Should People Without Symptoms Get an Alzheimer’s Blood Test?

Alzheimer’s blood tests are advancing rapidly, but should people without memory symptoms use them to determine if they have signs of the disease in their brains? At the Alzheimer’s Association International Conference, Being Patient founder Deborah Kan spoke with neurologist Dr. Marwan Sabbagh about the uncertainty surrounding testing, risk, and treatment.

Sabbagh is a behavioral neurologist, the Moreno Family Chair for Alzheimer’s Research in the Alzheimer’s and Memory Disorders Program at Barrow Neurological Institute and a professor of neurology. A longtime Alzheimer’s clinical trial investigator, he specializes in diagnosing and treating Alzheimer’s and other memory disorders and has contributed to hundreds of scientific publications.

Sabbagh explains why current guidance does not recommend Alzheimer’s blood testing for people without symptoms, including those with two copies of the ApoE4 gene. He also discusses emerging approaches to removing amyloid, the continuing search for treatments targeting tau and neuroinflammation, what researchers learned from unsuccessful semaglutide trials, and why repurposed cancer drugs may offer another path for Alzheimer’s drug development.

Deborah Kan: It seems like the hotly contested question: should people who don’t have symptoms get a blood test?

Dr. Marwan Sabbagh: So we’re expecting practice guidelines to come forth, but the answer so far is no. We would not expect a person who is asymptomatic to go and get a blood test because we’re worried about the predictive value of a future cognitive decline. 

It’s funny, because I’ve heard — if you’re biomarker positive but clinically normal, are you absolutely going to get Alzheimer’s? And that’s a hotly debated discussion in the field. We do not know the answer to that. Because I now have patients who are biomarker positive, clinically normal, and they’re terrified. They’re literally terrified. “Oh my gosh, I’m going to get Alzheimer’s.” 

And so we’re in an unknown space. We went from not having any certainty now to having too much certainty. And I’ve heard debates. Some people say it’s not only a risk factor, but an absolute. I’ve heard a new term for it at this conference, called “cognitively unimpaired Alzheimer’s disease.” I’ve never heard of that before.

Kan: We hear a lot of comments from people in our community, namely people who find out they’re ApoE4 homozygous. They have two copies of E4. And they come to us and say, “should I get a blood test, or where can I get a blood test?| It’s a really hard question to answer. How should we be answering it?

Sabbagh: I’m now speaking to you as a colleague. This is not a position statement or an official interpretation. The risk is high. It’s real. 

Actually, I’m leading the ApoE4 Action Alliance’s position statement that’s going into a journal. So I’ve been following this space very closely. If you look at a 4/4 (meaning someone who inherited an ApoE4 gene from both biological parents), their lifetime risk of developing Alzheimer’s is about 60 percent. It’s a real risk. 

We think we should intervene early, but I would tell them, on an individual basis, maybe not yet. Because the chances are they may come back with an abnormal p-tau, and we don’t know what to do about that yet. Because if their p-tau is elevated, then they’re cognitively unimpaired with Alzheimer’s. We don’t have a good, effective treatment for them yet. But I will tell you that 4/4 — I’m talking to a lot of these people, and they’re all scared. And so the position statement is no, but I understand the driver for that.

Kan: And not to mention the therapies that are available, they pose a higher risk for the E4 homozygous.

Sabbagh: Absolutely. Absolutely, and those are for patients with symptoms, not asymptomatic. We’re seeing those studies unfolding now, and we’ll have an answer for that, but we don’t have an answer for that yet.

Kan: I attend these conferences, and there’s so much going on. What’s exciting to you this year.

Sabbagh: So I think we’ve baked the amyloid story. Every time we hear amyloid, we’re hearing about third-generation monoclonal antibodies, removing amyloid even faster. It’s clear to me that drugs — the third generation, the trontinemab etc. — will be used as induction therapy. Remove the amyloid, but that will not be the long-term maintenance. That’ll be the induction therapy, like a chemo. So that’s one part.

Kan: So get rid of the plaque, but then you have to move on to something else.

Sabbagh: So the tau stuff is struggling. We still see this BIIB080, which is showing some signal efficacy for clearly reducing CSF tau. That’s Biogen. Removing tau, lowering tau PET. It’s an antisense oligonucleotide. Some clinical efficacy signal, but some mixture of interpretation of the tau signal. So we’re still struggling as a class to get good tau approaches. 

And something that we know is going on is neuroinflammation. The whole semaglutide was a bust, all anti-inflammatories was a bust, but there’s still a need. People recognize there’s a gap around neuroinflammation, so we’re still waiting to see some good progress there as well.

Kan: I’ve thought a lot about the semaglutides, because isn’t it really hard to prove something prevents something? In a two-year study, are you really going to understand that?

Sabbagh: I do, and I think we’re mixing the data. And I actually am writing an editorial for a journal on the postmortem on the semaglutide story. There’s so much to say there. 

One thing that we’re looking at is semaglutide doesn’t even cross into the brain. So maybe the idea was a good one. Maybe we just picked the wrong drug. That’s one option. 

Another option, of course, is that the take-home message is that semaglutide, as a GLP-1 in biomarker-confirmed people with Alzheimer’s, does not affect their progression but had a teeny, tiny effect on inflammation — with the idea that we need to find better targets on inflammation. 

So there are a lot of unanswered questions coming out of that study. But it’s negative. It was a very successful study in testing the hypothesis, and the hypothesis was: semaglutide is not useful to treat Alzheimer’s.

Kan: There’s a lot in the pipeline for drug discovery. Is there one particular drug that you’re keeping an eye on?

Sabbagh: I’m biased. We reported our first report of a lenalidomide, the cancer drug repurposed for Alzheimer’s disease. We are the first to show that the null hypothesis was not met in a phase 1b, and that we were able to manage safety in a patient population. We were able to give patients who don’t have cancer a cancer drug. So that whole idea of using cancer drugs repurposed for Alzheimer’s — we were the first proponents of it. There are like six of them now tested. So I’m excited to see that through.

Kan: Why cancer drugs? What does that have to do with that?

Sabbagh: So cancer drugs have particular appeal because we already tried the anti-inflammatories. Every anti-inflammatory you’ve ever heard of was tried for treatment or prevention, so that’s done. So that’s problem one. 

Problem two is we understand inflammation in the brain of people with Alzheimer’s disease. But the concept is you can’t use an NSAID (nonsteroidal anti-inflammatory drug), you have an inflammatory process. It turns out that cancer small molecules, they get into the brain, they can target inflammation.

And I’m also wanting to see the autophagy story develop, and I think the drugs have some movement, but could be a lot more movement in the autophagy program.