Detecting the Earliest Signs of Alzheimer Disease and Brain Amyloid Status

Michael Weiner, MD

New advancements in both treatment and preventative measures for Alzheimer disease (AD) space have defined the space in recent months, namely through the approval of aducanumab (Aduhelm; Biogen) and the promise of blood biomarkers. Michael Weiner, MD, principal investigator, Alzheimer's Disease Neuroimaging Initiative, and director, Brain Health Registry, spoke with NeurologyLive on a systematic review published in Alzheimer’s Dementia earlier this year, which was initiated to identify better ways to predict the status of amyloid-beta (Aß) plaque in the brain. Weiner, who is also professor of radiology and biomedical imaging, medicine, psychiatry, and neurology at the University of California–San Francisco, discussed the findings of the review, for which he was the corresponding author, as well as key takeaways for clinicians.

Since the completion of the systematic review, additional findings have further confirmed the potential of blood tests as a biomarker for AD. Due to the nascent research at the time Weiner and his colleagues conducted the review, little was information was available; although, Weiner remains hopeful that blood tests will offer a convenient, cost-effective method to predict AD status by measuring Aß, tau, and neurofilament levels. Weiner further outlined the parameters of the systematic review, recent advancements in the AD field, as well as his thoughts on future research. 

NeurologyLive: What prompted the systematic review? Was it initiated to address a research need or a clinical need?

Michael Weiner, MD: The reason why we did this review is because we now know that Alzheimer disease is a disease that produces progressive cognitive decline and dementia, and that Alzheimer disease is caused by the accumulation of amyloid in the brain, which leads to the development of tau, which causes neurodegeneration.

A very important thing is to be able to diagnose who has Alzheimer disease, and almost by definition, that means that people who have a lot of amyloid and tau in the brain. So how do we determine who's got amyloid and tau in the brain? Well, in the past, we relied on autopsies, but that doesn't help in terms of diagnosis of living people. We now have amyloid PET scans, which tell us whether people have high loads of amyloid in the brain, but those PET scans are expensive, and in the United States, they're not reimbursed by Medicare. There has been a big question of, is there a way to predict who has amyloid in the brain without the use of PET scans, or at least what information will actually predict whether somebody has a positive PET scan? That's why we did the review, to determine what other measurements could be done that would predict who has amyloid in the brain. 

When we did this literature search—it was completed about a year and a half ago—and fundamentally, what we found was that there were certain information and certain tests that you could do on people that would help predict who had amyloid in their brain, but taken together, it really wasn't all that predictive. What's happened, though, just in the year and a half…is that a lot of new blood tests have come out, which seem to be very, very predictive. That’s a very exciting development, and what we hope to do is to redo the review to bring everything really up to date, to the present. This is a field that has just dramatically changed in the last 18 months to 2 years, with the development of blood tests for Alzheimer disease.

How will findings from the review inform future research and clinical practice? How will this affect how clinicians are measuring biomarkers?

I don't think that the key findings of our systematic review would be a surprise to any clinician because what we found was that the major predictors of whether people have amyloid in the brain are age—that's no surprise, we've known that for a long time—whether or not somebody has a family history has some predictive value, and then whether or not people have complaints. If people say that they have problems with their memory, that their activities of daily living have changed—just the answers to those questions do have some predictive value.

Furthermore, memory tests also have some predictive value, because obviously, people who are impaired or have a problem with their memory function, they're more likely to have Alzheimer disease. At the time we did the systemic review, the blood tests were in a very early stage, and there wasn't that much literature demonstrating that the blood tests were effective in predicting amyloid. As I mentioned earlier, that's really been a big advance in the last 18 months.

What advances have been made this year in biomarker tests and blood tests within the AD space?

There’s been really 2 big advances in the Alzheimer's disease field just in the last year. The first, the most dramatic, is the approval of at aducanumab, or Aduhelm, by Biogen, that was approved by the FDA several months ago. The results of their trials have been somewhat controversial. The approval process by the FDA was controversial. It's not certain whether or not this treatment is going to be paid for by the [Centers for Medicare & Medicaid Services]. Just yesterday, the Veterans Administration, which is the single biggest health care system in the United States, announced that it has low enthusiasm for paying for Aduhelm, and it's not putting Aduhelm on the national formulary, which is not encouraging news for Biogen, but that's because the treatment has been controversial.

Nevertheless, I think most experts in the field believe that certainly one of the Biogen trials was extremely encouraging in slowing and progression for people who are treated with the high dose of Aduhelm, and there are 2 or 3 other medications that are antibodies that seem to remove plaques from the brain and have shown some evidence of slowing progression. The good news is that going after amyloid plaques seems to have some effect, and more and more treatments are being developed. 

Two treatments, [Eli] Lilly's treatment (donanemab) and Eisai’s (lecanemab) antibodies have been given a fast track, breakthrough designation, and so they may get approved by the FDA as well. That’s on the treatment side. 

On the diagnostic side, it used to be said, “What's the point of diagnosing Alzheimer disease? There isn't anything you can do about it.” Well, now that we have treatments that seem to be effective, that raises the importance of diagnosing Alzheimer disease. As I said at the beginning, the disease is not cognitive decline and dementia; cognitive decline and dementia are the symptoms that arise from the disease process. The disease itself is amyloid plaques, tau tangles, leading to neurodegeneration, and Alzheimer disease is also very frequently accompanied by other comorbid diseases, especially cerebrovascular disease that is small strokes, and Lewy body disease, which is caused by a protein alpha synuclein. This is also the same protein that causes Parkinson disease. There’s another protein called TDP-43, which also produces memory decline, especially in older people. Alzheimer disease doesn't occur in a vacuum, and in fact, the majority of people who develop dementia have at least one other disease process along with the Alzheimer disease process. 

We’re in a very exciting space with diagnostics. Currently, amyloid PET scans are the gold standard for identifying who's got amyloid in the brain, meaning really who's got Alzheimer disease, but as I said earlier, they're very expensive, they can be $3,000 to $5,000, they're not paid for by Medicare, and I don't think anybody believes we can start doing PET scanning on everybody who's over age 65 to see whether they got Alzheimer disease or not. We don't have that many PET scanners. We need some more low-cost, scalable approaches to identify people at risk and to identify who's got Alzheimer disease.

I think that blood tests are very exciting. There are several types of blood tests, one type of test measures amyloid in the blood, and looks at changes in amyloid levels in the blood because they seem to be associated with brain amyloid changes. Another set of tests looks at tau in the blood, specifically phosphorylated tau, and there's different species of phosphorylated tau. Finally, there is another chemical called neurofilament light, which is associated with neurodegeneration. So, we have amyloid in the blood, tau in the blood, neurodegeneration measurements in the blood, [and] some kind of combination of all of these is probably going to ultimately be used in diagnosis of people with Alzheimer disease. 

And then there's what we call the digital biomarkers, that is using the internet to have people take assessments and take tests of brain function, a memory test or something like that, that's also going to help identify who's symptomatic, who's at risk, and may lead people to get the blood test. I think we are entering into an era where soon, blood tests are going to be available, and they won't be that expensive. We’ll start testing lots of older people, and we'll be following them longitudinally, and perhaps a person who's completely normal who is in their 60s or 70s, or 80s, there might be some longitudinal change in some blood level that will indicate that they have or are developing Alzheimer disease, and that will lead them into some kind of an algorithm where they'll get treatment. Hopefully, it won't be too long before we can show that some treatments will really prevent the onset of symptoms. That's really what's most important.

Of course, we've got people who are symptomatic now that have impairments or dementia, and we want treatments for them, but if we can find a way to identify people who are healthy, who are at risk, and treat them before they develop symptoms, then we could essentially prevent Alzheimer disease and eliminate Alzheimer disease from our population, which would be a phenomenal accomplishment, and I think it's something that can be achieved.

Is there anything else you feel is important to note about the systematic review?

Just to summarize, it's a very exciting time for our field. We've got new treatments being developed that seem to be effective, [and] we have new tests being developed, which seem to be more and more predictive. Taking everything together, we're going to find ways to be able to make more measurements among people in the community and find treatments that are effective [in slowing] the progression of Alzheimer disease and ultimately prevent it.

Transcript edited for clarity.

REFERENCE

Ashford, MT, Veitch, DP, Neuhaus, J, et al. The search for a convenient procedure to detect one of the earliest signs of Alzheimer's disease: A systematic review of the prediction of brain amyloid status. Alzheimer's Dement. 2021;17:866–887. doi:10.1002/alz.12253