The Breakthrough Blood Test for Alzheimer's Disease

The p-Tau217 Biomarker for Prediction and Prevention

In the Alzheimer’s brain tissue, Amyloid plaque in brown, Tau tangles in blue

Back in 2020, a major milestone of progress emerged: a very accurate biomarker in the plasma —p-Tau217—for tracking brain neuropathology, without the need for cerebrospinal fluid (CSF, requiring a lumbar puncture) or a PET scan. This was from the pioneering work of Oskar Hansson and colleagues from the University of Lund in Sweden, demonstrating in multiple cohorts how this biomarker discriminated Alzheimer’s disease (AD) from other neurodegenerative diseases (non-AD). As Hansson summed up: “The p-tau217 predicted with nearly 100% certainty whether or not the trial participants had Alzheimer’s disease pathology in their brains.”

Since that discovery of a blood biomarker for Alzheimer’s disease, there has been remarkable further advances, including the availability of the test over the past year at a cost of approximately $200. In this edition of Ground Truths, I’ll go through the key questions as follows:

1. What is p-Tau217 measuring?

   How does it compare with other phosphorylated Tau proteins, CSF and PET scans?

2. How can we predict AD over 20 years in advance?

3. What can be done to lower p-Tau 217?

4. Where is this field headed?

1. What is p-Tau217 measuring and how does it compare with other tests?

The Tau protein is essential for neuron function (via stabilizing microtubules) but with damage it can undergo excessive phosphorylation at over 80 sites, one of which is at threonine (T) 217 in the proline rich domain (Figure). The hyperphosphorylation disrupts Tau’s function, the basis for forming neurofibrillary tangles, a precursor to Alzheimer’s disease.

The Figure below shows how the aggregation of these 2 proteins, amyloid β peptide (Aβ) and Tau, give rise to different types of plaque in the brain that ultimately lead to Alzheimer’s.

There have been comparisons to many other phosphorylated Tau proteins, but p-Tau217 consistently outperforms the others as shown below for accuracy and specificity in predicting Alzheimer’s disease.

Surprisingly, it is as good or superior to cerebrospinal fluid tests (CSF, Figure below) and as accurate as tau-PET scans in people who are cognitively unimpaired (lower Figure below). It can even be used to stage the disease in lieu of tau PET scans and changes in pTau-217 occur earlier than abnormal findings on a PET scan.

Ironically, even though p-Tau217 is directly connected to Tau, it appears to be tracking the build up of amyloid plaques in the brain very closely. It is apparently capturing the overall neurodegenerative process rather than being indexed only to Tau. As you will see below, it also is the earliest biomarker detection of risk, well over 20 years in advance.

2. How can p-Tau217 predict AD over 20 years in advance?

First it’s important to recognize that the process for developing Alzheimer’s disease is extremely slow and long, with 15-20 years before there is the onset of mild cognitive impairment (MCI), which precedes AD by a number of years (Figure).

The first biomarker to show up is p-Tau217 in the plasma or cerebrospinal fluid, more than 20 years before symptom onset.

Below is the graph for dominantly inherited Alzheimer’s disease, which you can see is quite similar to the one above for the >20 year lead time from abnormality of p-Tau217 and before other markers. (EYO-estimated year of onset)

In the 2020 longitudinal study paper by Oskar Hansson and colleagues you can see how p-Tau217 increased over time in clinically unimpaired (CU) individuals that progressed to Alzheimer’s disease, with no or very little increase in those who did not over a 6 year period (MCI-mild cognitive impairment). Multiple studies have shown that p-Tau217 can predict the onset of Alzheimer’s in CU individuals within a specific time frame, such as four years, with high accuracy.

3. What Can Be Done to Lower p-Tau217?

A major new finding is that p-Tau217 is dynamic and responds to interventions, such as treatment to reduce the burden of amyloid or exercise. This further extends to utility of the biomarker from accuracy, prognosis, and differential diagnosis to treatment response (Figure)

Below are 2 studies to show reduction with exercise, one with p-Tau217 and the other with p-Tau181, which correlates closely with p-Tau217. p-Tau217 is now being used for clinical trials of new drugs to prevent Alzheimer’s disease.

This past week at the annual American Academy of Neurology meeting in San Diego results of a study of 54 participants who had brain biomarkers assessed and were given lifestyle improvement recommendations and compared with 17 individuals in a control group. The intervention group had substantial improvement in p-Tau217 and other biomarkers (from the presentation, peer review pending). One of the participants in the intervention group was profiled and summarized below.

The very close correlation of p-Tau217 with cognitive impairment over time. That suggests that reduction in levels will slow the natural history of progression. These findings suggest that beyond exercise other lifestyle factors and drugs have the potential to change the course—to delay the onset or prevent MCI or Alzheimer’s disease.

This has led to a new vision for how p-Tau217 will be used in the future, such as by Randall Batemen, a leading neurology researcher at WashU Medicine. As we now routinely check LDL cholesterol levels and prescribe statins and lifestyle modifications when needed, will we use p-Tau217 to guide people for lowering their future risk of Alzheimer’s disease?

“It’ll be just like going to get your blood cholesterol checked and then being given statins if levels are too high.” —Randall Bateman, MD

4. Where is the field headed?

There are many other blood biomarkers for MCI and Alzheimer’s disease that are being reported and studied, including many other phosphorylated-Tau proteins (such as Ser262, Ser356, pictured below, conceivably earlier detection than p-Tau217), microtubule-binding region containing residue 243 MTBR-tau243, glial fibrillary acidic protein (GFAP),neurofilament light chain (NfL),any many other plasma proteins (such as GDF15 , LTBP2). Their potential complementarity or superiority has yet to be firmly established and unlike p-Tau217 they are not commercially available. There are some limitations of p-Tau217, such as it begins to go lower at the late stage of the disease, and it may not be as useful in people age 80 plus.

Suffice is to say the p-Tau217 breakthrough has stimulated much work in the field to find other highly informative blood brain biomarkers for predicting and preventing the disease.

Unfortunately, the Alzheimer’s Association has advocated for broad screening with p-Tau217. This has engendered considerable controversy, because, among other issues, it proposes labelling people with an elevated p-Tau217 as Stage 1 Alzheimer’s disease. As far as I’m concerned, this is not the right path forward. As I wrote in my new book Super Agers (brief excerpt below).

Concluding Remarks

The p-Tau217 biomarker is one of the most exciting advances in neurology for decades, giving us a new opportunity to accurately predict and potentially prevent (or at least substantially delay) MCI and Alzheimer’s. That it rises so early in the course of the disease—which incubates over 20 years—gives us a long runway of opportunity to intervene, be it with lifestyle factors or drugs. I now refer to the former as lifestyle plus because it is no longer just about the details of diet, exercise and sleep. There are several other dimensions of modifiable factors.

An APOE4 allele or a polygenic risk score for Alzheimer’s tests are binary. They only tell us if a person has increased risk (yes or no) but not when . It makes a huge difference if that at age 98 or 68. With serial assessment of p-Tau217 (several months or years apart) as part of a comprehensive assessment using multimodal A.I., it is very likely that the temporal plot (see Figures under Question 2 above) can be defined at the individual level. I lay out the blueprint for this and lifestyle plus fully in Super Agers. Individuals with elevated p-Tau217 at high-risk many years before the onset of any symptoms creates a new path for surveillance and prevention. Multiple new drugs are in the pipeline to be part of a prevention program.

Even though it intuitively appears to be the case, more work needs to be done to determine whether lowering one’s p-Tau217 will alter the brain plaque progression and be seen as a disease-modifier. Clearly there is now a hunt for even better blood tests that may one day supersede p-Tau217 or be in a panel with it.

There’s the big question of who should get a pTau-217 test. I don’t think these biomarkers are going to be useful in people at low risk. However, with many layers of data for a person that include family history, genomics, proteomic brain clocks (previously reviewed in Ground Truths), and more, we are in a unique position to identify people who are at high-risk and for whom the test may have considerable value, fulfilling the need for a high pre-test probability and its potential usefulness. Of course, like APOE4 and other tests for Alzheimer’s risk, these all have to be considered optional, since many people have no interest in knowing such risk.

In contrast, for many getting Alzheimer’s disease is their worst fear. If there’s a way to markedly delay or prevent this dreaded condition it would be a momentous step forward. For the first time, we may be on the cusp of realizing that goal. That would be fulfilling the dream of primary prevention of such a devastating age-related disease, which wasn’t previously considered to be possible.

A Quick Poll

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As you can imagine, I’m excited to get my new book out. I've worked with my publisher, Simon & Schuster, to share an exclusive offer just for Ground Truths subscribers. Through May 5, you can pre-order a hardcover copy of the book at Bookshop.org and get 15% off with code SUPERAGERS15. It’s notable that Bookshop.org supports independent bookstores across the country. Of course there’s also Amazon which currently offers a discount on the book, but it’s certainly not helping these bookstores.

In this post, I’ve only scratched the surface about the content of the book. Here’s the back cover to give you an idea of what some people had to say about it.

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