Studies target amyloid plaques and tau tangles
For a long time now, scientists studying treatments for Alzheimer’s disease have focused on telltale plaques that appear in patients’ diseased brains as a target for therapy. The plaques are clumps of a small protein called beta-amyloid that build up in the space around nerve cells and interfere with normal brain function. Thus, the thinking goes, if plaques can be prevented from forming or cleared with medicine, the disease could be slowed.
But earlier this month at an international conference, different tangled structures inside neurons took center stage alongside plaques. These so-called neurofibrillary tangles involve another protein, called tau, that normally functions to move critical supplies around neurons. Tau tangles are now being targeted with new experimental therapies.
“Still today, many would say that we don’t have a full grasp of how amyloid and tau interact, or what really is the original trigger of the disease,” says Maria Carrillo, director of medical and scientific relations at the Alzheimer’s Assn., an advocacy organization that supports service and research efforts. “Perhaps those are just byproducts of some other pathology that is really the more important key. We really don’t know all that yet.”
Doctors say that having multiple therapeutic targets is a good thing, especially with a disease that so far has been unstoppable. Currently approved therapies for Alzheimer’s disease alleviate symptoms of the disease, but they don’t affect the underlying changes in the brain.
Here’s a closer look at what is known about beta-amyloid plaques and tau tangles, and why many researchers who study Alzheimer’s think that both hold the key to better treatments, better diagnoses and better understanding of the disease.
Plaques and tangles
Alzheimer’s disease is a type of dementia in which people lose their ability to think normally or to remember things. In addition to memory loss, patients can become disoriented and suffer mood swings. The disease is progressive and ultimately results in death.
When the German physician Alois Alzheimer first characterized the disease a hundred years ago, he described both amyloid plaques and neurofibrillary tangles in the brains of patients who had died. Since then, people have been arguing about the relative importance of these two brain abnormalities, says Dr. William Jagust, who studies beta-amyloid in aging and dementia using brain imaging techniques at UC Berkeley. Yet amyloid plaques have dominated the research field.
One reason for the amyloid focus is that all the gene mutations that have been linked to the disease so far result in the increased production of beta-amyloid, Jagust says, which suggests the protein is central to the disease.
Another reason is that amyloid plaques, unlike tau tangles, occur outside of neurons and thus are easier to observe and manipulate, Carrillo adds.
But there are plenty of good reasons to study tau, despite its location and the lack of tau genetic links to the disease. The main one is that tau tangles are more closely tied to symptoms of dementia than amyloid plaques. “You can have a lot of amyloid pathology in your brain and not have symptoms,” Jagust says. “But if you have a lot of tau pathology in the brain, you’re much more likely to have cognitive symptoms.”
Also of note is that people can have tau tangles — and associated cognitive deficits — with diseases that aren’t Alzheimer’s, adding support to the idea that the tangles are bad brain players. For example, boxers and football players who have suffered multiple head injuries can have tau-related pathology, as can patients with a rare brain disorder called frontotemporal dementia.
“My feeling is that there are a number of ways you can get the abnormalities of tau,” Jagust says. “One of them may be driven by changes in the amyloid protein.”
Many scientists believe that beta-amyloid abnormalities come first. Carrillo says the cascade of effects goes like this: Changes in beta-amyloid occur, perhaps 10 to 15 years before disease diagnosis; faulty amyloid then triggers certain changes in tau protein, resulting in tangles; tangles lead to memory deficits. The disease worsens over time, until the brain is loaded with amyloid plaques and tau tangles, neurons die and brain function progressively deteriorates.
This sequence of events is bolstered by loads of data, much of it based on experimental diagnostic procedures that include PET and MRI scans as well as testing for faulty amyloid and tau in spinal fluid. A January paper in the journal Lancet Neurology, co-authored by Jagust, reviews the state of the field.
The cascade hypothesis also may explain why therapeutic strategies that target amyloid have been unsuccessful, Jagust says: By the time people have lots of plaques, they are in late stages of the disease. So many neurons have been damaged by amyloid and tau (and perhaps other unknown processes) that breaking up plaques at this stage does not slow the disease. Amyloid therapies given at an earlier stage may work, but those studies have not been done yet.
But though the sequence of events described above is a working hypothesis for many scientists, it is not yet a consensus view. Some believe that early tau changes in a brain area called the entorhinal cortex (which were shown to precede measurable amyloid changes in a 1997 study) may be the initiating event. It goes to show that no one knows what the first lesion is, says Dr. Gary Small, who directs the UCLA Center on Aging.
Earlier signs
Whatever the case, it’s becoming clear that both abnormal protein structures start building up in the brain many years before major symptoms crop up. Small, who directs the UCLA Center on Aging, has developed a PET scanning method that labels both amyloid and tau problems in patients’ brains. In a study presented in December at a professional meeting, his team scanned 42 volunteers with normal cognition, then followed them for two years.
Subjects whose initial scans showed more plaques and tangles suffered more cognitive decline over two years. In addition, rescanning their brains revealed increased brain pathology.
“It correlates extremely well with disease progression,” Small says of his diagnostic method.
Some promising results with tau therapies in animal models of Alzheimer’s disease were reported at the Honolulu conference. Researchers are still years away from knowing whether the strategy will work in patients, however. Meanwhile, some two dozen other approaches are being tested in clinical trials, including more amyloid-targeted therapies (some of which aim to block formation of the protein) and drugs that combat inflammation in the brain.
