Dr. Tharick Pascoal, Associate professor of psychiatry and neurology at the University of Pittsburgh, talks about a possible link between ADHD and Alzheimer’s disease.
Interview conducted by Ivanhoe Broadcast News in 2023.
What’s the link between ADHD and Alzheimer’s disease?
Pascoal: This is a very good question. Some months ago, we have an article that was publishing a very large cohort in Sweden where they analyzed more or less seven million of people and they found epidemiological link between the presence of ADHD and Alzheimer’s disease. Was the first robust suggestion that this disease would be connected. Then you start to think how we could also test this in a smaller scaling, our cohort, but I also have a result involving other aspects of Alzheimer’s, is not only the diagnostic of Alzheimer’s disease and ADHD, but also the biomarkers of Alzheimer’s disease are also the symptoms of Alzheimer’s disease and ADHD. And then you start to look around and you’re looking for many cohorts. If you have a cohort of elders that have the diagnostic of ADHD and biomarkers of Alzheimer’s disease. You could not find. We looked in many countries, we sent many mails and could not find any record that have this data. What we did after this was we started to think how we could test, nowadays, this hypothesis if we don’t have this data. And we realized that we don’t have this data because the population that’s elderly today, in their time, the diagnostic of ADHD was very rare. The gold standard for the diagnosis of ADHD is the diagnostic of ADHD when the people is in young age, and then after when they get in the old age, some people remain with ADHD and some people don’t remain with the diagnostic of ADHD, but the fact is we need the diagnostic in the early age. And these people nowadays that have 65, 70, don’t have this diagnostic. Then we realized that to have a gold standard diagnostic we’re going to need to build our cohorts ourselves. But in the meantime, we imagine the possibility to reach the diagnostic of ADHD. That is a polygenic risk score. A polygenic risk score is a study where they take millions of people with ADHD, they do this genetical, the [inaudible 00:03:44]of these people, the genetical assessment of this people, and they found the genes that are more associated with ADHD. They composed a value for this gene, so they have a polygenic risk score. This polygenic risk score is highly associated with ADHD. What we did here was use this polygenic risk score, because you have cohorts with Alzheimer’s disease that you have how the gene sequence for every single patient. We went to this gene sequence, we did a polygenic risk score for each patient and this polygenic risk score is more or less the probability or the genetical probability that this patient has to have ADHD, it’s not the diagnostic of ADHD. And what we found, we found that people that have a high genetic probability to have ADHD have also a high probability to present cognitive decline over 2, 3, 4, or 5 years. In the same time, we start to ask ourselves, what’s the reason of that? Then you start to imagine maybe the reason of that is because the people that is in late ages have ADHD, of course, they have more problems with the cognition, maybe it’s something that act in addition to Alzheimer’s disease. For example, these people were progressive to Alzheimer’s disease, but maybe what’s going on here is that this is an additive thing that work together for Alzheimer and just increase the risks for the people who have more progression of Alzheimer’s disease. However, what we found was not this. We found that, in fact, the people that have a higher genetic probability to have ADHD, and also have the pathology of Alzheimer’s in the brain, then you have the cognitively impaired people. Normal elders that have the pathology of Alzheimer’s in the brain, and high probability to have ADHD were the ones that progress to dementia over four or five or six years. And the people in our cohort, and the people that have, for example, only the high probability to have ADHD- the high genetic probability to have ADHD, and did not have the pathology of Alzheimer’s in the brain, they did not progress or they did not have high likelihood to progress to dementia over the years. The same thing for people that have the pathology of Alzheimer’s disease, because Alzheimer’s disease is characterized by the presence of two pathologies in the brain, mostly characterized, that’s amyloid and tau. What we were able to measure in our population was the presence of these two proteins, amyloid and tau. And we saw that the patients that have more amyloid in the brain, and this is where we’re talking about cognitively normal elders, not about patients of Alzheimer’s disease, the cognitively normal elders that have more amyloid in the brain and a higher probability to have ADHD were the ones that progress to dementia. People that have only amyloid in the brain, that’s the pathology of Alzheimer’s, did not have a very high probability to progress to dementia over four years. Then we found that a combination of these two things, ADHD, but ADHD not the diagnostic, the vulnerability to ADHD, the genetical vulnerability to ADHD and Alzheimer’s disease pathology were the ones that presented cognitive decline over short time-frames. I hope you can use some of it- a lot of it.
So, ADHD isn’t necessarily a new disease, but it’s just something that wasn’t diagnosed, right?
Pascoal: No. ADHD is a disease that you know for a long time, is a common disease that we normally associate with young people, we normally associate with child that go to the school and cannot concentrate, have attention deficits to concentrate, have difficulty to concentrate, have hyperactivity, is a very common diagnostic. However, normally we think this diagnostic occur when we’re a child, then when we are adults, we don’t have ADHD. Nowadays, we know that you have ADHD when you’re adults. What you are showing here of different is that if you have this [inaudible 00:08:00]to have ADHD when you are an adult, you have also a high likelihood to progress to Alzheimer’s disease. Then what we’re showing here different is the link between the genetical vulnerability to ADHD and the develop of Alzheimer’s disease in the later ages with 65, 70 years old.
So, it isn’t something that ADHD turns into Alzheimer’s, it’s something that just the likelihood of increases, right?
Pascoal: Not at all. And this is why I also mentioned as a limitation of our study because as I said for you in the beginning, we don’t have the diagnostic of ADHD. The diagnostic for in order to have ADHD is a clinical condition. A physician needs to do a lot of tests and define clinically that you have ADHD. We did not have this in our population because it doesn’t exist, elderly population that have this diagnostic of ADHD and Alzheimer’s disease biomarkers. What you have is genetic vulnerability, then the people that have genetic vulnerability does not mean they transform to ADHD, they have a higher risk to progress to ADHD.
Does this mean that ADHD and Alzheimer’s can be detected in a gene test now?
Pascoal: Let’s talk about ADHD, first. ADHD is a disease that you have the clinical diagnostic, but you don’t have biomarker for ADHD. We don’t have a blood biomarker that you can detect the presence of ADHD. Therefore, this type of disease that don’t have biomarkers, they explore much more other ways to detect a disease, such as the genetical risk factors. We cannot do the diagnostic of ADHD with genetical risk factors, but if you have this polygenic risk score, the person have a high likelihood to have ADHD. You cannot do the diagnostic of ADHD. Alzheimer’s is a complex answer, because Alzheimer’s disease, we have two types of Alzheimer’s disease. We have the Alzheimer’s disease that start normally before 65 years old. That’s the autosomical dominant Alzheimer’s disease. This Alzheimer’s disease is purely genetic. There are mostly three genes, that is the Presenilin 1, Presenilin 2, and APP, and if you have abnormality in one of these three genes, you’re going to have Alzheimer’s disease. Thus, in these patients, the diagnostic is genetic, yes. We call autosomical dominant genetic Alzheimer’s disease, but this is not the majority of Alzheimer’s disease, this is some familiar case of Alzheimer’s disease. On the other hand, we have this sporadic Alzheimer’s disease. This is the Alzheimer’s disease that you hear all the time. This is the Alzheimer’s disease that people- that normally start after 65 years old, can start before, but normally start after 65 years old. This is the common Alzheimer’s disease. This Alzheimer’s disease, we have one genetical risk factor that is very famous called APOE. And these genetic risk factors is a risk factor. Increase the probability to have ADHD. I cannot do the diagnostic of ADHD for this because this is a sporadic, this is not a autosomical dominant, this is not a genetic. Then the APOE, increase the probability, however, you cannot do the diagnostic of this sporadic Alzheimer’s disease with genetical test at all. We only can do the diagnostic in the autosomical dominant, that’s one type of Alzheimer’s disease.
Should somebody be going and getting a test to see if they have Alzheimer’s?
Pascoal: What normally happens in conference that you are presenting this data as the people that had the diagnostic of ADHD when they’re child, they said, should I go there and test for Alzheimer’s disease? No, because maybe I have the increasing risk. I think the results that you have, because our analysis is a retrospective analysis, not a perspective, there are a lot of limitations in the results that don’t have the diagnostic. I think this is too early to say that. I will say for the patients, don’t worry for this right now. We are working here in Pittsburgh to develop. We have some cohorts here that to-that the people who are followed with ADHD, and now they are 40-50 years old. These cohorts are getting mature, and we have the whole interests to work in these cohorts. And try to identify and be sure to answer your question better if actually a diagnostic of ADHD in your life is associated with a higher risk of Alzheimer’s disease. This is too neat to be elucidated, we cannot say that.
How predictive is it?
Pascoal: We cannot say this because we don’t have this study yet, it doesn’t exist in the world; this study yet, that’s what would be the idea of define if I can answer your question? Would be the idea that I have a cohort that they have the diagnostic of ADHD in early age. I follow this cohort over time and I follow also individuals that don’t have ADHD, and I see the odds ratio, I see the probability of having ADHD to develop Alzheimer’s disease. This is study that doesn’t exist. We are working on this study, but this study doesn’t exist yet. We cannot give this answer. This answer in the future, maybe 10-15 years from now, maybe this answer will be yes or maybe this answer will be no.
How do you measure the risk?
Pascoal: I think if a person is in the late ’80; and this is important concept, if you have a person that are in the late’80s how is the best way to tell her? Older, is that a good way to say? If they have a older adult, that they have a concern with their memory or their cognitive function regardless of they have ADHD or not, I think is prudent and make sense. They look for help and look for a doctor to do evaluation because we learn over time and this is very well established that something that you call subjective cognitive decline. For example, you think that you have the decline, but the tests or the society or their work is not showing any decline. We know that this is a risk for developers who emerges as well, then I think everyone that have a concern with memory- a reasonable concern with memory should ask help, and be evaluated by a clinician regardless of having ADHD or not.
Tell us about your study, how did it come about, what’s the motivation behind it?
Pascoal: The publication. The study was, as I told you we had this publication last year where they show epidemiological link between ADHD, Alzheimer’s disease. They found these seven million Swedish individuals that the people that have more ADHD had also more Alzheimer’s disease, and then this gives us the motivation to try to go to our cohorts because we work with mainly for Alzheimer’s disease and try to see if you could find, identify characteristics of ADHD in our population. And that was the motivation of our study.
Could the ADHD gene also be linked to other things aside from Alzheimer’s?
Pascoal: I think that there are other risks and this is an interesting thing. There are some common risk factors for ADHD Alzheimer’s such as obesity, such as vascular disease. And then this was a concern of our study. Maybe what we’re seeing here are the common risk for the two diseases that when you do the analysis looks like the disease are linked, but we control for these risk factors that the ADHD is disconnected and the ADD is connected and they resort to remain that what increase our certainty about our results.
It seems like we’ve diagnosed more ADHD and Alzheimer’s in the past 20 years than ever before. Does this have anything to say about the link between the two because they’re being diagnosed now. Is that making it?
Pascoal: Let’s talk a little bit more related for our study that’s ADHD in older populations, I think we now recognize that ADHD is not a disease that help only in child. Now we recognize that these are diseases that help also in adults and older adults. The look more into this. Before I think this was highly overlooked at. We are looking more into this then you have more and a higher number of diagnostics about Alzheimer’s disease what’s going on now is that the population is aging. For example, what’s going on now that you have ideas of medicine, the data improve a lot over the years such as cardiology and oncology and we are live longer than ever before. However, we are arriving this later age with health bodies, but not with health brains. And then what we are looking is that the number of Alzheimer’s seems that are much increasing. But in fact, what is increasing is the population that is aging. And I don’t think so that in this case of our study, have any link of the diagnostic because our study did not use any type of diagnostic for ADHD, we used the genetic vulnerability that will be the same regardless of the diagnostic and also use biomarkers for Alzheimer’s disease that also is unrelated to the diagnostic, is talking about the pathology and the existence of Alzheimer’s disease pathology in the brain of the individuals. Then I do not think that the increase in the diagnostics are associated with our results.
Why is it that ADHD and not other behavioral disorders?
Pascoal: Our study focus in the ADHD based on that study, we cannot say anything about the other. We’re not saying that the others are not associated. Our data does not support that. Actually, we are working right now in polygenic risk scores of another disorders. But the results are not ready yet, but we are investigating that so far we cannot say that is ADHD only. Between us here it looks like it’s ADHD only, but between us the results are not ready.
So, it’s not something that’s been studied?
Pascoal: Yeah. We’re studying this, but I think this is only ADHD but we don’t have the results yet.
What’s next in your research?
Pascoal: What we’re are doing here is in collaboration with aged because we’re Alzheimer’s disease researchers. And we have a very prominent ADHD research here in Pittsburgh, called Dr. Brooke Molina, and she has a cohort of individuals that she follow for 20-30 years, maybe I’m wrong in these numbers, but it’s more or less like this. She follow for very long time. And these individuals have now 40-50 years old. We are collaborating now, and what we want to do from now on, and we start to measure the biomarkers of Alzheimer’s disease in these individuals and do the clinical assessments related to Alzheimer’s disease in these individuals to be able to answer most of the questions that you make here for me today. That the question is in relation to the diagnostic, what’s the probability that these patients are going to have to develop Alzheimer’s disease in relation to patients that don’t have ADHD. If patients with ADHD, we’re going to appear with biomarkers abnormalites of Alzheimer’s disease before the patients without ADHD. Then the next step is prospective study, where we’re able to follow these individuals that are being followed already for 30 years, follow for more 30 years and wait they develop out the diseases that they will develop. It’s not a good say the way they developed the disease, but we wait the progression of their aging and development of the disease to try to understand the natural history of this relation between ADHD and Alzheimer’s disease. That’s not clear at all.
Is the study that you’re doing strictly on data or you’re looking for patients, is there something you’re looking at?
Pascoal: These patients are already part of our cohort that are followed for 30 years here in Pittsburgh, these cohort have rare disease, they follow up these patients every year. What we are doing now, we are asking us to funding to try to put in these cohort the biomarkers of Alzheimer’s disease. We have a plan to send people to collect blood of these individuals in their home. And in the blood of these individuals we’re going to measure the biomarkers of Alzheimer’s disease and we’re going to follow them yearly over the next decade or so. These individuals already exist and they are a cohort here in Pittsburgh.
Is there anything that we’ve missed?
Pascoal: Well, Alzheimer’s disease and related dementias are devastating conditions that affect today more than six million people in the US only. And this number is set to increase because we know that the population is aging. For example, with advances in areas like cardiology and oncology, the population is living longer than ever before. However, these population’s arriving in the later years of age with healthy brains, with healthy bodies but not with healthy brains which rob important 10 or 20 or 30 years of their life that they could have a high quality of life with their family. Very recently we have for the first time- some months ago, we have for the first time approved by the FDA for clinical use the first true medications capable to halt the progression of Alzheimer’s disease. People to give back to the patients these important years. However, you have limitations for the use of these medications. That these medications have the ability to make a diagnostic or calculate diagnostic Alzheimer’s disease, the clinical practice without the help of biomarkers. For example, if you go to the Prime Medicare and you have dementia symptoms less than 50 percent of the time, the primary care will give a cost for your [inaudible 00:25:35]. So we’ll give a diagnostic for you less than 50 percent of the time. If you go to the best specialists in Alzheimer’s disease, the best centers we know from research that this specialist will get your diagnostic wrong if you have Alzheimer’s and so if you don’t have Alzheimer’s, you have another condition 30% of the time. If you have a clinic that you receive patients, 100 patients in a week, 30 patients will have the incorrect diagnostic. And then this earlier but to introduce our research here, what you do here is the development validation offer in vivo biomarkers capable to capture the pathology of AD and increase the likelihood of the diagnostic clinical practice. What are- what are in vivo biomarkers? In vivo biomarkers are when you go to a clinician, they ask a lot of blood tests for your data biomarkers. Biomarkers are techniques that you use to measure molecules that are associated with the presence of the pathology. For example, in Alzheimer’s disease, there are two pathologies that are characterized. The Alzheimer’s is characterized by the presence of two pathologies, amyloid and tau. What do you use biomarkers for? You use biomarkers to find these molecules of amyloid and tau in the brain of the patient, to find the presence of these molecules. Here in UPMC in our clinic here, if a patient arrived with a diagnosis of dementia, the biomarker that you have to support this diagnostic and the biomarker that approved by the FDA, the biomarker that’s covered by the health insurance are the measure of this proteins in the cerebrospinal fluid of the patients after a lumbar puncture. The cerebrospinal fluid of the patients are liquid that stay around the brain, it’s the sewer of the brain. And how the proteins that are in the brain go to the cerebrospinal fluid. What we do here, we do a lumbar puncture. We collect the cerebral spinal fluid, and we measure the presence of these proteins. Then what you can do with this, you can identify if the patient has Alzheimer’s disease or if the patient has not Alzheimer’s disease. This is one form of identifying the presence of these proteins and is the form that you have available in clinical practice. However, we have here and maybe this is one of the first sites in US that we have available ways to measure the presence of these proteins in the brain with a simple blood test. We more or less three years ago, we and others, we discovered that a liquid of these proteins that are first in the cerebrospinal fluid leads to these proteins go to the blood. Then with the develop of cutting-edge technologies, we are able to measure this very local entities of these proteins in the blood and with a simple blood test tell if the patient has or has not Alzheimer’s disease. And these are the first tests that are simple, cost-effective, and scan for Alzheimer’s disease and are starting actually to revolutionize the field of Alzheimer’s disease. However, we still have some limitations and some understanding of this test, for example have the case- for the case the- the CSF or the cerebrospinal fluid measure of this test. This test is measuring lots of health for a few years. Then we have some limitations. What we’re doing here in the University of Pittsburgh Medical Center, we are making available this book test for our patients or our patients that go to the UPMC network, we make available for free. And the clinicians are able to ask these tests, to have the results, and to increase the likelihood of having correct diagnostic of Alzheimer’s disease. We want to use this data, it’s not a research setting because this is both tests are being measured with something called [inaudible 00:29:40]for FDA. They are measuring a lab where you can use as this test for FDA approval, but they only can use if they are measuring a designated lab. The research part you’re going to collect this data and you’re going to try to provide data to FDA to approve of this test to those in clinical practice. And this is a big advantage in relation to the cerebrospinal fluid because the cerebrospinal fluid is an invasive test, you need to insert a needle in the patient, collect the blood. And this test here in the blood, you can collect the blood to measure your kidney function, your thyroid function and also if you have high probability to have Alzheimer’s disease. For these tests are a lot of people come in and they’re democratizing the diagnostic of it, because before you have a high-end diagnostic FID, you need to come for a centralized UPMC that have the highest technology. But now with this test you may be in the countryside and you’re going to also be able to go to collect and have a high-end diagnostic FID. There is another way to- another biomarker that you need to be a very specialized environment. That is a way to measure these proteins directly in the brain. Because if you understood here what you are doing, we’re measuring the proteins in the brain that escaped CSF. We are collecting- we are collecting cerebrospinal fluid, and then after escaped to the blood we are measuring blood. But there is a way to visualize this proteins in brain directly. And this we’re not going to go to the tails this, but we can imagine this, as this is a neuroimaging, is some similarity with MRI and CAT scan, but instead you see the form of the brain, the morphology. The only thing that you can see in this is the presence of these proteins. Then they can do an image of the brain and they can see if the patient has or has not this protein in the brain. This test has some advantage in relations to this test in the fluid- in this cerebrospinal fluid in the blood. Because actually we are visualizing directly the presence of the protein in the brain. And also in the case of the- we call this PET scans. In the case of PET scans for tau pathology, that’s one of the protein in FID as you mentioned, in the position of amyloid and tau pathology. We also can correlate the presence of the protein side of the brain. We can compare it with the symptoms of the patient. For example, if the patient has adenosine language we can see that we’re going to have higher levels of tau pathology in the left temporal lobe. That’s the side of the brain that control language. And this capability to relate the topographical idea with the symptoms, increase the confidence of the clinician that that symptom came from that lesion. Then these tests are more robust than the fluid biomarkers but they’re much more expensive and very difficult that there will be used widespread. But in many cases to have inconclusive tests with fluid biomarkers, dispatched biomarkers can help to give a better diagnostic performance.
With the blood test or with any of the tasks you described, are they black and white either yes, you have it, no, you don’t, or is there an area where you might get it?
Pascoal: Yeah. This is a very important point. Most in relation to the fluid biomarkers there are undetermined results that we cannot define if the patient has. One thing that’s important as I mentioned before this, none of these tests rule out or avoid that you’re going to have the clinical content between the physician and the patient. The clinical content is key for the diagnostic. The biomarker is an add that the clinician has to have a good diagnostic. Therefore, no these tests are not black and white. Depending on the level of the test, on the painting of the results, I can rule out Alzheimer’s disease or I can be sure but there are some gray zone and these gray zone needs to be defined by the clinician, and the contacts between clinicians and patients.
END OF INTERVIEW
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