Finally, a Blood Test for Alzheimer’s?

A promising advance-but not for healthy brains (yet).

TL;DR: A less invasive test for Alzheimer’s is a big advance. But it’s not perfect, and is not meant to screen healthy people.

The US FDA recently approved a new blood test to diagnose Alzheimer’s disease.

The test, called Lumipulse, measures two proteins in plasma: pTau217 and ß-Amyloid 1-42. These proteins clump together to form plaques in the brains of people with Alzheimer’s. The ratio of these two proteins in blood is highly correlated with the presence or absence of amyloid plaques in the brain, an important signature of Alzheimer’s.

FDA approval means the test meets federal standards for safety and effectiveness, and it can now be used in certified clinical laboratories to help assess Alzheimer’s disease.

Tau tangles (orange) inside a brain cell (neuron) and amyloid plaques (blue) in the surrounding area. Source: Brightfocus.org

A Blood Test: Easier than a Spinal Tap

This is a big step forward because, until now, diagnosing Alzheimer’s typically required more invasive and expensive tests. For a long time, Alzheimer’s could only be definitively diagnosed postmortem via autopsy, when plaques could be seen directly in brain tissue. Advances in the last two decades have enabled earlier and more accurate diagnosis.

• PET (positron emission tomography) scans inject radioactive tracers into people to better image plaques and tangles inside the brain (you can imagine the downside of that).

• Tests of cerebrospinal fluid (CSF) require lumbar puncture (also known as a spinal tap) with a big needle in the lower back.

Not surprisingly, the expense and availability of these tests have limited their use.

Not that Spinal Tap…but if know this reference you might be worried about cognitive decline.

How well does the new blood test work?

Overall, the test performs well—for people who already show signs of the disease. No test is perfect, and the balance between false positives and false negatives often determines how useful a test really is.

According to the FDA press release, the approval was based on a study in which 91.7% of people who tested positive on the blood test also had amyloid plaques confirmed via PET scan or CSF test. That figure represents the positive predictive value (PPV): the probability that someone with a positive test actually has the disease.

Also important is the negative predictive value (NPV)—the probability that someone with a negative test result truly does not have Alzheimer’s. In this study, 97.3% of people with a negative blood test were also negative for amyloid plaques by the gold-standard methods. This means we wouldn’t be missing a lot of people who have the disease and giving them a false sense of security or losing the opportunity for treatment.

To avoid misclassification, the test uses a “two-threshold” approach, meaning some people fall into an “indeterminate” result zone. According to the FDA, “fewer than 20%” of the 499 patients tested received this indeterminate result, but the details are still sparse, so this is something we will want to know more about.

These predictive values are closely tied to a test’s sensitivity and specificity. Sensitivity refers to the probability of correctly identifying people who have the disease (true positives), and specificity is the probability of correctly identifying those who don’t (true negatives). While the FDA didn’t release exact numbers, based on the PPV, NPV, and previous studies of this blood-based marker, we can reasonably assume sensitivity and specificity are both high—likely above 90%.

Can I take the test to look for early signs of Alzheimer’s?

Right now, the test is only approved for people aged 55 and older who already show signs of cognitive impairment—and not the kind we all think we have with age, but impairment that shows up on validated cognitive tests. It’s not recommended for “cognitively unimpaired” people.

One reason is that diagnostic tests don’t perform as well in populations where the disease is rare. This is because the prevalence of a disease (how common it is in the group being tested) interacts with sensitivity and specificity to determine the positive predictive value (PPV).

For example, a test with 92% sensitivity used in a group where half the people have Alzheimer’s would yield a PPV of about 92%—a good number. That means only 8% of those with a positive test don’t actually have the disease. Intuitively, since a pretty large fraction of the group truly has the disease, a positive test is less likely to be a “false” positive.

But if you test a population where Alzheimer’s prevalence is just 5%, the PPV drops dramatically (you can play with a calculator here). In that scenario, the test would only correctly identify 38% of positives—meaning 62% of positive results would be false alarms. That’s a lot of people unnecessarily worried and potentially subjected to more invasive follow-up, especially about something as scary as Alzheimer’s disease.

That said, people with a strong family history or genetic predisposition may have baseline higher prevalence as a subgroup. In theory, this would improve test accuracy for them, and blood tests like this may one day be used for earlier screening in those high-risk groups. But we’re not quite there yet.

Photo by Kelly Sikkema on Unsplash

So how can the tests be used now?

• More accessible diagnosis for those who may benefit from treatment.
  Two new drugs—lecanemab and donanemab—target amyloid-beta buildup and have shown modest slowing of cognitive decline (but are not without controversy). More people with current symptoms who might benefit from these treatments will be able to be tested. This means testing will happen first within specialist dementia care, but may eventually expand to primary care.

• Better screening and measurement for research trials.
  PET scans are expensive and impractical for large-scale clinical trial recruitment. A reliable blood test changes the game, enabling faster, cheaper screening to identify eligible participants. Blood biomarkers can also serve as endpoints to monitor disease progression, making research trials more efficient. This will make testing new interventions a lot easier (yay science)!

The Alzheimer’s Association is leading the development of evidence-based recommendations for specialists to help guide them through the decision-making process around who should be tested with these new blood tests and when. They plan to share the guidelines this summer at the Alzheimer’s Association International Conference. Until then, the Association refers providers to the 2022 recommendations for blood tests in clinical practice and trial settings.

BOTTOM LINE: Alzheimer’s science is progressing.

The new Alzheimer’s blood test is good news overall, marking the beginning of a new era of easier diagnosis and hopefully testing of interventions and disease progression. As someone with a family history, I am watching this space carefully.

The test is currently NOT meant for early diagnoses in healthy people who are not cognitively impaired. Even if you tried to get one, a positive test would be more likely to be a false alarm than a real diagnosis. The science is progressing however, and it’s possible similar blood tests could be used for earlier screening and prevention in the future. Stay tuned!

Stay well,

Jenn

Additional links:

What to Know About the First FDA-Cleared Blood Test for Alzheimer’s Disease