Zeroing In On A Killer

Before Washington budget-cutters hack any deeper into science spending, they should consider the short history of Alzheimer's disease research. Scientists have yet to produce a cure for this killer, which afflicts 4 million Americans. And controversies still rage over what triggers AD's complex progression of interlinked disorders.

But recently, in quick succession, scientists have nailed the gene combinations that say who is at risk, created a model in transgenic mice to speed drug development, and devised better diagnostics. By any measure, "these are stunning advances," says Pennsylvania University neuropathologist John Trojanowski. And nearly all were funded by the National Institutes of Health.

There's more to come. Armed with a wealth of scientific data, researchers are mapping increasingly sophisticated drug strategies for the early 21st century. The goal, says Harvard Medical School neurologist Dennis J. Selkoe in Boston, is "to understand AD's cascade of pathology and find compounds that block it in distinct steps."

LETHAL CLOG. The most ambitious efforts aim to identify probable causes and correct them in an early stage (table). Most of the 20-odd companies developing drugs have zeroed in on plaques made of protein fragments called beta amyloid. These clog and possibly kill the brain's neurons, just as cholesterol clogs arteries and burdens the heart. And like heart doctors, whose first strategy against atherosclerosis is lowering patients' cholesterol, AD researchers hope to limit amyloid buildup, if they can discover the mechanism.

Leading the charge is Athena Neurosciences Inc., a South San Francisco company co-founded by Selkoe. In January, Athena and Eli Lilly & Co. unveiled the first animal model for the disease: a genetically engineered mouse that builds up AD-like plaques. With it, says Ivan M. Lieberburg, vice-president for research, Athena can test drugs to block amyloid-producing enzymes. Athena has likely candidates for the enzyme, as do Cephalon Inc. and Bristol-Myers Squibb Co.

Scientists at Gliatech Inc. in Cleveland have a different view on AD's cause. Chief Technical Officer Robert C.A. Frederickson says most cases can't be explained by plaque overproduction. The problem is clearance: AD patients' brain cells secrete protein sugars that bind to amyloid, causing it to accumulate. Backed by Janssen Pharmaceutica, a Belgium-based affiliate of Johnson & Johnson, Gliatech is developing small-molecule drugs to prevent binding. Safety tests in humans are still three to five years out.

Others are following genetic signposts to treat the disease. Three years ago, AD pioneer Allen D. Roses at Duke University linked a gene on chromosome 19 with a common form of the illness that strikes older patients. The gene codes for a cholesterol-carrying protein called APO-E, which comes in three variants. People with the least common one, called E2, seem the least likely to develop Alzheimer's. So Roses is looking for compounds that mimic E2 and possibly postpone the onset of the disease.

LOGISTICAL HURDLES. Roses says E2 guards a protein inside neurons called tau. In AD, tau grows abnormally and oozes from the cell to form fibrous tangles found in most AD victims' brains. Detractors say Roses hasn't identified E2's protective mechanism. But that didn't dissuade British pharmaceutical giant Glaxo Holdings, which inked a research deal with Duke last September to pursue the E2 drug. Jonathan Knowles, director of the Glaxo Institute for Molecular Biology in Geneva, calls Roses' APO-E work "groundbreaking" and doesn't worry about clashing theories. "It's not a matter of either/or,"

he says.

Many researchers are wary of tinkering with the body's production of amyloid. Rather, says chemist Peter Lansbury at Massachusetts Institute of Technology, future drugs should intervene only at the point when the protein aggregates into filaments and turns toxic to nerve cells. Other strategies target calcium, which increases abnormally when amyloid touches a neuron's surface. It is implicated in tangle formation.

All these proposals face huge logistical hurdles. They address biological mechanisms that are poorly understood, and they're aimed at patients in early stages of disease. Even with new diagnostics, including a combined blood test and brain scan from the University of California at Los Angeles, nobody can be sure who will fall victim or how the disease will progress. That means any new crop of drugs will have to be tested on individuals who are essentially healthy. "The Food & Drug Administration will insist on unequivocal safety," says UBS Securities Inc. biotech analyst Marc J. Ostro. "These therapies are at least 10 years from the market."

Disease victims may not have to wait that long. The NIH's National Institute on Aging is researching ways to contain secondary brain damage that can cause memory loss (box). Through the Alzheimer's Disease Clinical Studies Unit, a consortium of 35 medical centers based in San Diego, it's testing drugs to fight oxidative free radicals and inflammation that causes AD symptoms.

Some of the NIA's trials with antioxidants and anti-inflammatories use compounds already marketed for other diseases. The consortium is also evaluating evidence that estrogen delays the onset of AD in postmenopausal women. The trial drugs "could modify the disease course or slow the rate of decline," says consortium director Leon Thal.

Although some researchers scoff at anti-inflammatories as a "Band-Aid on cancer" tactic, such therapies could make AD victims more comfortable and keep them out of nursing homes. UBS's Ostro figures Americans spend at least $40 billion a year to care for AD patients--much of it flowing to institutions. But families resort to homes mainly when patients become agitated or aggressive. Even conventional drug therapies should be able to offer some relief, says Neil Buckholtz, who heads drug discovery at the NIA. That's a far cry from the miracle cures sought by neuroscientists and their biotech spin-offs. But in their absence, soothing the misery of victims and their families would be no small triumph.

Better Drug Strategies to Stave off Dementia


Athena, Cephalon, and Gliatech are screening small-molecule drugs that either prevent buildup of damaging plaques or help the brain break them up. Glaxo is chasing a drug to delay disease onset by mimicking proteins that protect neurons.


Somerset Pharmaceuticals and the National Institute on Aging are testing drugs that scavenge free radicals, which are toxic to cells. Also in tests: anti-inflammatories to slow dementia and estrogen therapies to delay the disease onset.


CytoTherapeutics and Somatix are studying genetically engineered cell implants to deliver nerve-growth factors to damaged parts of the brain. Cortex, Gliatech, and Neurocrine Biosciences are developing memory- and cognition-boosting drugs.

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