Two proteins clogging the brains of people with Alzheimer's are widely seen as hallmarks of the mysterious disease: sticky, brain-clogging amyloid plaques and tangles of so-called tau proteins. But scientists disagree over the role the two proteins play in causing Alzheimer's.
While the dominant view has been that the sticky plaques are the prime culprit, some experts think that the protein tangles are the main problem. In recent years, other theories emerged including that Alzheimer's is caused by inflammation or a disease-causing biological imbalance known as oxidative stress.
Dennis Selkoe, a leading amyloid researcher, says newer studies support his long-held view that reducing amyloid is the way to tackle Alzheimer's. “Amyloid buildup is necessary but not always sufficient to cause clinical Alzheimer's disease,” he says. “But since we don't know a factor that precedes the amyloid — and I don't doubt there are factors — the best way to ultimately treat the disease is to treat this common factor.”
He points out that other amyloids cause disease in the liver, spleen and joints, and that by removing these amyloids, the patient typically recovers.
However, promising clinical trials of a vaccine to clear amyloid plaques from the brain were halted after some patients developed dangerous inflammation in their brains.
Scientists “had to go back to basics … and try to develop second-generation vaccines that removed amyloid without causing inflammation,” says Marcelle Morrison-Bogorad, former director of the National Institute of Aging's Neuroscience Division. “And of course that depends on amyloid being the causative factor.”
The Journal of the American Medical Association recently tried to summarize the confusion over the role of amyloid: “Several population-based postmortem studies have now shown that amyloid pathology is widely present among non-cognitively impaired older individuals. Moreover, many elders with dementia symptoms have pathologic features besides amyloid plaques and tangles that may have contributed to the clinical syndrome.”
George Perry, a professor of biology at the University of Texas, San Antonio, thinks amyloid may protect the brain against Alzheimer's, rather than cause the disease. “The amyloid idea is fundamentally a very unusual idea for biology,” he says. “It presupposes that the brain has mechanisms that cause the brain's destruction — which goes against evolutionary theory.”
Some researchers theorize that as so-called free radicals — highly reactive atoms with unpaired electrons — accumulate in the brain, they damage nerve cells, contributing to Alzheimer's. Free radicals are produced as molecules split during body metabolism. Normally, the body stabilizes free radicals, but if they become excessive it can be difficult for the body to keep up, especially as we age.
Another theory is that the disease is caused by floating small clumps of amyloids — called oligomers — rather than the amyloid plaques that accumulate in large masses in the brain. Solving the mystery of amyloid plaques could happen soon — or decades from now. “There's an awful lot of wonderful research going on,” says Morrison-Bogorad. “But I'm a true believer that nature sends us curve balls all the time.”
— Beth Baker