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.” 
 Dossier
1. 2005-2006 Progress on Alzheimer’s Disease: Journey to Discovery, by the National Institute on Aging [nia.nih.gov/Alzheimers]. An excellent overview of ongoing research—as well as information on clinical trials testing drugs to slow the progression of the disease, cognitive rehabilitation strategies to improve memory, and prevention trials.
2. Decoding Darkness: The Search for the Genetic Causes of Alzheimer’s Disease, by Rudolph E. Tanzi and Ann B. Parson (Perseus Books, 2000). An in-depth portrait of the scientific camaraderie and secrecy behind the decades-long search for the renegade genes that cause Alzheimer’s.
3. “Inside the Brain: An Interactive Tour,” by the Alzheimer’s Association [alz.org/alzheimers_disease_4719.asp]. A graphic tour of the destruction and dramatic changes that the hallmark plaques and tangles of Alzheimer’s cause in the brain.
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