ISTAART RELAY Podcast – Down Syndrome & Alzheimer’s Disease PIA

Narrator:

Hello and welcome to season seven of the Dementia Researcher ISTAART Relay Podcast. In this series, members of the ISTAART's Professional Interest Areas interview each other about their PIAs and the hot topics in their fields. Each guest then becomes the next episode's host, passing the conversation along from one researcher to the next. We are releasing one episode a day in the run up to the Alzheimer's Association International Conference this year in London and online, showcasing the work of the ISTAART PIAs. Thank you for listening.

Lillian Morgado:

Hello and thanks for tuning in. I'm Lillian Morgado, a research coordinator at Georgia State University in Atlanta, Georgia, USA. I'm also the social media and Communications Chair for the Health Policy PIA. Today, I'm delighted to be talking with Dr Patrick Lao from the Down Syndrome and Alzheimer's Disease PIA. Hello, Patrick. Can I start by asking you to introduce yourself?

Dr Patrick Lao:

Hi, Lillian. Yeah, so I'm Dr Patrick Lao. I'm an assistant professor at Columbia University. I'm the current Programmes Chair for the Down Syndrome Associated Alzheimer's Disease PIA and the incoming Vice Chair.

Lillian Morgado:

Congratulations on your vice chair role.

Dr Patrick Lao:

Thank you.

Lillian Morgado:

And then before we talk about your work with the PIA, can you tell me a little bit about your own research?

Dr Patrick Lao:

Sure. So, my background is in medical physics, and I do a lot of neuroimaging. Yep, so I use multimodal biomarkers to look at the disease course across different forms of Alzheimer's disease. So that includes genetic forms like Down syndrome associated Alzheimer's disease or autosomal dominant Alzheimer's disease, as well as sporadic forms, so like late onset Alzheimer's disease.

And even within the different clinical presentations of Alzheimer's disease, there are certain subgroups like posterior cortical atrophy, where there's more visuospatial impairment and more posterior involvement of brain regions, or logopenic variant primary progressive aphasia, where there's left temporal involvement that leads to language impairments.

And so, looking across all these different forms of Alzheimer's disease allows us to compare and contrast, see what pathways might be generalizable and essentially a target for therapy for everyone, or which pathways are specific to specific subtypes where more of a personalised approach might be warranted. And so, by doing this work, we can use the unique aspects of each form of Alzheimer's disease to kind of gain new insight.

So, for example, adults with Down syndrome, they have trisomy 21, which is the triplication of chromosome 21, and that's where the amyloid precursor protein gene is encoded. So, from birth, they're overproducing the amyloid precursor protein. And this is happening in every person with Down syndrome. And a lot of our work has shown, we've mapped out the amyloid cascade in these individuals, so starting from amyloid, going to tau, going to neurodegeneration, and finally, cognitive impairment.

And since I do a lot of multimodal work, I've been really interested in incorporating vascular and inflammatory pathways into these cascades. And by doing so, several groups across the world working with cohorts of adults with Down syndrome have put out a lot of cross sectional work and, more recently, longitudinal work, essentially showing that this happens in a very stereotypical pattern and we can use chronological age to essentially approximate disease progression in this population.

And so now we're starting to characterise the timeline of the natural history of disease, and this will really help inform clinical trial design.

Lillian Morgado:

Okay, that is really interesting. And I have some questions because this is, I mostly do qualitative research, so some of this is outside of my normal stuff. You had mentioned that you work in medical physics, I believe. Is that correct?

Dr Patrick Lao:

That's correct.

Lillian Morgado:

Okay. That sounds like a very niche field. Which side did you start on, the physics or the medicine?

Dr Patrick Lao:

Well, I did a dual degree in biology and physics in undergrad. And so, they always kind of came hand in hand for me. I was originally thinking about going to medical school, and then I had heard about medical physics as an option, so then I ended up going that route. So yeah, I think it's simultaneous in this case.

(chuckles) But yeah, it's essentially leveraging kind of the properties of radiation and how they interact with human tissue to generate either meaningful images or to treat things like cancer with radiation therapy.

Lillian Morgado:

Actually, leads to my follow up question. You had mentioned doing multimodal imaging, and I was curious what that means. Are we talking about looking at brain scans or tissue samples? What sort of images are you comparing?

Dr Patrick Lao:

Right, yeah, I guess multimodal could mean a whole host of different things depending on what type of biomarker. But since I normally do neuroimaging, I'm just talking about different brain scans. And so, some of the ones that we use are amyloid PET scans. And this will show you how much amyloid is in your brain. And these are really useful for clinical trials right now that target amyloid.

So, all the anti amyloid antibodies, to show eligibility for the study, a participant has to be amyloid positive, and so they'll get a scan or a blood test prior to enrolment. And then after treatment with the drug, they're going to scan them again to see if there was treatment related amyloid clearance. And so, imaging is the gold standard for this type of stuff just because we can get that spatial information that we're used to getting from autopsy.

Whereas a blood measure will kind of just tell you a global burden of amyloid. And so, in the amyloid cascade, after amyloid comes tau pathology. And so, we have these tau PET scans. Only one of these tracers is FDA approved. The rest are still only for research. And so, these methods are still being developed in terms of visual reads and quantification and harmonisation across tracers. But tau PET is really, really useful in showing how the tau pathology spreads across the brain.

So, for amyloid, it's more important how much you have in these Thal phase regions, which is kind of a global phenomenon. But for the Braak staging, it's really the tau spreading across the brain that gives you information about the progression of the disease.

Lillian Morgado:

What is Braak staging?

Dr Patrick Lao:

Sure, so I mentioned that PET imaging is sort of the gold standard because it relates to autopsy. And so, autopsy is how we kind of definitively show pathology at end of life. And so, while a person is alive, we can't do that. And so, we have to use imaging biomarkers to kind of get a sense of that. And with the spatial information from imaging, it sorts of maps onto autopsy best.

And for amyloid, the spatiotemporal progression of amyloid plaques across the brain was first characterised by Dietmar Thal. And so, we call those the Thal phases. And so those go from one to six. And then for tau tangle pathology across the brain, that was first characterised by Dr. Braak. And Braak, I think, is a husband wife pair. And so, Braak staging essentially describes the progression of tau across the brain from stages one to six.

Lillian Morgado:

Okay, thank you so much for clarifying that, because I was like, ooh, which sounds really important. So, it sounds like imaging is really cool because it tells you where the biomarkers are deposited, whereas if you do a blood draw, it just says if they're there or not. And another thing you had mentioned was that through using this imaging technology, you're able to figure out the Alzheimer's disease staging for people with Down syndrome based on chronological age.

So, does that mean you can say, all right, when someone who has Down syndrome is, I don't know, 40 years old, we can expect this level of accumulation, and they may need this level of support?

Dr Patrick Lao:

Right, I think that's the ultimate goal, to be able to place them on the disease timeline based on something as simple as chronological age in order to give guidelines to these individuals, their families, their caregivers, their clinicians, to know what to screen for at a particular stage of life. And when we start to look at these different genetic forms of Alzheimer's disease, I think it's been more widely studied in autosomal dominant AD, where there are mutations in the amyloid precursor protein, Presenilin 1 or Presenilin 2.

But essentially, what comes out of that is a concept called estimated years to onset, or EYO. And this is how predictable their clinical symptom onset is based on their parent's symptom onset if they had that mutation. So, for example, if someone has autosomal dominant AD and they're 45 years old, and their parent with the mutation got symptoms at 55, they would be negative 10 on EYO, or essentially 10 years away from their clinical onset.

Lillian Morgado:

Okay, so it's like a countdown clock.

Dr Patrick Lao:

Mm hmm. And yeah, and that differed across the different mutation types. But here for trisomy 21, we tend to use a single age for symptom onset.

Lillian Morgado:

And another thing, and I apologise because you may have already answered this, but you do such cool work, I want to learn more about it. One of the things that I do know about folks with Down syndrome is that people with Down syndrome are living longer than ever due to a lot of really cool medical advances and additional supports that people are able to offer. Does that mean that Alzheimer's disease for these folks is a growing concern?

Dr Patrick Lao:

Yeah, absolutely. So, the life expectancy in the 1960s was around 10 years old, and that was limited by the high incidence of congenital heart disease in this population. And it wasn't till the '80s or so where the surgeries were developed to fix these congenital defects, and even later for being offered to the Down syndrome population because they were concerned about how they would tolerate surgery. And so, with that, life expectancy is now in the '60s to '70s, depending on what country you're looking at.

And now Alzheimer's disease represents sort of the upper limit on people's lifespan. The single age of onset that I referred to earlier is 54 years old. So that's when you can typically expect symptoms. Yeah, that's rough because it's early. But I think it's really important that you're able to figure out a typical age of onset because that probably allows people and their families to better plan for what they'll need to support themselves and have the best quality of life. Thank you for doing that work.

Yeah, and something else that we're looking into is, I am kind of talking about this in terms of like stereotyped process or what happens on the overall population level. But we do see individuals that might show some resilience, and there's actually a range around that 54 years. Some people can get it as late as their '60s or '70s. And on the flip side of that, there might be some individuals showing increased risk where they could get it as early as 30.

And so, we're trying to look at those extreme cases and see what's different about them to see what kind of pathways we can target for therapy. And so, while there is this population level progression, there is still some inter individual variability that we're hoping to leverage, yeah.

Lillian Morgado:

Didn't the Down Syndrome and Alzheimer's Disease PIA publish something about resilience research? I think it was in 2024 or 2023.

Dr Patrick Lao:

Yeah, it might've been 2024. Yeah, that was a product of one of our working groups. And so that working group is still active. There's a paper investigating risk and resilience mechanisms in Down syndrome associated Alzheimer's disease, because for a lot of our early work, we were focused on developing these timelines that apply to the population overall to sort of inform clinical guidelines and clinical trials. But as we're doing more and more work, we're realising that not every individual falls onto these timelines perfectly.

And so, some people will get it much later, and maybe they're doing different things like in terms of lifestyle, or maybe they have some other protective factors in terms of comorbid co occurring conditions, or maybe their overall morbidity rate is lower. And so, we're trying to figure out what factors, even in a genetically determined form of Alzheimer's disease, might push these timelines apart for individuals.

Lillian Morgado:

That is really interesting. And are there any other really hot topics or exciting things in your field right now that you want to talk about?

Dr Patrick Lao:

Yeah, so I've been talking about sort of these timelines and all of this data coming out to really support clinical trials. And so, we're really now just at the start of that. So, there are three in the pipeline that are going to be including individuals with Down syndrome. So even though they're at this ultra high risk for Alzheimer's disease, they've been excluded from all of the previous anti amyloid therapies due to safety concerns or protections for individuals with intellectual disability.

But because these people are at such high risk and there is no other way to treat it, we've been advocating a lot through our work in the PIA for individuals to be included in these trials so that we can get the safety information necessary for them to enrol. And so, one of these trials, for example, is using Lecanemab, which is an FDA approved anti amyloid that was evaluated in the non-Down syndrome population.

And so, they're doing a phase IV sort of safety extension trial in adults with Down syndrome. So, we already know it works. We have a general sense of the safety. We have additional safety guards for the participants with Down syndrome, like stricter inclusion criteria, but we are allowing them to take the drug. And so, we'll see what other special considerations we need to make for people with Down syndrome when we're providing these treatments. And so, I think that's a really critical step forward.

Lillian Morgado:

That is really interesting. And another follow up question. I know one of the issues with clinical trials is getting enough people of certain populations in it, and people with Down syndrome are a pretty small portion of the population. Were you involved, or do you have any knowledge of the recruiting process that was used to get those folks into the clinical trial or any of that part?

Dr Patrick Lao:

I'm not super familiar with the entirety of it, but there are clinical trial ready cohorts that are being established to where we do this multimodal characterization over time. So, we essentially have all their baseline characteristics, and we can use themselves at baseline compared to them after treatment as the comparison group. And so, one study that I'm involved in called the Alzheimer's Biomarker Consortium Down Syndrome, or the ABC DS study, is one of those clinical trial ready cohorts.

And so, a lot of our participants co enrol into this TRC DS, and then they can be recruited through that mechanism into these ongoing clinical trials based on what they want to do.

Lillian Morgado:

That is so exciting, and I'm so glad that you're able to use that information you're getting all the imaging and being able to do the stereotyping, to moving it to seeing the specific situations and how things can be done to make it better. That's got to be really satisfying.

Dr Patrick Lao:

Yeah, it's been a really influential time in the field to see how much has changed in the last 10, 15 years, especially even with the most recent revised criteria for the diagnosis and staging of Alzheimer's disease that came out. Previously, this was essentially to establish a way to diagnose Alzheimer's disease with biomarkers and not have to wait the 20 years until cognitive symptoms appear. And so, they established this amyloid tau neurodegeneration framework in order to stage individuals.

But still, the starting point was someone had to be amyloid positive. And if we really want to know what's driving amyloid in the first place, we have to look earlier than that. And so, in these genetic forms of Alzheimer's disease, like autosomal dominant AD or Down syndrome associated AD, they have now been included as stage zero in this framework. And so, we can study the earliest pathways in the disease because we know that they will eventually develop it.

And so that was a huge change in the field as well. So, both on the research and clinical trial areas, I think, there's been a lot of progress.

Lillian Morgado:

That is really interesting. That's really helpful to set the scene for what I want to talk about next, which is the work of your PIA. So how does the work of your PIA really support your field of research? And I know we talked about you guys had that workgroup that had that impressive publication. I'm sure you're doing other cool stuff too.

Dr Patrick Lao:

Yeah, so in addition to the risk and resilience working group, we have another working group in development where we're expanding to other forms of intellectual disability and autism. And so, we had a all members meeting about a month ago to engage sort of all the members, not just our executive committee, in these regular meetings. And we broke out into working groups, and this allowed for smaller interactions.

And each of the breakout rooms was tasked with talking about where we want to go with this PIA, what kind of new working groups do we want, what would they like to see us do? And so, one of those was about the broader umbrella of intellectual disabilities.

And someone had been working, Eric Rubenstein had been working with electronic health record data, and they started noticing that a dementia diagnosis, dementia, all cause, as in sort of an umbrella term in the health record, was maybe being overused in certain cases. For example, in individuals that were too young for that to be a possibility.

And now we're developing a survey to send out to clinicians to get a sense of what their level of experience with people with intellectual disabilities is and whether any additional clinical training or guidelines would be more helpful in terms of understanding when to use that diagnosis or when to use that code. And similarly, for our first working group for the Risk and Resilience, Dr.

Lydia Vasquez and Sigan Hartley, they have been developing this survey to send out to get a better sense of the risk and resilience factors in Down syndrome. So, following up on that first paper.

Lillian Morgado:

That is really interesting. Two questions about the new working group. So, the first one is you're saying that the code for dementia is being used potentially more liberally than it should by healthcare practitioners on folks with autism specifically, is that correct?

Dr Patrick Lao:

Yeah, autism spectrum disorder or intellectual disabilities, yeah.

Lillian Morgado:

And I understand that this still needs to be researched, but is the hypothesis or the suspicion that the healthcare providers are doing this because they don't know what the appropriate baseline is for these folks?

Dr Patrick Lao:

Yeah, I think that would feed into it. Or there are things like regression disorder in adults with Down syndrome where it's kind of like a very sharp decline and they might mistake that for dementia. And so, it's really getting a sense of how many patients have they seen with these baseline conditions and how did they sort of handle it when they suspected dementia. Right. That's really cool, because then you guys can, like you said, we can see, all right, do these folks need extra training?

What else can we do to help these people? So, who are you looking to join that group? 'Cause you said it was still being formed. Are you looking for members still, or is it closed? Yeah, absolutely. Yeah, it's still in its very early stages, and we're actually still developing that survey. The target audience for that survey would be clinicians only since we're interested in sort of getting at that diagnosis.

Lillian Morgado:

And then the other one you're working on is the group that did that great publication on resilience. And now you're working on another survey where you're looking at the resilience factors. Correct?

Dr Patrick Lao:

Yeah, I believe so, yeah.

Lillian Morgado:

Okay, that is so exciting.

Dr Patrick Lao:

Yeah, I think it really helped shape the message that we can provide back to the participants in the community when we can start to focus on these resilience factors and what people can do about it. Like for example, in relation to enrolment in clinical trials rather than just sort of this inevitable progression, yeah.

Lillian Morgado:

What initially brought you to join the PIA?

Dr Patrick Lao:

A colleague reached out and asked if I wanted to join. And at the time, I wasn't doing any networking at all. I was pretty shy, but they just told me about it. I figured why not? So, I joined as a student member. And then from there, it just turned into a really great opportunity for engaging with more senior scientists and really hearing the way people think about certain topics or how they sort of plan or organise different events.

And so, after that, I signed up to be programmes chair and then will be the new vice chair. So, it's been a really helpful, successful collaboration. And then I'm in it for the long term.

Lillian Morgado:

I love that, and I cannot overstate, as someone who also joined as a student member, the importance of just being in the room and listening to the people who have been in it for longer, their thought processes and what their thoughts are on the trajectory of things.

I feel like I should say that there's something more structured about the PIAs that is useful, but I think that is one of the most useful experiences, because, you know, different places do webinars, but to get actual time with senior people that's unstructured is really valuable.

Dr Patrick Lao:

Yeah, absolutely.

Lillian Morgado:

What does your PIA have planned for the coming year?

Dr Patrick Lao:

Yeah, so earlier this year, I guess I forgot to mention how this would be another way that the PIA contributes to, I guess, the field of research is that through our ISTAART, we applied for funding from the Alzheimer's Association and we got funding for a conference. And so, this conference is called the Down Syndrome Associated Alzheimer's Disease/Autosomal Dominant Alzheimer's Disease Conference, or essentially the DSAD/ADAD Conference. And it's essentially to bring together researchers from different fields, studying these different kinds of genetic forms of Alzheimer's disease.

And we just had our third meeting, third annual meeting earlier this year. And the fourth one has been announced for London in next fall. So, if anyone's interested in attending that, that one's a really great small format conference that engages the audience a lot. And so, conference planning for that will be ongoing this year. We're also going to have a PIA Day event on July 11th, I believe.

And there, we're going to be talking about the return of results for observational research studies as well as some of these clinical trials. And what's the best way of doing it? Are the participants able to understand this scientific information because it's a risk, not really a diagnosis? And is there any sort of like psychosocial factors that we need to consider in how we relay this information? So, there'll be pre disclosure and post disclosure surveys, interviews, and engagement with MDs throughout the process.

And so that'll be a really interesting topic. That's already a big topic in the non-Down syndrome field on how to do that best. And so, it'll be very interesting to see that panel discussion. And we have two featured research sessions for the conference. One will be on these general timelines, and the other one will be on the risk and resilience factors that pull individuals off of those general timelines.

Lillian Morgado:

Okay, so your PIA Day, you're doing return of results, and is that focused just on the Down syndrome community, or is that in general?

Dr Patrick Lao:

We're going to be bringing experts in general to help inform how we're going to do it for Down syndrome specifically.

Lillian Morgado:

Okay, that is so exciting. I know that's a big new thing everybody wants to make sure they're doing it correctly. So, I'm really excited you guys are looking at that. And then you also said you guys have a featured research session. Do you know what day that's going to be?

Dr Patrick Lao:

I believe they're both on the first day of the conference. First or second day, yeah.

Lillian Morgado:

Okay. You're opening things up, and then you have your whole own conference happening separately. I don't think you're as excited as you really should be about that. Like that's a big deal. (laughs)

Dr Patrick Lao:

Yeah, it has been super successful. That is the brainchild of Dr. Juan Fortea in Barcelona, and he's hosted it there the first three years.

Lillian Morgado:

What a lovely venue. And if somebody wants to learn more about that conference you guys are planning, what should they do or who should they reach out to?

Dr Patrick Lao:

Yeah, they can reach out to anyone in the Down Syndrome Associated Alzheimer's Disease PIA, or they can do a Google search with that great acronym, DSAD/ADAD. (laughs) And then we have a dedicated conference website where they can find more information.

Lillian Morgado:

Before we go, I have one final question. What advice do you have for someone who's just learning about ISTAART and how has it helped you with being involved?

Dr Patrick Lao:

Yeah, that's a great question. I think, because I was so shy at the beginning, just getting involved. So, reaching out to people. They are way nicer than I ever expected, especially with the sort of professional stage difference. But everyone was willing to help answer questions, respond to emails and just, like we said earlier, just being in the room with them. It's just getting involved early, and that really accelerated my career path.

Lillian Morgado:

Thank you so much, Dr Patrick Lao, for taking the time to join us today.

Dr Patrick Lao:

Yeah, thank you.

Lillian Morgado:

Thank you for listening. You can find profiles on myself and my wonderful guest and information on how to become involved in ISTAART on our website at dementiaresearcher.nihr.ac.uk, and also at alz.org/istaart. There's a link in the show notes. I'm Lillian Morgado, and you've been listening to the Relay Podcast from Dementia Researcher and the Alzheimer's Association. Hit subscribe on YouTube or in your favourite podcast app to ensure you don't miss an episode. Thank you so much. Goodbye.

Dr Patrick Lao:

Bye.

Narrator:

You have been listening to the Relay Podcast, delivered as a collaboration between Dementia Researcher and ISTAART. This podcast is made at University College London with generous funding from the NIHR, Race Against Dementia, Alzheimer's Association, Alzheimer's Research UK, and the Alzheimer's Society. Please like and subscribe and share your thoughts in the comments.