Not Fade Away

EVERY SUNDAY OF HIS CHILDHOOD, Sam Gandy witnessed the effects of dementia, visiting his grandmother in a nursing home even as the disease corroded her memory of him. Relatives said she was senile and thought her condition was just what happened when you got old. Now, four decades later, there’s an awareness that Alzheimer’s disease, like other maladies associated with aging, is not inevitable. But that makes it no less terrifying, and as tens of millions of baby boomers enter their later years, they monitor parents, one another and themselves for signs of what could be the start of a slide into oblivion.

Less than a year ago, 38 years after “senility” claimed Gandy’s grandmother, his father-in-law began to suffer from forgetfulness and confusion. Gandy, director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia, told him it was the same disease. “It was horrible to admit we can do nothing to stop it,” he says.

Alzheimer’s is the bad news about our new, longer life spans. At age 65, fewer than 3% of people show signs of the disease, but after age 85, as many as 40% suffer its effects. Today, there are 5.1 million diagnosed sufferers of Alzheimer’s disease in the United States. That number is expected to rise to 7.7 million by 2030 and to 13 million by 2050—and caring for those patients could bankrupt Medicare and Medicaid.

Yet against this backdrop, researchers are strikingly sanguine, confident they’re close to finding ways to slow the ravages of the neurodegenerative disease. During the past 15 years the field has seen revolutionary advances, the fruit of some of the largest dementia research studies ever funded. “I’m very optimistic that we’ll be able to arrest the progression of Alzheimer’s disease in my lifetime,” says Gandy, who is 53. “And I think our ability to diagnose the disease early will become so good that eventually we’ll be able to prevent it.” With nine drugs currently in the final phase of clinical testing, adds Paul Aisen, an internist and professor of neurology at Georgetown University in Washington, D.C., “we are on the verge of a new therapeutic age for Alzheimer’s disease.”

THE LANDSCAPE OF DEVASTATION THAT Alzheimer’s disease causes was first revealed in 1906, when Alois Alzheimer, a German psychiatrist and neuropathologist, described what he found in the autopsied brain of a demented 51-year-old woman. Inside her neurons were tangles of twisted protein threads. Clumped between the neurons were sticky plaques of protein, decayed neuron remnants, and whole cells called microglia that digest damaged cells or foreign substances.

Both the plaques and tangles appear to be linked to a brain substance known as amyloid precursor protein (APP) that is thought to play a role in the normal function of brain cells. Enzymes clip APP into fragments of different sizes—peptides of beta-amyloid, or A-beta—that float freely in the brain until they are cleared by the bloodstream. There is debate about what function, if any, A-beta serves, but some fragments—of a particular type called A-beta 42—seem to be toxic. People with Alzheimer’s have higher than normal concentrations of A-beta 42, and some researchers believe these protein clumps do the chief damage of Alzheimer’s as they find their way into the synaptic gaps among neurons, short-circuiting signals between brain cells. (The clumps then form long, spaghetti-like fibrils, which in turn condense into the gooey plaques of Alzheimer’s.) Although many scientists consider the plaques themselves just as dangerous, others now theorize that they could be protective, absorbing A-beta 42 strands to keep them from further impairing cell-to-cell communication.

Once plaques start forming, neurodegeneration worsens with the abnormal accumulation of the protein tau. Normally, tau stabilizes microtubules, structures inside neurons that transport nutrients through brain cells. But in the brains of Alzheimer’s sufferers, tau pulls away from the microtubules to twist with other strands of tau, causing the neuron’s transport system to collapse.

As neurons lose connection with one another and their food source, they die. Alzheimer’s first destroys neurons in the parts of the brain, particularly the hippocampus, that form and store memory. Then it attacks areas in the cerebral cortex responsible for language and reasoning before finally causing so much of the brain to atrophy that the person with Alzheimer’s becomes helpless and unresponsive.

Therapies do little to stem this decline. Drugs developed during the 1970s and 1980s—three of only four FDA-approved Alzheimer’s medications now on the market—increase the level of the neurotransmitter acetylcholine, the chemical used by neurons in forming memories, by inhibiting an enzyme that breaks it down. (The fourth drug blocks the action of the neurotransmitter glutamate, which is overactive in people with Alzheimer’s.) But the drugs do not slow the inevitable death of neurons—they treat just the symptoms, not the disease.

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.

The results encouraged Elan and Wyeth researchers to proceed with two approaches. They are now testing passive immunization, which involves injecting antiamyloid antibodies manufactured in the laboratory. Because the body is not making its own antibodies and stimulating an immune response to A-beta 42, there is no danger of brain inflammation. Passive immunization also allows researchers to control or stop the delivery of the engineered antibodies. The drawback is that injected antibodies aren’t as powerful as those the body produces, so this type of immunotherapy must be given repeatedly.

The second new approach immunizes trial participants with only a fragment of A-beta 42 attached to an inactivated diphtheria toxin—a standard component of many vaccines. This technique also avoids a reaction by white blood cells, but it induces a highly specific antibody response to A-beta 42. “We hope that more than 70% of patients will develop antibodies,” Schenk says.

In a Phase II clinical trial of yet another type of passive immunization, a research team from New York–Presbyterian Hospital and Weill Cornell Medical Center in New York City found that cognition in sufferers with mild to moderate Alzheimer’s stopped declining after they received an infusion of intravenous immunoglobulin derived from human plasma collected at blood banks and used to treat immune disorders and leukemia. Immunoglobulin contains natural antibodies that have been shown to latch onto beta-amyloid.

AS RESEARCHERS CONTINUE TO EXPERIMENT with these and other Alzheimer’s therapies, two wide-ranging quests are attempting to solve basic mysteries about what causes the disease and how best to gauge its symptoms. The $60 million Alzheimer’s Disease Neuroimaging Initiative (ADNI), supported by $20 million from the drug industry and the largest-ever Alzheimer’s grant from the National Institutes of Health, is studying the brains of 200 people older than 65 who show no signs of Alzheimer’s, 400 with amnesic mild cognitive impairment (MCI, a precursor to Alzheimer’s) and 200 with full-blown disease. The research subjects are tested every six months for three years using magnetic resonance imaging, positron emission tomography and analysis of blood and cerebral spinal fluid.

The goal is to identify the most reliable biomarkers of Alzheimer’s, the measurable, outward indications of the disease’s largely hidden progression. For example, researchers hope to be able to correlate the degree of memory decline with the rate of hippocampus shrinkage and to standardize those measurements so clinical trials can proceed faster and with fewer participants. “Before ADNI, investigators would use different biomarkers in their trials, and it was very hard to compare and contrast results,” says Michael W. Weiner, the study’s principal investigator and professor of radiology, medicine, psychiatry and neurology at the University of California, San Francisco. The study, scheduled to be completed in 2010, also breaks new ground by immediately posting on a Website all of its data and neuroimages for any qualified researcher to use. “This is a new standard for data sharing,” says Weiner. “Scientists aren’t holding on to their data just so they can be the first to write a paper.”

The second grand undertaking involves the ongoing hunt for Alzheimer’s genes, and if the MGH’s Tanzi succeeds, by summer 2008 the majority of genes causing late-onset Alzheimer’s disease will have been discovered. Using gene chip technology that allows researchers to test 80% to 90% of all genes in the human genome simultaneously, Tanzi and his colleagues are searching for Alzheimer’s genes in 2,400 families—more than 5,000 individuals—in what may be the largest family-based genetic study for any disease. Unlike early-onset Alzheimer’s, the much more common late-onset disease has a complex genetic profile, with multiple genes interacting with one another and the environment. In 1993 the gene ApoE4 was found to have a strong association with late-onset Alzheimer’s, elevating the risk of getting the disease by three to 10 times, depending on whether an individual inherits a copy of the gene from one or both parents. Since then, researchers have tested 400 other genes, of which roughly two dozen reveal a much weaker association with the common form of Alzheimer’s.

By searching the entire genomes of many families rather than merely guessing where to look for genetic culprits, Tanzi is confident his team will find a few genes that may double the risk of the disease, along with several dozen “Little League” genes that bump up the odds only slightly. “Based on the sheer number of genes we’ll find, I think every single case of Alzheimer’s will turn out to have a genetic component,” says Tanzi, citing recent Swedish studies of identical twins that suggest at least 80% of late-onset disease is dictated by heredity. Scientists can then work on developing an algorithm capable of assessing all genetic variations at once to predict a particular person’s risk. “The beauty of finding these genes is that each one tells you something biologically about the disease,” Tanzi says. “That gives us another shot at discovering the best therapies to treat or prevent it.”