening the agonizing behavioral symptoms of the disease, which blunt its victim's attributes of Homo sapiens' humanness - memory, language, skilled movements, personality, sapience. The plaques and tangles mostly attack the neurons in regions of the hippocampus and cerebral cortex, which orchestrate these distinctive, humans-only traits.

From Cognitive Compound To Neuron-Hitting Antigen

But not a single drug - in existence or on drawing boards - takes point-blank aim at Ab, the presumed perpetrator of these outrages against cognition. So a couple of years ago, neurobiologist Dale Schenk set about dragooning hit-man accomplices to do the job - namely, the human immune system.

Schenk co-founded Athena Neurosciences Inc., of South San Francisco, in 1986; it merged a decade later with Elan Corp. plc, of Athlone, Ireland, and Schenk became that company's vice president of neurobiology.

"Athena has had a long history in the diagnostic area," he told BioWorld Today. "I was the head of that effort for years. We've also been working on therapies for AD. The idea of a vaccine against the amyloid-beta peptide was rather simple. I was trying to think of ways to alter its steady-state levels in the brain," he recalled. "My reasoning was, 'Gee, if only we could get an agent in there that would bind to beta peptide. Wouldn't it be nice to have an antibody to take on that antigen?' It suddenly hit me that all serum proteins at very low levels do get into the brain. We're all taught that there's a blood-brain barrier, and you can't get by it. Well, that's not entirely true. Most proteins at very low levels, on the order of one-tenth of a percent, do get through. So then the idea was that such a small percentage might be enough to alter or perturb amyloid. And maybe that will have an effect."

His concept came to fruition in today's Nature, dated July 8, 1999. The report, of which Schenk is lead author, bears the title: "Immunization with amyloid-b attenuates Alzheimer-disease-like pathology in the PDAPP mouse."

That transgenic mouse is a model of AD pathology. "Actually," Schenk said, "it overproduces human beta amyloid." This means it mimics the hallmark neuronal pathology of the disease. Whether the animal also reproduces the behavioral deficits of AD is another matter.

"As far as the mouse's AD behavior is concerned," Schenk said, "the studies in our Nature paper don't address that. We've focused entirely on the pathology, because that's the definition of the disease one sees at autopsy."

He added: "That's an important question, because mice aren't humans. In most aspects of AD, the patient loses high-order thought processes, and it's very hard to mimic these in mice. So, for example, there have been drugs in the clinic that worked exceedingly well on cognition in rats, but have failed in AD. So, the bottom line is, no, we haven't looked at behavior in our mice, and I wouldn't trust it if we had. But ultimately, we want our vaccine to treat the human's ability to think and perform, and until we get into clinical trials and try it, one doesn't know."

That prototype vaccine is a synthetic amyloid beta peptide, 42 amino acids long, plus an adjuvant.

Schenk and his 24 co-authors carried out two experiments in their AD-surrogate rodents - one to test the vaccine's ability to prevent the onset of disease, the other to treat it after symptoms have been diagnosed.

"The first study," he said, "was to immunize the animals early and see what happens. The other allowed the rodents to get the disease, then start vaccinating them. Both types of experiments, quite frankly, worked dramatically well. Not only was plaque burden reduced substantially in both studies, so was neuritic dystrophy, or nerve-cell damage, and brain inflammation in general, as detected by astrocytosis."

In the initial, prevention arm of their preclinical trial, the co-authors aimed at replicating the asymptomatic situation in which an elderly person approached the Alzheimer's-disease age of 70 or 80, with risk factors such as a presenilin gene, or close family members already diagnosed with the disease. The team vaccinated nine six-week-old mice monthly for 11 months, then took stock of their immune responses. Seven of the nine "had no detectable amyloid-b deposits in their brains," the Nature paper reported.

Following up on that ounce of prevention, the co-authors then zeroed in on the proverbial pound of cure. They let 24 transgenic mice grow up to 11 months, an age that simulated the human Alzheimer's disease patient with advanced symptoms. Half of this cohort received repeated injections with the vaccine, while the other 12 got shots of saline as controls.

At 12, 15 and 18 months of age, groups of treated and untreated animals had their excised brains examined. At 18 months, Nature reported, "the Ab burden in controls had increased by more than 17-fold to 4.87 percent," whereas vaccine-treated animals "had a greatly reduced amyloid burden of only 0.01 percent."

With what Schenk characterized as "very encouraging results," can human trials be far behind? "Actually," he revealed, "we're in the process of putting together a package to submit an [investigational new drug application] to the FDA in the next several months. If they are favorable, we could be into early Phase I safety studies before the end of the year. These would enroll a small number of individuals, all AD patients. I think both the FDA and Elan would be more comfortable with that, for ethical reasons."

"I certainly hope," Schenk concluded, "that this sort of study will generate additional research, not only in AD but in other neurological diseases, where the vaccine approach has never been considered before."