William Jagust, MD, a professor of public health and neuroscience at the University of California, Berkeley, studies Alzheimer’s disease and dementia. Alzheimer’s is the 6th leading cause of death in the U.S., and one of the greatest fears many people have about getting old. Here, Dr. Jagust explains new scans that look for signs of early Alzheimer’s, and how they are being used to develop new drugs to slow—and perhaps even stop—this cruel disease.
What’s the difference between Alzheimer’s disease, dementia, and age-related memory loss?
Dementia is a general syndrome characterized by loss of cognitive function. The signs and symptoms of dementia are progressive. They get worse over time. Eventually they interfere with all kinds of cognitive abilities and daily function. Alzheimer’s disease is one cause of dementia. Alzheimer’s accounts for between 60 and 80 percent of all dementia.
Age-related memory impairment is much trickier to define. People notice changes in their memory as early as their 30s or 40s. We don’t fully understand what causes those changes. Age-related memory loss is usually benign. People have trouble remembering a name or forgetting where they put their keys. People in their 60s and older who develop cognitive problems may be experiencing the initial stages of Alzheimer’s. But based on symptoms alone, unless they are serious, it’s very difficult to say that mild memory loss associated with aging is actually an early sign of Alzheimer’s disease. It certainly could be, in some people, but right now we know that many older people with these mild symptoms are doing just fine.
So how is Alzheimer’s disease diagnosed?
In the past, all we had to go on were clinical symptoms of Alzheimer’s. There was no lab test. A clinician interviewed the patient, interviewed the family, did some tests to rule out other possible disorders, in some cases referred patients for detailed cognitive assessment, and then said, yes, this looks like Alzheimer’s. But over the past decade we’ve developed imaging tests that can show specific changes in the brain that are associated with Alzheimer’s.
What kinds of brain changes signal Alzheimer’s?
We define Alzheimer’s on the basis of changes in the brain related to two proteins that have been studied in autopsy brains for many years. One protein is called amyloid. This is a sticky protein that can begin to clump together and form what we call plaques. Amyloid plaques are a hallmark of Alzheimer’s. The other protein is called tau. It begins to form unusual accumulations inside brain cells, called tangles. The clinical side of the diagnosis is symptoms of dementia. The pathological side is the presence of amyloid plaques and tau tangles. We think these plaques and tangles do a lot of damage to the brain. Neurons, or brain cells, become sick and die. That leads to the loss of synapses, or connections between brain cells, and eventually decline of cognitive ability.
Positron emission tomography, more familiarly known as PET scans, have been used to detect amyloid plaques for more than ten years in research studies, and are now approved by the FDA. A similar PET scan to detect tau was developed a little over a year ago. And while that test is still being worked out, we think it will be very useful.
But I want to make it clear that diagnosing Alzheimer’s is not a simple matter of detecting these proteins. Amyloid plaques begin to show up in some people in their 60s, and the likelihood of finding them goes up with age. By the age of 75, there’s about a 30 percent chance of finding plaques. But not everyone who has plaques shows symptoms of dementia. When people are in their 50s, we begin to see tau tangles forming in a part of the brain called the hippocampus, which is associated with memory. By the time people reach their 80s and 90s, almost everyone has them. But you can have those tangles in the hippocampus and not have dementia. It’s when they spread to other parts of the brain that symptoms of dementia seem to occur. We now think that Alzheimer’s occurs when amyloid plaques are present and tau tangles have spread outside the hippocampus. Amyloid plaques may set the stage for tau tangles to spread widely throughout the brain. When this occurs, and plaques and tangles are widespread, we think that is what defines Alzheimer’s. But the development of this process may take 15 or 20 years or more.
How could these scans someday help treat or even prevent Alzheimer’s?
Scans that detect amyloid are already having a big impact by making it easier to evaluate new drugs that might slow the disease. Pharmaceutical companies have developed many drugs that lower amyloid plaques in the brain. But testing them hasn’t been easy. Before the scans for amyloid were available, researchers had to rely on a clinical diagnosis of Alzheimer’s, based on symptoms, to recruit patients for studies. But once the scans were introduced, we discovered that about 10 to 15 percent of people who were diagnosed with Alzheimer’s don’t have amyloid in their brains. Obviously, a drug designed to reduce amyloid plaques isn’t going to have any benefit for them. The scans enable researchers to recruit only people who have measurable amyloid plaques, so the results will be much more meaningful.
Perhaps even more importantly, the scans allow us to test drugs in people far earlier in the disease process. If you treat someone who already has Alzheimer’s disease, it may be too late to really make a difference. By testing them in people with mild cognitive impairment who also have amyloid plaques, we’re focusing on a group in which at least some people are at higher risk of developing Alzheimer’s. So we’ll get a clearer understanding of whether we can slow the disease process or keep it from progressing to Alzheimer’s. There’s even a new study underway to treat people in their 70s with amyloid plaques but no symptoms whatsoever. That’s an attempt to target the disease even earlier in the process, and it wouldn’t have been possible without amyloid imaging scans.
You’ve talked mostly about amyloid. What about the other hallmark of Alzheimer’s, tau?
We’re very interested in tau. In fact, the association between tau and Alzheimer’s is much stronger than for amyloid. You can have tons of amyloid in the brain and no symptoms. That’s not so for tau. If you have lots of tau, especially when it’s distributed throughout the brain, you almost always have symptoms of cognitive problems. The only reason there hasn’t been more interest, really, is that there hasn’t been a good way to measure tau in the brain in living people. But now we have one. Once we work out all the methods for interpreting the results, I think we’ll see more development of potential drugs aimed at tau. That’s very good news. The more targets we have for drug development, the more likely we’ll discover something that slows and even prevents Alzheimer’s.
Are you optimistic that doctors can sometime prevent or treat Alzheimer’s?
I am. We’re learning more and more about what these abnormal proteins are doing in the brain. Developing drugs that reduce or eliminate them is a very reasonable approach. There are no guarantees. I certainly can’t say when we’ll have an effective treatment. But yes, we’re making real progress, and I’m optimistic that what we’re learning will help us find ways to slow this terrible disease.
If someone is worried about Alzheimer’s, should they get tested?
I think that really depends on what kind of problems they have. If someone is having serious symptoms of cognitive loss or dementia, evaluation by a physician is very important particularly in finding other causes of the problem that could be treated. But as far as people who have no symptoms, there is no reason to undergo PET scanning. We don’t yet have effective treatments to offer people, and the test results can’t say precisely who will get Alzheimer’s and who won’t.
In fact, the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging recently came out with a policy statement recommending that people who have no symptoms should not be tested. Here’s why. If you test people in their mid to late 70s, with no cognitive problems, about one-third will show the presence of amyloid plaques. The trouble is, we can’t say with any certainty who will go on to develop Alzheimer’s. There’s a growing body of evidence to suggest that if you have this amyloid in your brain, you’re at greater risk of getting Alzheimer’s in the next 15 to 20 years. But we can’t say who is at greatest risk or when they will get into trouble. And some people with plaques will never get Alzheimer’s.
An even better reason for not being tested at the moment is that there’s nothing we can do to slow the progress of Alzheimer’s. That’s why, even though the test is approved by the FDA, Medicare doesn’t reimburse for it. They don’t see evidence that being tested will have an impact on people’s health.
That doesn’t mean no one should be tested. For people who have symptoms of significant cognitive decline—especially where it is difficult for doctors to arrive at a diagnosis—the scans could help rule out Alzheimer’s. But even a positive scan won’t establish that it is definitely Alzheimer’s. The results can only suggest that Alzheimer’s might be a cause.