(2 of 3)
The fact that optimism does exist comes mostly from scientists' ability to apply two important lessons learned from the disappointments of the past. The first involves timing. Experts are now convinced that it's crucial to treat Alzheimer's patients as early as possible, perhaps even before they show signs of memory loss or cognitive decline, rather than attempt to improve a brain already scourged by the disease. The second involves the scope of the medical assault: adopting a multipronged approach that addresses as many of the disease's complex abnormalities as possible may improve the chances that new therapies used early on will not only delay symptoms but also reverse them.
Shifting the focus to the earliest stages of the disease wasn't as obvious as it seems in hindsight. Cognitive decline is a natural consequence of aging, and confusion and memory loss are often just inconvenient parts of getting older. It was understandable, then, that doctors were reluctant to introduce more uncertainty by attempting to tease apart Alzheimer's dementia from the so-called senior moments typical of normal aging.
So rather than make the attempt, they focused on the most obvious target: the buildup of a protein called amyloid in the brains of Alzheimer's patients. While amyloid in living patients can be detected with a spinal tap, its presence doesn't necessarily indicate the disease; it's the accumulation of the protein into plaques, which also include cellular debris like dead and dying neurons, that is linked to the disease's symptoms. A definitive Alzheimer's diagnosis is thus possible only after the patient's death, when an autopsy of brain tissue can verify the hallmark lesions. Initially it made sense for researchers and drugmakers to focus on finding ways to shrink plaque buildup and reduce the amyloid burden in the brain. That, surely, would lead to improvement.
But to date, these well-intentioned efforts have been fraught with failure and riddled with side effects. The agents that target amyloid plaques affect other processes in the body too, including those that regulate how cells communicate as well as the development of heart, pancreas and immune-system cells. What's more, it's not even clear that getting rid of the plaques has any effect on brain function at all. When scientists analyzed the autopsied brains of patients in the failed vaccine trial, for example, they noted that the subjects had fewer plaques than before they received the vaccine but still had shown no improvement on tests of mental function. To confuse matters more, in tests involving animals with the equivalent of Alzheimer's, mice whose brains were loaded with amyloid performed as well as those without the plaques. When so self-evident an A does not lead neatly to a B, science gets awfully flummoxed.
There were several explanations for the seemingly conflicting results, all of which meant that the researchers might unfortunately have steered their work too heavily in one direction. Perhaps amyloid was not a critical contributor to the disease at all but a red herring, and something else was driving the death of neurons. Or perhaps amyloid was a factor in the pathology but only one of many. It was also possible that amyloid was indeed pushing the disease but that the vaccine and drugs used to dissolve the plaques were introduced too late and in too small a dose. Many of those drugs were designed to block the breakdown of amyloid into smaller fragments, which have a greater tendency to clump together. "By the time a person is impaired to the point of dementia, there is probably sufficient damage done to the brain that we really can't reverse it," says the Mayo Clinic's Petersen. "It has gone too far."
If that's the case, then testing the drugs on patients whose brains are just beginning to accumulate amyloid might yield more success. But finding such patients, many of whom show no signs of memory loss or decline in mental function, is a challenge. So in 2004, the National Institute on Aging (NIA), part of the National Institutes of Health, partnered with pharmaceutical companies to create the Alzheimer's Disease Neuroimaging Initiative, a $60 million project tasked with identifying easily detectable differences preferably through blood tests or brain scans between Alzheimer's patients and unaffected individuals. It was nuts-and-bolts science, unglamorous but essential, and it wound up attracting 600 patients who either already suffered from symptoms of Alzheimer's dementia or had mild cognitive impairment a preliminary stage of the disease as well as 200 cognitively normal control-group volunteers.
Already the program has isolated a few dozen intriguing protein markers in blood and spinal fluid that may herald Alzheimer's disease and could help researchers identify high-risk individuals before symptoms set in. Also, newer, better brain scans are helping detect the amyloid patterns that previously could be verified only by autopsy. Being able to say, "This patient appears to have Alzheimer's" as opposed to, "This deceased patient had Alzheimer's" is no small thing. Still, as with the blood and spinal-fluid tests, the challenge remains to understand the link between the plaques and the actual symptoms. What is the threshold between normal and diseased states?