You may have read recently about a new, more accurate test for identifying people with Alzheimer’s disease (AD). Finding a reliable marker of the disease has long been a goal of researchers. The ability to confirm diagnosis would help improve research of all kinds, but especially drug trials, because there would be more certainty that participants in the trials had Alzheimer’s and not another form of dementia. An early marker of AD would also be enormously helpful for designing prevention studies. We know, however, that many stories about Alzheimer’s disease in the media exaggerate or misinterpret the findings of studies. So we decided to take a look at the article about the new diagnostic tool, which has been published on-line in JAMA.
The paper reports on findings from three studies of people with and without Alzheimer’s. The goal of the three studies was to test how well a marker found in blood samples, P-tau217, distinguished between people with a confirmed diagnosis of Alzheimer’s disease and people without the disease. Tau, as you may know, is a protein normally found in nerve cells that can become twisted, forming one of the primary markers of Alzheimer’s disease, neurofibrillary tangles. P-tau217 is a marker of those abnormal cells.
Study 1 consisted of people with and without dementia who had volunteered to be followed over time until their death. Plasma samples of P-tau217 were obtained prior to death and compared with postmortem findings in the brain as well as with prior diagnosis.
Study 2 was part of a large Swedish study that was following people with Alzheimer’s Disease and other neuropathological disorders and well as persons without dementia. Amounts of P-tau217 were compared to other markers of the disease as well as to diagnosis.
Study 3 used a sample from an ongoing study in communities in Colombia, where many people have an autosomal dominant gene for Alzheimer’s disease that leads to the disease at early ages, typically when carriers of the gene are in their 40s. Blood samples were obtained from people with and without the gene who were part of the study.
What did they find?
Across the three studies, P-tau217 from blood and plasma differentiated between cases of Alzheimer’s disease and non-disease subjects better than or as well as other markers, including findings from PET and MRI scans and samples of P-tau217 from cerebral spinal fluid. P-tau217 was highly correlated with the amount of tau (tau density) found in the brain at autopsy in Study 1 and with estimates of tau in the brain from PET scans in the other two samples. In Study 3, people with the dominant gene for Alzheimer’s disease began showing increased P-tau217 in their mid-20s, or about 20 years before symptoms typically occur.
What are the implications?
The main take away from the study is that P-tau217 is a reliable marker of Alzheimer’s disease and of one of the main pathologies in AD, neurofibrillary tangles. The blood test for P-tau217 is easier to administer and less painful than tests using cerebral spinal fluid, and more readily available and less expensive than PET scans, but just as accurate for determining diagnosis as either of the other methods.
But does P-tau217 predict Alzheimer’s among people who are not symptomatic? Here the media loudly proclaimed that P-tau217 could detect AD up to 20 years prior to symptoms. This was based on the finding that people in their 20s in the Colombia sample who carried to dominant gene for AD and could expect to become symptomatic in their 40s had elevated levels of P-tau217. It remains to be determined higher levels of P-tau217 are found years before onset of symptoms only in certain genetic variants of the disease, or if they can be detected early across most or all cases of AD. That’s a big “if.”
Is P-tau217 ready for widespread use for diagnosis?
No. There are two hurdles that are by no means easy to overcome. First, there needs to be a reliable cut-off score, that is, how much P-tau217 indicates a disease process. The cut-off used in this research worked well in differentiating people already characterized as having AD from controls without the disease, but whether that score would work as well in community samples where people may have early symptoms remains to be seen. Every effort to push diagnosis earlier in the disease process runs the risk of increasing false positive diagnoses.
The second hurdle is how far ahead can P-tau217 reliably predict AD. P-tau217 may predict in a sample with a strong genetic determinant, where we know that people holding the gene will develop the disease, but may not do as well as a predictor for other forms of the disease. Studies to determine how far ahead a P-tau217 score might predict symptoms would take considerable time to conduct—doing the test today and waiting a few years or more to find out who gets the disease and who does not.
Do you want to know your risk for Alzheimer’s?
This is, of course, the key question. Would you want to know? One reason to consider the test is if one of the rare, dominant gene forms of AD runs in your family. In that case, getting a genetic test would be more definitive than the P-tau217. For cases that occur in later life, 60+, the APO E4 allele has been linked to AD. The APO E4 is not a dominant gene so having one copy of it does not mean you will get AD, and even having two copies may not result in AD. Genetic tests can identify if you have one or two copies of the APO E4 allele.
The other reason to consider the P-tau217 test is if you think you are having symptoms. Having occasional memory lapses is not reliably a symptom of AD. Everyone forgets. But if memory and other cognitive abilities seem to worsen, then the P-tau217 test could help clarify what is behind the cognitive problems.
But the question still remains – would you want to know? If you tested positive for a gene associated with AD or for P-tau217, what would you do differently? What changes would you make in your life?
Growing older has been described by our friend Bo Malmberg as “sooner or later.” Sooner or later, something bad will happen. The implication is to live a full life now.
Reference: Palmqvist, S., et al. (2020). Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA, doi:10.1001/jama.2020.12134 (published on-line with free access).
No comments:
Post a Comment