Alzheimer’s disease is the most common cause of dementia in older adults, accounting for an estimated 60 to 80 percent of cases. In the past, the presence of Alzheimer’s could only be definitively confirmed through an autopsy. In recent years, lumbar punctures and PET scans have proven to be effective tools for rendering accurate diagnoses. However, both of these methods have drawbacks, and clinicians have long hoped for simpler and less expensive tools to diagnose the disease and make decisions about treatment.
Now a new generation of blood tests is shaking up the field. These tests are designed to measure the two proteins linked to Alzheimer’s—amyloid, which can form plaques in the brain, and tau, which can accumulate in the brain as the disease progresses. Last year, the FDA approved two of these tests for use in helping to diagnose Alzheimer’s, while several others are available for use in research and to a lesser extent in patient care.
We asked William Jagust, MD, an Alzheimer’s disease expert and a professor of neuroscience at UC Berkeley—and a member of our editorial board—to explain the significance of these developments.
Wellness Letter: Where do things stand at the moment in the Alzheimer’s field?
William Jagust: The field has pretty much settled on the idea that the presence of amyloid plaques is a crucial aspect of Alzheimer’s disease, and that drugs that target the lowering of amyloid should be effective. There have been two clinical trials resulting in FDA approval of immunotherapies that are infused into the bloodstream, take amyloid out of the brain, and slow the rate of decline of Alzheimer’s patients. According to the approvals, these drugs shouldn’t be started without evidence of brain amyloid, but they don’t explain how that evidence is to be obtained.
WL: How is it determined that amyloid is present?
WJ: When I was in medical school decades ago, an autopsy was the final determination of whether a diagnosis of Alzheimer’s had been accurate. If a pathologist found amyloid plaques and tau pathology at autopsy, that supported the diagnosis. But over the years, there have been increasingly accurate ways of detecting amyloid and tau while someone is alive—specifically, with a lumbar puncture or a PET scan.
A lumbar puncture allows us to extract cerebrospinal fluid from the spinal column, but it’s an invasive procedure and many people don’t want to have it. And with PET scans, if you see amyloid, there’s a very high likelihood that that person will have amyloid plaques in their brain at autopsy. But a PET scan is costly and time consuming, and some people don’t want the radiation risk. I think everyone agrees that, on a societal level, it would be better if we had a cheaper and more accessible approach to this.
WL: And that’s where the newer blood tests come in?
WJ: Exactly. Now we have these blood tests. The goal of the tests is to try to determine who has amyloid and tau in the brain. And there are two questions we need to ask. One is whether the person has Alzheimer’s disease. The other is, if they do, what treatment they should receive, which is complicated because there are various criteria for who should be treated. There is also some controversy about how well the drugs work, but detecting amyloid with a blood test could be the first step in deciding whether a person should be treated with an amyloid-lowering drug.
Someone in an early stage of Alzheimer’s has amyloid plaques and just a little tau in the brain. Someone in an advanced stage of Alzheimer’s has amyloid plaques and a lot of tau throughout the brain. We think the tau stage is going to determine how likely a person is to respond to the amyloid-lowering therapies. Someone who has a lot of tau throughout their brain may not benefit from lowering amyloid. They may need a separate drug for tau. We don’t have that yet, although we think we will at some point.
One blood test that has generated excitement and was the first to receive FDA approval measures the ratio of two specific variants of the tau and amyloid proteins. It seems to have a very high sensitivity and specificity for having amyloid in the brain. There are ongoing studies in which this test is being used to determine who should get treated with amyloid-lowering drugs in clinical trials.
WL: How does this play out in clinical care?
WJ: The short answer is, we’re just at the beginning. It is only because of these recent advances that we’ve been able to measure these amyloid and tau proteins in the blood. Some of these tests are very highly correlated with amyloid and tau in the brain, as measured with PET scans, but exactly how they can be used to diagnose and stage Alzheimer’s disease is still being worked out.
There are some problems with the tests. We can’t yet use them for determining the stage of the disease, which involves assessing how much tau is in the brain. Furthermore, the tests are not all interchangeable. You’re not necessarily going to get the same answer if you use different tests or laboratories. It’s not like a blood test for diabetes. When you get a blood sugar test, everyone agrees on what that means.
Some clinicians are in fact starting patients on treatment based on blood tests. But one of the problems is that you can’t track the effect of treatment with the blood tests, as you can with PET scans. If you do a PET scan, find amyloid, and start someone on an amyloid-lowering therapy, you can follow them with PET scans and see if their amyloid is going down. It’s not clear that the blood tests parallel the treatment effects the way the PET scan does.
WL: Does that mean the tests are not quite ready for use by primary care physicians, as opposed to specialists?
WJ: That’s right. They’re being studied for use in primary care but they’re certainly not being widely used. Interpreting the results really requires a clinician who has extensive experience with Alzheimer’s. One issue is that Alzheimer’s patients are likely to have some other pathology as well, or multiple pathologies. Many of them will have had strokes. Many of them will have other kinds of brain degeneration—there are a few such pathologies that are very commonly seen in conjunction with Alzheimer’s disease.
That means that just because someone has evidence of amyloid in their brain, you don’t know for sure that it’s the amyloid that’s driving the majority of their symptoms. So a blood test on its own isn’t enough to make that determination. You need a specialist to do a comprehensive clinical examination and a thorough review of the medical history to determine whether they think the person’s symptoms are likely to be caused by the amyloid.
WL: Given these complications, what is the bottom line here for the consumer?
WJ: At this point, there is absolutely no role for these tests in someone without cognitive symptoms. For those with such symptoms, depending on a number of circumstances, blood tests may be helpful in establishing a diagnosis or evaluating whether an individual might benefit from one of the new amyloid-lowering therapies.
Interpreting these tests is complicated, and they should be ordered and interpreted by a clinician experienced in the diagnosis and management of Alzheimer’s disease. But I think the most important message to get across is that this whole field is rapidly changing and rapidly developing. It is actually a very exciting time.
