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Name:
Front Row - Dr. Zetterberg
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Front Row - Dr. Zetterberg
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Language: EN.
Segment:0 .
[MUSIC PLAYING]
MALORYE BRANCA: Thank you so much for joining us. And this is such an important topic. Now, in terms of activity and drug development, biomarker development science, what do you think are the things that will propel us forward and-- mainly in terms of biomarkers.
HENRIK ZETTERBERG: Thank you very much for this important question. It has been such an exciting time in Alzheimer research lately. We have been able to detect and monitor Alzheimer's disease pathology in the brain for 10, 15 years now using imaging and cerebrospinal fluid tests. But during the past five years, we have now seen blood tests being developed. And these we can start to use now, in both population-based studies and also in clinical practice, to detect brain changes in Alzheimer's disease.
HENRIK ZETTERBERG: And by doing so, we have learned that brain changes appear 15 to 20 years before you are demented from the disease. And this gives us an opportunity, a window of opportunity, to save neurons. So I think this would be an important thing we will see during the coming years, that we detect Alzheimer's pathology. We can initiate treatments and thereby save neurons.
MALORYE BRANCA: But what has been the challenge with blood biomarkers? Why has it taken so long?
HENRIK ZETTERBERG: Yeah, it's such a low-- the concentrations we are trying to measure are so low, and that is the main reason. We have the blood-brain barrier, which sort of protects the brain from the body and from also other-- I mean, if you have bacteria in the eye or something else, you have the blood-brain barrier protecting the brain. But it also makes brain-derived molecules being released to the blood at very low concentrations.
HENRIK ZETTERBERG: But these analytical methods that we have developed, they now allow us to measure in the subfemtomolar range. And it's sometimes hard to understand what that really is, but it's like if you had a fragment of a sugar cube and put it in an Olympic swimming pool. That is the concentration we are talking about.
MALORYE BRANCA: But has the science of Alzheimer's-- has our understanding of what causes Alzheimer's changed in order to allow this to happen, or is this just a development that has driven on the past knowledge?
HENRIK ZETTERBERG: Yup, it's a combination, I would say. So we know that the brain changes in Alzheimer's disease are amyloid plaques that deposit in the brain tissue and sort of spread in the brain. Amyloid plaques are surrounded by activated microglia and astrocytes, cells that are trying to protect the neurons from the amyloid plaques. And then we have the neurons themselves, where amyloid is inducing tau phosphorylation, which makes the axons, the neuronal extensions, fall apart, basically.
HENRIK ZETTERBERG: So the idea that amyloid is the core pathological change, that has been suspected from genetic and biochemical studies. And this view has been reinforced by the biomarker findings. So the first change we can detect in humans at risk of Alzheimer's disease is amyloid deposition, using plasma Abeta 42/40 ratio as the main biomarker.
HENRIK ZETTERBERG: And that is followed by tau phosphorylation. And then eventually, you get neurodegeneration. And for all of these pathological processes, we now have biomarkers, and they actually-- now, they also work in blood.
MALORYE BRANCA: But have they-- why have they not worked before? What has changed that is now making them useful?
HENRIK ZETTERBERG: Yeah, basically, it's technological advancements making it possible to measure them at low concentrations. This has been a stepwise change that has happened over the years. We started out with developing sensitive lasers where we could measure, for example, beta amyloid at concentrations of around 50 to 100 picogram per milliliter. Then we had Meso Scale Discovery and electrochemical luminescence methods, making the assays 10 times more sensitive that we could measure, still in cerebrospinal fluid but not in blood.
HENRIK ZETTERBERG: Then we have developed digital lasers that are sensitive. And suddenly, we could just start to measure these molecules.
MALORYE BRANCA: Can you tell us a little bit about these technologies and why they are so special?
HENRIK ZETTERBERG: Yeah, they are not special by any means. They are standard technologies where we measure proteins using antibodies to capture them and detect them. Basically, these are sandwich ELISAs, Enzyme-Linked Immunosorbent Assays. But now, we do this on magnetic beads. So we capture beta amyloid, or phospho-tau, or total tau, and neurofilament light, or the other key molecules on magnetic beads that we incubate together with the sample.
HENRIK ZETTERBERG: And then these magnetic beads with very specific antibodies, high affinity antibodies, they sort of take out all of the analyte and bind the analyte to the magnetic beads. And then we pull down these magnetic beads into microwells, which are tiny, tiny wells. And then we add the detector antibody that is labeled with an enzyme that can cause a fluorescent signal. And the microbeads into these small wells will then be-- then you can monitor the emission of fluorescence in these tiny wells.
HENRIK ZETTERBERG: And this digitalization or compartmentalization of the detection reaction, that is the trick. That is what has made these assays super sensitive. So we can count molecules. If we dilute the sample so that most of these microbeads are negative for fluorescence, then we can state that the microbeads that have-- that emit light, they contain one molecule. So most of the--
MALORYE BRANCA: Goodness.
HENRIK ZETTERBERG: It's quite cool, actually. So this was really the transformative step here, I think.
MALORYE BRANCA: Biologically, what does this mean?
HENRIK ZETTERBERG: We now know, through the blood biomarker work-- or have reinforced the sequence of-- our knowledge on the sequence of events in Alzheimer's disease. So Alzheimer's disease starts when you are 50, 55, 60, by deposition of amyloid in the brain. That is reflected in the plasma by a reduced Abeta 42/40 ratio. In CSF, this is really a bimodal biomarker change. So you can detect people switching from being non-depositors to becoming amyloid depositors, and it takes one or two years for people to start to do that.
HENRIK ZETTERBERG: And that is also seen in plasma, but it's clearer in the CSF, because in plasma, you also have peripheral beta amyloid, which is produced by blood platelets, and myocytes, and cells not affected by the pathology. So we now know how to detect the onset of amyloid aggregation. And then we have, in longitudinal cohort studies, been able to see that when amyloid starts to change the blood, a few years later, 5 to 10 years later, phospho-tau levels start to increase.
HENRIK ZETTERBERG: And then eventually, you will have a neurofilament light increase as a neurodegeneration sign, and that coincides with onset of symptoms. But they all predict the dementia phase. So we hope that this will be very useful in clinical practice, because if you know that you have Alzheimer's running in the family, or if you're worried about your cognition, you could go and check these blood levels.
HENRIK ZETTERBERG: And then if they start to change, one could hopefully initiate treatment with the new amyloid antibodies or with some of the other drugs that are in development.
MALORYE BRANCA: So what does the influence of hereditary have to do with this? I mean, is it a strong influence, or is it just something you pay attention to?
HENRIK ZETTERBERG: It's a relatively strong influence. If you have older parents with Alzheimer's, you are at increased risk of getting Alzheimer's as you age. But it's not black and white. It's an increased risk, and one should pay attention to it a little bit. But it's not-- you can also have-- I mean, it's not like a dominant trait. Then there are the mutations causing autosomal-dominant Alzheimer's disease, but that is known in these families, because then you see 50% getting ill in every generation.
HENRIK ZETTERBERG: And the disease comes earlier, much earlier often, so between 35, 40, 50 years of age. The major susceptibility gene for sporadic Alzheimer's disease, the common Alzheimer's whom we are-- many of us know people with is the APOE epsilon 4 allele that 15% to 20% of us carry. And if you have one allele, you get the Alzheimer's 10 years earlier. And if you have two alleles, you get Alzheimer's 20 years earlier, with a confidence interval, of course.
HENRIK ZETTERBERG: It's--
MALORYE BRANCA: Is any of this leading to actual tests that will be used in the clinic?
HENRIK ZETTERBERG: Yeah. I mean, you can already now get to know your APOE genotype, for example, through the commercial companies doing this business. But I think it's ethically questionable at the moment. The blood tests are available in our lab and in some labs in the US. There is-- so you can request plasma Abeta 42/40 ratio on patients now, and you can also do plasma neurofilament light.
HENRIK ZETTERBERG: Plasma phospho-tau, which is my favorite biomarker at the moment, giving us the most information on Alzheimer's, I think that's phospho-tau. And then, there is currently no laboratory doing this in clinical chemistry practice, but it's happening. We are having a project here in Gothenburg where we will set up this method during the autumn. Everything is in place to do this. There are several methods that can measure phosphorylated tau forms.
HENRIK ZETTERBERG: They correlate well with each other. As a biomarker community, we have compared different assays. And I would say it's ready to go. It's possible to do this now.
MALORYE BRANCA: Ready to go? That sounds like it's--
HENRIK ZETTERBERG: Yeah.
MALORYE BRANCA: --already headed to the clinic. Is that correct?
HENRIK ZETTERBERG: Yup, that is pretty much correct. So it's--
MALORYE BRANCA: Does that have any impact on drug discovery?
HENRIK ZETTERBERG: Yup, that's a good question. We hope it will have an impact on how you-- how rapidly you can determine if a drug is effective or not. And we also hope it will make the clinical trials less expensive and perhaps faster, because one could think about using these blood tests to screen for people who are very likely to have Alzheimer's and not wait until you have done an amyloid PET scan or a tau PET scan. Those are very expensive, and if you get negative results, that's a waste of money, basically.
HENRIK ZETTERBERG: If you start by screening a population you would like to include in a clinical trial, if you know that you want to include people who are amyloid positive, screening in people who are positive with plasma phospho-tau will increase the likelihood for the patient to be amyloid positive and perhaps also have some tau changes. And then those patients could be enrolled more quickly. If the drug is effective, the plasma phospho-tau levels are likely to go down, and that could happen in three to six months.
MALORYE BRANCA: But what is the diagnostic gold standard right now?
HENRIK ZETTERBERG: The diagnostic gold standard right now I would say is amyloid PET or CSF Abeta 42/40 ratio. These are the two methods which you, with very high diagnostic accuracy, can determine if a patient does have or does not have amyloid pathology. And these have been validated against neuropathology, and we know that these tests work really well. Now, we are then trying to use the blood tests to become as good as these reference tests, sort of.
HENRIK ZETTERBERG: And some of the plasma phospho forms look like they can really do a good job on this, almost replacing these more expensive examinations.
MALORYE BRANCA: Do you imagine that people will quickly adopt the blood biomarkers, or will they use them in concert with other tests?
HENRIK ZETTERBERG: I think they will be used in concert with other tests, as many clinical chemistry tests are used. And it will be super important to keep a nice clinical-- you still have to do a very good clinical workup. And you have to consider all aspects of the patient's symptoms. And you also have to be very careful as a clinician not to label anyone with Alzheimer's on the basis of a single biochemical test result.
HENRIK ZETTERBERG: So if-- I think this would be another tool, yet another tool, to determine the likely diagnosis of a patient. If you find out that the patient is likely to have Alzheimer's pathology, then you still have to link this pathology to the person-- to the symptoms that the patient presents. Because it might be that you have a patient who has depression, cognitive problems because of the depression.
HENRIK ZETTERBERG: And then with the biomarker tests, you also find out that there is some Alzheimer's pathology. But this could well be preclinical Alzheimer's pathology that would give the patient symptoms in 10 or 15 years time. Perhaps these pathological changes are not what is causing the symptoms now. So you will still have to be a very careful clinician and make a diagnosis taking all aspects of the clinical presentation of the symptoms into account.
MALORYE BRANCA: What about overlap with other dementias?
HENRIK ZETTERBERG: That's an excellent question also, because the biomarkers do not solve that issue, basically. So we have then good positive biomarkers for Alzheimer's pathology, amyloid tau and neurodegeneration. But, I mean, there are 50 other diseases that can cause dementia, the most common of which is cerebrovascular disease and perhaps also comorbid Alzheimer's and cerebrovascular disease. Then you have frontotemporal dementia, dementia with Lewy bodies, Parkinson's disease dementia.
HENRIK ZETTERBERG: And for those, we need to have other biomarkers. For Lewy body dementia and Parkinson's disease dementia, there is now a possibility of detecting the pathognomonic alpha-synuclein inclusions with the cerebrospinal fluid tests. Those are starting to enter clinical practice, but they have not been validated yet. For frontotemporal dementia, we can detect the neurodegeneration with neurofilament light, but we do not have any positive biomarkers to detect the underlying cause of FTD.
HENRIK ZETTERBERG: So here, we have to continue to work on better biomarkers.
MALORYE BRANCA: Excellent. And where do you see this going forward now? What do you think are the next steps?
HENRIK ZETTERBERG: Yeah, I think that what we will see now is clinical implementation of the blood tests, and that will go quite fast, I think. We already now know that the amyloid tests have been approved for use in the US. We use neurofilament light in Europe and in some American labs also to detect neurodegeneration. The phospho-tau markers, I'm sure, will become clinically available also in the next few years. We still have to develop a better understanding on how the biomarkers perform in multi-ethnic populations and in patients with comorbidities, morbidities of different kinds, more heterogeneous study cohorts than we might have examined the biomarkers in.
HENRIK ZETTERBERG: I mean, we have, for example, seen other results, and we have seen cohort studies that are quite homogeneous. But in more-- in clinical settings where there might be people who come in with a lot of different somatic and psychiatric issues, then we have to make sure that the biomarkers work there as well. But I think that will also happen during the next few years, through all the different initiatives that are ongoing, both in the US and Europe and in Asia.
HENRIK ZETTERBERG: So--
MALORYE BRANCA: What are some of those initiatives? What are the biggest ones that you're looking-- you're watching.
HENRIK ZETTERBERG: Yeah, the ADRCs, the Alzheimer's Disease Research Centers, in the US are making big, big efforts now to collect and analyze blood samples, to determine how well they work in the clinical setting where the patients are. And there, we will see validation studies on their diagnostic performance in more heterogeneous populations, and this is extremely important. I am hopeful that this will work out quite well in most settings.
MALORYE BRANCA: Just to take a step back, can you explain how the biomarkers relate to the biology and the development of the disease?
HENRIK ZETTERBERG: Yup. So, in Alzheimer's disease, the first thing that happens in the brain is the deposition of amyloid in the brain tissue. And this is a special form of amyloid. Amyloids are aggregation from proteins where the longer forms are more aggregation than the shorter forms. So Abeta 42, the 42 amino acid long form of beta-amyloid, is prone to deposition in the brain tissue.
HENRIK ZETTERBERG: And if you take Abeta 42 concentration and divide it by Abeta 40, which is the most water-soluble form, then you have a nice test for amyloid deposition. You get a selective depletion of Abeta 42 into the brain tissue and a lowering of the ratio. This is something that we have been able to do in cerebrospinal fluid over 20 years. But now, since five years, approximately, we have plasma tests that detect this onset of amyloid degradation.
HENRIK ZETTERBERG: This starts when you are 50, 55, 60, if you are to get Alzheimer's when you're 70, 75, 80. A few years later, you get tau phosphorylation, and that's really also an amyloid-instigated process. And then this tau phosphorylation is followed by neurodegeneration, which can be measured by neurofilament light in both CSF and blood. So we have biomarkers for amyloid, biomarkers for tau phosphorylation and tangle formation and then neurodegeneration in the form of neurofilament light.
HENRIK ZETTERBERG: So these three biomarkers have really-- they really form the core blood biomarkers for Alzheimer's disease-related processes, amyloid, tau, neurodegeneration.
MALORYE BRANCA: How confident are you in these biomarkers?
HENRIK ZETTERBERG: Yup, it's-- the amyloid test in blood is a little bit difficult, because there is such a small change when amyloid starts to deposit in the brain. There is a 15% reduction in the ratio, and that is-- that you can actually compare to what happens in cerebrospinal fluid. But there is a 50% reduction. And that is because in CSF, there are no other amyloids that are not related to the brain tissue.
HENRIK ZETTERBERG: In blood, there are amyloids from blood platelets, and myocytes, and some other cell types not affected by Alzheimer's disease. And that is a bit of a problem. We have repeatedly started seeing that the reduction is reproducible, but to be able, in clinical laboratory practice, to week by week have assays that are so stable that you can detect this type of relatively small percentage reduction, that is a challenge.
HENRIK ZETTERBERG: And there, I think we will still see really strong results that will make it important to do a CSF analysis or an amyloid PET scan on those patients. So we will see patients where we can't tell on the basis of blood if there is or is not amyloid in the brain. Phospho-tau happens in close association-- phospho-tau increase happens in close association with amyloid onset.
HENRIK ZETTERBERG: So then, one could instead also look at phospho-tau as an amyloid marker, almost. So when neurons are affected by amyloid, they secrete-- they will phosphorylate and secrete tau at a higher rate. So the phospho-tau increase could potentially replace the amyloid test in plasma a little bit, but they are not completely interchangeable. And the amyloid test is always a little bit earlier than the phospho-tau test.
MALORYE BRANCA: So is anyone using these tests now?
HENRIK ZETTERBERG: Yup, they are used more and more. You can order a plasma Abeta 42/40 ratio in the US from a private company, and they combine the information with the age of the patient and also a brief genotype and give you a likelihood ratio of amyloid positivity. And in Sweden, we have been using plasma neurofilament light for a couple of years now in clinical laboratory practice and are just about to start doing the phospho-tau tests. So it is happening now, I think.
HENRIK ZETTERBERG: And one important piece of work that will also happen now is that we will develop some kind of appropriate use criteria for these biomarkers so that we can help guide clinicians on what these biomarkers mean and what they do not mean also, because that's also important.
MALORYE BRANCA: Yes. Thank you again for your time, and we look forward to hearing from you again.
HENRIK ZETTERBERG: Thank you. [MUSIC PLAYING]
Segment:0 .
[MUSIC PLAYING]
MALORYE BRANCA: Thank you so much for joining us. And this is such an important topic. Now, in terms of activity and drug development, biomarker development science, what do you think are the things that will propel us forward and-- mainly in terms of biomarkers.
HENRIK ZETTERBERG: Thank you very much for this important question. It has been such an exciting time in Alzheimer research lately. We have been able to detect and monitor Alzheimer's disease pathology in the brain for 10, 15 years now using imaging and cerebrospinal fluid tests. But during the past five years, we have now seen blood tests being developed. And these we can start to use now, in both population-based studies and also in clinical practice, to detect brain changes in Alzheimer's disease.
HENRIK ZETTERBERG: And by doing so, we have learned that brain changes appear 15 to 20 years before you are demented from the disease. And this gives us an opportunity, a window of opportunity, to save neurons. So I think this would be an important thing we will see during the coming years, that we detect Alzheimer's pathology. We can initiate treatments and thereby save neurons.
MALORYE BRANCA: But what has been the challenge with blood biomarkers? Why has it taken so long?
HENRIK ZETTERBERG: Yeah, it's such a low-- the concentrations we are trying to measure are so low, and that is the main reason. We have the blood-brain barrier, which sort of protects the brain from the body and from also other-- I mean, if you have bacteria in the eye or something else, you have the blood-brain barrier protecting the brain. But it also makes brain-derived molecules being released to the blood at very low concentrations.
HENRIK ZETTERBERG: But these analytical methods that we have developed, they now allow us to measure in the subfemtomolar range. And it's sometimes hard to understand what that really is, but it's like if you had a fragment of a sugar cube and put it in an Olympic swimming pool. That is the concentration we are talking about.
MALORYE BRANCA: But has the science of Alzheimer's-- has our understanding of what causes Alzheimer's changed in order to allow this to happen, or is this just a development that has driven on the past knowledge?
HENRIK ZETTERBERG: Yup, it's a combination, I would say. So we know that the brain changes in Alzheimer's disease are amyloid plaques that deposit in the brain tissue and sort of spread in the brain. Amyloid plaques are surrounded by activated microglia and astrocytes, cells that are trying to protect the neurons from the amyloid plaques. And then we have the neurons themselves, where amyloid is inducing tau phosphorylation, which makes the axons, the neuronal extensions, fall apart, basically.
HENRIK ZETTERBERG: So the idea that amyloid is the core pathological change, that has been suspected from genetic and biochemical studies. And this view has been reinforced by the biomarker findings. So the first change we can detect in humans at risk of Alzheimer's disease is amyloid deposition, using plasma Abeta 42/40 ratio as the main biomarker.
HENRIK ZETTERBERG: And that is followed by tau phosphorylation. And then eventually, you get neurodegeneration. And for all of these pathological processes, we now have biomarkers, and they actually-- now, they also work in blood.
MALORYE BRANCA: But have they-- why have they not worked before? What has changed that is now making them useful?
HENRIK ZETTERBERG: Yeah, basically, it's technological advancements making it possible to measure them at low concentrations. This has been a stepwise change that has happened over the years. We started out with developing sensitive lasers where we could measure, for example, beta amyloid at concentrations of around 50 to 100 picogram per milliliter. Then we had Meso Scale Discovery and electrochemical luminescence methods, making the assays 10 times more sensitive that we could measure, still in cerebrospinal fluid but not in blood.
HENRIK ZETTERBERG: Then we have developed digital lasers that are sensitive. And suddenly, we could just start to measure these molecules.
MALORYE BRANCA: Can you tell us a little bit about these technologies and why they are so special?
HENRIK ZETTERBERG: Yeah, they are not special by any means. They are standard technologies where we measure proteins using antibodies to capture them and detect them. Basically, these are sandwich ELISAs, Enzyme-Linked Immunosorbent Assays. But now, we do this on magnetic beads. So we capture beta amyloid, or phospho-tau, or total tau, and neurofilament light, or the other key molecules on magnetic beads that we incubate together with the sample.
HENRIK ZETTERBERG: And then these magnetic beads with very specific antibodies, high affinity antibodies, they sort of take out all of the analyte and bind the analyte to the magnetic beads. And then we pull down these magnetic beads into microwells, which are tiny, tiny wells. And then we add the detector antibody that is labeled with an enzyme that can cause a fluorescent signal. And the microbeads into these small wells will then be-- then you can monitor the emission of fluorescence in these tiny wells.
HENRIK ZETTERBERG: And this digitalization or compartmentalization of the detection reaction, that is the trick. That is what has made these assays super sensitive. So we can count molecules. If we dilute the sample so that most of these microbeads are negative for fluorescence, then we can state that the microbeads that have-- that emit light, they contain one molecule. So most of the--
MALORYE BRANCA: Goodness.
HENRIK ZETTERBERG: It's quite cool, actually. So this was really the transformative step here, I think.
MALORYE BRANCA: Biologically, what does this mean?
HENRIK ZETTERBERG: We now know, through the blood biomarker work-- or have reinforced the sequence of-- our knowledge on the sequence of events in Alzheimer's disease. So Alzheimer's disease starts when you are 50, 55, 60, by deposition of amyloid in the brain. That is reflected in the plasma by a reduced Abeta 42/40 ratio. In CSF, this is really a bimodal biomarker change. So you can detect people switching from being non-depositors to becoming amyloid depositors, and it takes one or two years for people to start to do that.
HENRIK ZETTERBERG: And that is also seen in plasma, but it's clearer in the CSF, because in plasma, you also have peripheral beta amyloid, which is produced by blood platelets, and myocytes, and cells not affected by the pathology. So we now know how to detect the onset of amyloid aggregation. And then we have, in longitudinal cohort studies, been able to see that when amyloid starts to change the blood, a few years later, 5 to 10 years later, phospho-tau levels start to increase.
HENRIK ZETTERBERG: And then eventually, you will have a neurofilament light increase as a neurodegeneration sign, and that coincides with onset of symptoms. But they all predict the dementia phase. So we hope that this will be very useful in clinical practice, because if you know that you have Alzheimer's running in the family, or if you're worried about your cognition, you could go and check these blood levels.
HENRIK ZETTERBERG: And then if they start to change, one could hopefully initiate treatment with the new amyloid antibodies or with some of the other drugs that are in development.
MALORYE BRANCA: So what does the influence of hereditary have to do with this? I mean, is it a strong influence, or is it just something you pay attention to?
HENRIK ZETTERBERG: It's a relatively strong influence. If you have older parents with Alzheimer's, you are at increased risk of getting Alzheimer's as you age. But it's not black and white. It's an increased risk, and one should pay attention to it a little bit. But it's not-- you can also have-- I mean, it's not like a dominant trait. Then there are the mutations causing autosomal-dominant Alzheimer's disease, but that is known in these families, because then you see 50% getting ill in every generation.
HENRIK ZETTERBERG: And the disease comes earlier, much earlier often, so between 35, 40, 50 years of age. The major susceptibility gene for sporadic Alzheimer's disease, the common Alzheimer's whom we are-- many of us know people with is the APOE epsilon 4 allele that 15% to 20% of us carry. And if you have one allele, you get the Alzheimer's 10 years earlier. And if you have two alleles, you get Alzheimer's 20 years earlier, with a confidence interval, of course.
HENRIK ZETTERBERG: It's--
MALORYE BRANCA: Is any of this leading to actual tests that will be used in the clinic?
HENRIK ZETTERBERG: Yeah. I mean, you can already now get to know your APOE genotype, for example, through the commercial companies doing this business. But I think it's ethically questionable at the moment. The blood tests are available in our lab and in some labs in the US. There is-- so you can request plasma Abeta 42/40 ratio on patients now, and you can also do plasma neurofilament light.
HENRIK ZETTERBERG: Plasma phospho-tau, which is my favorite biomarker at the moment, giving us the most information on Alzheimer's, I think that's phospho-tau. And then, there is currently no laboratory doing this in clinical chemistry practice, but it's happening. We are having a project here in Gothenburg where we will set up this method during the autumn. Everything is in place to do this. There are several methods that can measure phosphorylated tau forms.
HENRIK ZETTERBERG: They correlate well with each other. As a biomarker community, we have compared different assays. And I would say it's ready to go. It's possible to do this now.
MALORYE BRANCA: Ready to go? That sounds like it's--
HENRIK ZETTERBERG: Yeah.
MALORYE BRANCA: --already headed to the clinic. Is that correct?
HENRIK ZETTERBERG: Yup, that is pretty much correct. So it's--
MALORYE BRANCA: Does that have any impact on drug discovery?
HENRIK ZETTERBERG: Yup, that's a good question. We hope it will have an impact on how you-- how rapidly you can determine if a drug is effective or not. And we also hope it will make the clinical trials less expensive and perhaps faster, because one could think about using these blood tests to screen for people who are very likely to have Alzheimer's and not wait until you have done an amyloid PET scan or a tau PET scan. Those are very expensive, and if you get negative results, that's a waste of money, basically.
HENRIK ZETTERBERG: If you start by screening a population you would like to include in a clinical trial, if you know that you want to include people who are amyloid positive, screening in people who are positive with plasma phospho-tau will increase the likelihood for the patient to be amyloid positive and perhaps also have some tau changes. And then those patients could be enrolled more quickly. If the drug is effective, the plasma phospho-tau levels are likely to go down, and that could happen in three to six months.
MALORYE BRANCA: But what is the diagnostic gold standard right now?
HENRIK ZETTERBERG: The diagnostic gold standard right now I would say is amyloid PET or CSF Abeta 42/40 ratio. These are the two methods which you, with very high diagnostic accuracy, can determine if a patient does have or does not have amyloid pathology. And these have been validated against neuropathology, and we know that these tests work really well. Now, we are then trying to use the blood tests to become as good as these reference tests, sort of.
HENRIK ZETTERBERG: And some of the plasma phospho forms look like they can really do a good job on this, almost replacing these more expensive examinations.
MALORYE BRANCA: Do you imagine that people will quickly adopt the blood biomarkers, or will they use them in concert with other tests?
HENRIK ZETTERBERG: I think they will be used in concert with other tests, as many clinical chemistry tests are used. And it will be super important to keep a nice clinical-- you still have to do a very good clinical workup. And you have to consider all aspects of the patient's symptoms. And you also have to be very careful as a clinician not to label anyone with Alzheimer's on the basis of a single biochemical test result.
HENRIK ZETTERBERG: So if-- I think this would be another tool, yet another tool, to determine the likely diagnosis of a patient. If you find out that the patient is likely to have Alzheimer's pathology, then you still have to link this pathology to the person-- to the symptoms that the patient presents. Because it might be that you have a patient who has depression, cognitive problems because of the depression.
HENRIK ZETTERBERG: And then with the biomarker tests, you also find out that there is some Alzheimer's pathology. But this could well be preclinical Alzheimer's pathology that would give the patient symptoms in 10 or 15 years time. Perhaps these pathological changes are not what is causing the symptoms now. So you will still have to be a very careful clinician and make a diagnosis taking all aspects of the clinical presentation of the symptoms into account.
MALORYE BRANCA: What about overlap with other dementias?
HENRIK ZETTERBERG: That's an excellent question also, because the biomarkers do not solve that issue, basically. So we have then good positive biomarkers for Alzheimer's pathology, amyloid tau and neurodegeneration. But, I mean, there are 50 other diseases that can cause dementia, the most common of which is cerebrovascular disease and perhaps also comorbid Alzheimer's and cerebrovascular disease. Then you have frontotemporal dementia, dementia with Lewy bodies, Parkinson's disease dementia.
HENRIK ZETTERBERG: And for those, we need to have other biomarkers. For Lewy body dementia and Parkinson's disease dementia, there is now a possibility of detecting the pathognomonic alpha-synuclein inclusions with the cerebrospinal fluid tests. Those are starting to enter clinical practice, but they have not been validated yet. For frontotemporal dementia, we can detect the neurodegeneration with neurofilament light, but we do not have any positive biomarkers to detect the underlying cause of FTD.
HENRIK ZETTERBERG: So here, we have to continue to work on better biomarkers.
MALORYE BRANCA: Excellent. And where do you see this going forward now? What do you think are the next steps?
HENRIK ZETTERBERG: Yeah, I think that what we will see now is clinical implementation of the blood tests, and that will go quite fast, I think. We already now know that the amyloid tests have been approved for use in the US. We use neurofilament light in Europe and in some American labs also to detect neurodegeneration. The phospho-tau markers, I'm sure, will become clinically available also in the next few years. We still have to develop a better understanding on how the biomarkers perform in multi-ethnic populations and in patients with comorbidities, morbidities of different kinds, more heterogeneous study cohorts than we might have examined the biomarkers in.
HENRIK ZETTERBERG: I mean, we have, for example, seen other results, and we have seen cohort studies that are quite homogeneous. But in more-- in clinical settings where there might be people who come in with a lot of different somatic and psychiatric issues, then we have to make sure that the biomarkers work there as well. But I think that will also happen during the next few years, through all the different initiatives that are ongoing, both in the US and Europe and in Asia.
HENRIK ZETTERBERG: So--
MALORYE BRANCA: What are some of those initiatives? What are the biggest ones that you're looking-- you're watching.
HENRIK ZETTERBERG: Yeah, the ADRCs, the Alzheimer's Disease Research Centers, in the US are making big, big efforts now to collect and analyze blood samples, to determine how well they work in the clinical setting where the patients are. And there, we will see validation studies on their diagnostic performance in more heterogeneous populations, and this is extremely important. I am hopeful that this will work out quite well in most settings.
MALORYE BRANCA: Just to take a step back, can you explain how the biomarkers relate to the biology and the development of the disease?
HENRIK ZETTERBERG: Yup. So, in Alzheimer's disease, the first thing that happens in the brain is the deposition of amyloid in the brain tissue. And this is a special form of amyloid. Amyloids are aggregation from proteins where the longer forms are more aggregation than the shorter forms. So Abeta 42, the 42 amino acid long form of beta-amyloid, is prone to deposition in the brain tissue.
HENRIK ZETTERBERG: And if you take Abeta 42 concentration and divide it by Abeta 40, which is the most water-soluble form, then you have a nice test for amyloid deposition. You get a selective depletion of Abeta 42 into the brain tissue and a lowering of the ratio. This is something that we have been able to do in cerebrospinal fluid over 20 years. But now, since five years, approximately, we have plasma tests that detect this onset of amyloid degradation.
HENRIK ZETTERBERG: This starts when you are 50, 55, 60, if you are to get Alzheimer's when you're 70, 75, 80. A few years later, you get tau phosphorylation, and that's really also an amyloid-instigated process. And then this tau phosphorylation is followed by neurodegeneration, which can be measured by neurofilament light in both CSF and blood. So we have biomarkers for amyloid, biomarkers for tau phosphorylation and tangle formation and then neurodegeneration in the form of neurofilament light.
HENRIK ZETTERBERG: So these three biomarkers have really-- they really form the core blood biomarkers for Alzheimer's disease-related processes, amyloid, tau, neurodegeneration.
MALORYE BRANCA: How confident are you in these biomarkers?
HENRIK ZETTERBERG: Yup, it's-- the amyloid test in blood is a little bit difficult, because there is such a small change when amyloid starts to deposit in the brain. There is a 15% reduction in the ratio, and that is-- that you can actually compare to what happens in cerebrospinal fluid. But there is a 50% reduction. And that is because in CSF, there are no other amyloids that are not related to the brain tissue.
HENRIK ZETTERBERG: In blood, there are amyloids from blood platelets, and myocytes, and some other cell types not affected by Alzheimer's disease. And that is a bit of a problem. We have repeatedly started seeing that the reduction is reproducible, but to be able, in clinical laboratory practice, to week by week have assays that are so stable that you can detect this type of relatively small percentage reduction, that is a challenge.
HENRIK ZETTERBERG: And there, I think we will still see really strong results that will make it important to do a CSF analysis or an amyloid PET scan on those patients. So we will see patients where we can't tell on the basis of blood if there is or is not amyloid in the brain. Phospho-tau happens in close association-- phospho-tau increase happens in close association with amyloid onset.
HENRIK ZETTERBERG: So then, one could instead also look at phospho-tau as an amyloid marker, almost. So when neurons are affected by amyloid, they secrete-- they will phosphorylate and secrete tau at a higher rate. So the phospho-tau increase could potentially replace the amyloid test in plasma a little bit, but they are not completely interchangeable. And the amyloid test is always a little bit earlier than the phospho-tau test.
MALORYE BRANCA: So is anyone using these tests now?
HENRIK ZETTERBERG: Yup, they are used more and more. You can order a plasma Abeta 42/40 ratio in the US from a private company, and they combine the information with the age of the patient and also a brief genotype and give you a likelihood ratio of amyloid positivity. And in Sweden, we have been using plasma neurofilament light for a couple of years now in clinical laboratory practice and are just about to start doing the phospho-tau tests. So it is happening now, I think.
HENRIK ZETTERBERG: And one important piece of work that will also happen now is that we will develop some kind of appropriate use criteria for these biomarkers so that we can help guide clinicians on what these biomarkers mean and what they do not mean also, because that's also important.
MALORYE BRANCA: Yes. Thank you again for your time, and we look forward to hearing from you again.
HENRIK ZETTERBERG: Thank you. [MUSIC PLAYING]
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