Podcast – A longitudinal research study of familial Alzheimer’s disease

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Welcome to the Dementia Researcher Podcast, brought to you by DementiaResearcher.nihr.ac.uk, a network for early career researchers.

Megan Calvert-O’Hare:

Hello everybody. Today, I am joined by Ivanna Pavisic and Antoinette O’Connor who will be discussing their project, longitudinal research study of familial Alzheimer’s disease. Alzheimer’s disease involves a long asymptomatic stage characterized by a number of changes, including amyloid deposition. Which is later accompanied by downstream neuronal degeneration and consequent cognitive decline. The presymptomatic period of Alzheimer’s disease with its sequence of potentially identifiable pathological events opens up an important therapeutic window for secondary prevention at an early and potentially more tractable stage. To take advantage of this window, reliable biomarkers and sensitive cognitive tests are needed. The Dementia Research Centre, the DRC, has had a long-standing research program in autosomal dominantly inherited familial Alzheimer’s disease, FAD. Led by Professor Nick Fox and Ivanna and Antoinette are both part of this centre.

Today, they’re going to talk about how the study provides a unique opportunity to study the presymptomatic period of Alzheimer’s disease as pathogenic mutations are effectively 100% penetrant and the age of onset is relatively consistent within families. So, Ivanna Pavisic is a second year PhD student and Antoinette is a clinical research fellow, both at UCL in the DRC. Welcome to you both.

Dr Antoinette O’Connor:

Thank you.

Ivanna Pavisic:

Thank you.

Megan Calvert-O’Hare:

Maybe we could start with the simple question, what is FAD and how is it diagnosed?

Dr Antoinette O’Connor:

So FAD or familial Alzheimer’s disease is an autosomal dominant or genetic form of Alzheimer’s disease. It’s responsible for less than 1% of Alzheimer’s disease. As you mentioned already, it’s caused by genetic mutations that are effectively 100% penetrant. So that means if one is a mutation carrier and survives long enough, one will inevitably develop the disease.

The mutations are located in the genes PSEN1, PSEN2 and the amyloid precursor protein gene. And actually, the APP gene was discovered here in London, back in the early ’90’s. Familiar Alzheimer’s disease clinically is similar to sporadic onset disease. With the exception of a younger age at onset. Age at onset is typically under 60 and both are characterised by progressive impairment of episodic memory. To come to the second part of your question of how is it diagnosed, familial Alzheimer’s disease can be diagnosed with a blood test looking for the genetic mutation. These tests are offered clinically for diagnostic purposes and those who have symptoms and a suggestive autosomal dominant family history. And by autosomal dominant, I mean every generation of a family is affected and the risk of passing it on if one is a genetic carrier is 50 50 to your children. Family members who are at risk can pursue predictive genetic testing. This requires a period of genetic counselling.

Megan Calvert-O’Hare:

So you’re both focusing on slightly different angles of this but both with the aim of increasing the understanding of FAD and the changes that occur. Could you maybe go into the details of your individual project Ivanna?

Ivanna Pavisic:

Sure. So I guess my projects have two aspects. One, I’m trying to study the early cognitive changes in this cohort. I’m working with one task that was first designed by Yury Petrov from Israel. And it’s actually a cognitive function that we use every day. So, if a person has to remember whether they’ve taken a yellow round pale or a long white one, they need to bind that information on the colour and the shape. And every time someone makes a cup of tea in the kitchen, you need to remember where those specific objects are. So you bind that identity and location.

So they’ve designed some tests, which I’m now looking at longitudinally to see how this performance at this task changes when a person approaches their expected age of onset. Which is the age at which their parents develop up symptoms. And a lot of studies have suggested that this function is impaired quite early on, which is the main reason to use it. And then another side of my PhD is mainly looking at the later clinical features of FAD, which are often under characterised or not well characterised because it’s difficult to follow individuals over time when they lose capacity. So those are the two aspects of my PhD.

Dr Antoinette O’Connor:

So I’m working on a project that’s trying to improve the reliability of biomarkers for detecting and tracking change in presymptomatic disease. With the hope that that will accelerate translational research and improve clinical trial design. Particularly trials in the presymptomatic stage. So one of my projects is looking at the utility of tau pet in presymptomatic Alzheimer’s disease. So I’m doing a longitudinal study to see how that can track change over time. Like Ivanna, I’m also looking at early in neuropsychology changes. Carrying on work done by Phil Weston, who is my predecessor on the familial Alzheimer’s disease study at UCL. And he looked at accelerated forgetting and found that that can detect changes earlier than standard cognitive measures by accelerated forgetting. The process where new material is learned and retained normally but then is forgotten at an abnormally rapid rate. I’m slowly carrying on this cross sectional work to do a longitudinal study to see not only can this detect change before standard measures but also is it better at tracking change over time.

And I’m also doing some collaborative work with Neil Oxtoby on using event-based modelling to determine the sequence and timing of cognitive change in preclinical familial Alzheimer’s disease. And in this, we’ll be including accelerated forgetting but also measures. So, subjective cognitive memory complaints and more standard neuropsychology measures. And also again, carrying on some of Phil Weston’s work with Henrik Zetterberg, looking at blood biomarkers of Alzheimer’s disease. So Phil published on the utility of cross sectional neurofilament light in presymptomatic Alzheimer’s disease. And then I was a co-author on a longitudinal paper showing that it can track change presymptomatically and I’m hoping to continue this work and maybe look at other blood biomarkers like plasma amyloid, potentially.

Megan Calvert-O’Hare:

So you said at the beginning, the familial Alzheimer’s disease represents less than 1% of the population with Alzheimer’s disease. So yeah.

Ivanna Pavisic:

Yeah, yes.

Megan Calvert-O’Hare:

So obviously then you’re using this cohort of people to study because you can track them from presymptomatic because you know with a hundred percent penetrance, they will get Alzheimer’s disease. But does that translate to sporadic cases of Alzheimer’s disease?

Dr Antoinette O’Connor:

So, yeah. That’s a really good question and a really important point. So in fact, lots of the research into familiar Alzheimer’s disease has informed much of our knowledge on sporadic Alzheimer’s disease. So as I mentioned, the discovery of the London mutation in amyloid precursor protein back in the early ’90’s. It was central to the development of the amyloid hypothesis and has really managed to accelerate research in that front. And from work in both the local study here at UCL and also part of the multi-centre study of familial Alzheimer’s, DIAN, we found that amyloid builds up in presymptomatic Alzheimer’s disease up to 20 years before symptom onset. And then this was subsequently found to also be the case in sporadic Alzheimer’s disease. And work done by Nick Fox, who’s my supervisor, he did work in hippocampal atrophy as part of his clinical fellowship with this very same cohort and found its ability to track change in familial Alzheimer’s disease. And now it’s a well-recognised outcome measure in sporadic Alzheimer’s disease.

And in addition, there’s also a similar clinical profile. So the majority of cases in both sporadic onset Alzheimer’s disease and familial Alzheimer’s disease begin with mainly episodic memory impairment. Now there are atypical phenotypes, however that occurs both in sporadic and familial and I think we’ve begun to see, even in more recent research. For instance, I mentioned neurofilament light earlier. We’ve seen that this increases both in MCI stage in sporadic AD but also in presymptomatic familial Alzheimer’s disease. Now obviously, there are important differences and a big part for our work with looking at cognitive change is, in sporadic Alzheimer’s disease, you have to disentangle the effects of Alzheimer’s disease from ageing. Whereas that’s less of an issue in familial Alzheimer’s disease due to the younger age of onset in the cohort.

Megan Calvert-O’Hare:

Because you said the age of onset is typically under 60.

Dr Antoinette O’Connor:

Is typically under 60, yeah.

Megan Calvert-O’Hare:

So 60 isn’t counted as old?

Dr Antoinette O’Connor:

No, exactly.

Megan Calvert-O’Hare:

Okay.

Dr Antoinette O’Connor:

Some of the onset in familial is some of the PSEN1 mutations have an onset as soon as 30, in their 30’s.

Megan Calvert-O’Hare:

Oh okay.

Dr Antoinette O’Connor:

Well, it obviously is an important difference. It does mean that there’s less issues with comorbid pathology. So there’s less comorbidities such as vascular damage. So it’s very pure Alzheimer’s disease model, in a way.

Megan Calvert-O’Hare:

Actually, coming back to that. Ivanna, you said that you’re looking at early cognitive changes but because you can look at it longitudinally… Because you know the parent’s age of onset, you can look at the offspring and say you’re coming up to that age, can we see any changes?

Ivanna Pavisic:

Exactly.

Megan Calvert-O’Hare:

And is it actually quite reliable saying the parents got it at 59, the children will also get it at 59.

Ivanna Pavisic:

I think it’s a tricky question but in general, yes. It’s quite reliable. I think there have been studies showing that it’s not always the case but it’s actually quite reliable. Which is why it’s a great model of AD and works, so yeah. Interesting to look at performance of individuals that are approaching their age at onset because that’s when things normally start to change in terms of symptoms. So yeah, it’s quite reliable.

Megan Calvert-O’Hare:

Okay but you said that the amyloid build up can be starting 20 years before age of onset. So, if someone’s getting it at 30 that’s…

Dr Antoinette O’Connor:

Yeah, one of the biggest studies, Kindreds of Familial Alzheimer’s Disease, in Columbia. Where there’s a PSEN1 E280A mutation. They’ve done some work on how there may even be structural changes before adulthood. Because the age of onset in that mutation is one of the younger ones, in the 30’s or early 40’s, depending. There’s a bit of a range but as Ivanna said, the parental age of onset or the estimated year of onset is reasonably reliable. There’s been a big review by Ryman in neurology in 2014, that did show it had a pretty good correlation.

Megan Calvert-O’Hare:

So with the similar clinical profile between sporadic Alzheimer’s disease and FAD. Is there actually any difference though, in the clinical profile between the different genes affected? So you’ve got PSEN1 and two.

Dr Antoinette O’Connor:

So that’s a really good question. So that’s been a big focus of research actually by another predecessor at the Dementia Research Centre, Natalie Ryan. And she published quite a detailed review in Lancet Neurology on this topic and how there are important phenotypic differences. And that is important to explore because it has important implications or implications for understanding of the pathophysiology of disease. And there’s been other work also the DRC done previously, looking at different atrophy patterns. So we know that amyloid precursor protein gene carrier or the APP mutation carriers tend to have more medial temporal lobe atrophy and thus, typically more present with episodic memory impairment. Whereas PSEN1 mutation, PSEN1 carriers, it tends to be more of a cortical pathology and that can affect presentation. And also even within the PSEN1 mutation before and after coding, 200 behave differently with atypical phenotypes being more common after codon 200.

Megan Calvert-O’Hare:

And is that why it affects people younger?

Dr Antoinette O’Connor:

Yeah.

Megan Calvert-O’Hare:

Because it’s affecting a different area of the brain.

Dr Antoinette O’Connor:

Well, it’s obviously not just the location but there’s probably to do with the pathophysiology and the link between gamma secretase. And it’s ability to cleave APP and the prosectivity of enzymes and how devastating a mutation is, is probably an important implication. There’s been some very nice work by Lucier Chavez Gutierrez, who I’m probably not pronouncing right but in Lausanne who worked in Bart De Stroopers lab, looking at age of onset and enzyme substrate binding and how that can affect age of onset. So it’s definitely an important area. And I think more exploration of that area will provide some important clues into potentially therapy design.

Ivanna Pavisic:

Yeah. Just to add as well, that it would probably inform better patient care as well if we know a bit more about different presentations within genes. Yeah.

Megan Calvert-O’Hare:

Yeah, so about the patients, is there any support out there for those affected or living at risk of FAD?

Ivanna Pavisic:

I think there’s still a lot to be done because it’s such a rare condition, but the DIAN studies, so both the observational and the trials one have various forums and they have a really useful Facebook group that a lot of our research participants often mentioned. And then I’m also one of the facilitators at Rare Dementia Support, which is a UK based charity. Which aims to provide advice, information, guidance on a number of different rare dementias, including FAD. And parts of the work we do is to make sure we’re signposting people to relevant organizations such as Young Dementia UK and Genetic Alliance.

So, I think there is some support out there. There’s still a lot to be done as well, in raising awareness. Because when you increase awareness of certain conditions that inevitably increases the support as well. And actually, there’s a new project that’s going to soon start, led by Professor Seb Crutch. Because at the moment, a lot of the support that we provide as part of our dementia is telephone based and information to websites. Whereas I think the plan is to create a centre where people can go and have one to one discussion and perform different activities. So there is stuff out there, still a lot to be done. Hopefully we’re heading in the right direction.

Megan Calvert-O’Hare:

And so less than 1% obviously counts as rare. What other types of dementia are bound up in the rare types?

Ivanna Pavisic:

Yeah, so posterior cortical atrophy. So PCA is a dementia that normally affects the way you perceive the world. So vision mainly. There is also FTD. So frontotemporal dementia, I’m going to be over simplistic but affects behaviour and social behaviour. And there’s actually a genetic form as well, known as FFTD. And then PPA, primary progressive aphasia affects language mainly. And there are different sub types where people have difficulties understanding the word or pronouncing it. And I think there’s a new group opening up soon with dementia. With dementia with Lewy bodies which isn’t as rare but that’s something that they’re also planning to do soon. I think those are the ones, yeah. Maybe forgetting one. I hope not but yeah.

Megan Calvert-O’Hare:

And how’s your research going at the moment? Do you actually work together on any parts of your research?

Ivanna Pavisic:

So we do work together, which is great. She’s great.

Dr Antoinette O’Connor:

Have to say that.

Ivanna Pavisic:

She’s really nice. It’s actually quite funny because the first two months that we started working together, I couldn’t understand her accent. I’m Italian and she’s Irish and I just had to-

Dr Antoinette O’Connor:

Nod and smile.

Ivanna Pavisic:

Nod and smile. And then I think I’m getting better at it now, which is helpful. Yeah, so I mainly do the cognitive assessments with participants and then Antoinette does more of the clinical and MRI.

Dr Antoinette O’Connor:

Yeah. I do some clinical assessments and bring participants to scan. But yeah, we’re a very collaborative process.

Megan Calvert-O’Hare:

It seems it’s a fairly small cohort of people given the rarity of the DRC. We’ll be working with the same patients.

Dr Antoinette O’Connor:

Yeah and same families.

Ivanna Pavisic:

Which is really nice.

Megan Calvert-O’Hare:

Yeah.

Dr Antoinette O’Connor:

Having seen actually, over the years. So my supervisor would have seen the parents of people that I’m seeing now.

Megan Calvert-O’Hare:

Oh gosh, yeah. Wow. And you said about genetic counselling. Could you elaborate a bit more on what that would mean for the patients?

Dr Antoinette O’Connor:

So because undertaking a presymptomatic test is obviously a big deal. Because it has huge implications for one’s own family, one’s children, one’s future planning. Genetic tests for presymptomatic individuals aren’t just offered as a blood test, people have to be fully informed of the implications before a test is offered when one’s presymptomatic. So, family members can undergo a referral to a genetic service, and they go through a period of counselling sessions with a genetic counsellor before they decide whether they want to have a test. And often people after having a few sessions will decide, actually maybe this isn’t for me. And the majority of participants in our cohorts don’t have a genetic test at the moment because there are no effective treatments. And generally, the majority for a living at risk but there is this opportunity to have genetic counselling. And then a percentage do go on to have the test and find out their stages and data. There is a visit as well after that, to see how they’re doing with that information.

Ivanna Pavisic:

Just to add that it would have to be referred via the GP. So, if an individual is thinking of genetic tests or genetic counselling, it has to go via the GP.

Megan Calvert-O’Hare:

Okay.

Dr Antoinette O’Connor:

And it’s a genetic service, not a neurology based service.

Ivanna Pavisic:

Yeah.

Megan Calvert-O’Hare:

Yeah. Have you had any difficulties with your research? This is a favourite question of the house.

Ivanna Pavisic:

I think it’s tricky to talk about difficulties when you’re just working with such an amazing group of people. And some of the people that we see are our age as well. So it’s just amazing how much dedication, they’re just great. So the only difficulties I would mention are technical problems that we sometimes have. So an MRI running late, in your case. Or just computers not working. Yeah, practical things that happen and you just want to make sure that you’re making use of time for the person there as well. And then in terms of research, I think research in general just takes time and there can be delays, which is just part of academia. So I think the normal amount of difficulties, probably in my case.

Dr Antoinette O’Connor:

When the person working with you can’t understand your accent, it’s a bit of a disadvantage.

Ivanna Pavisic:

But we got over that.

Dr Antoinette O’Connor:

But yeah no, I think research is really rewarding and we’re so fortunate to work with these families. They’re incredibly dedicated and really genuinely inspiring. But I come from a clinical background and I guess when you’re working on a hospital ward or an outpatient clinic, it’s quite easy at the end of the day to say I’ve seen these people, I’ve achieved these things. And there’s more of a tangible, rapid reward. Whereas in research, it’s a longer arch and I remember after the end of my first year going, what on earth have I achieved? And what am I doing here?

But then things happen. You get presentations, you start to see the data coming together and then it becomes quite exciting but it is definitely a slower burn.

Megan Calvert-O’Hare:

Because you’re doing a PhD.

Dr Antoinette O’Connor:

I’m doing a PhD. I’m funded by the Alzheimer’s society doing a clinical research training fellowship and it’s great. I was recently at their conference in London, which was really interesting and they’re great funders. And it’s a great opportunity to have ownership of my own project and getting to look at these areas with these amazing people. So I’m quite lucky to have the opportunity.

Megan Calvert-O’Hare:

Yeah. I guess when you see patients in outpatient clinics, you don’t really see the whole journey. Whereas you’ll see these people for three, four years. However long your PhD is.

Dr Antoinette O’Connor:

Yeah, exactly. And also because you get to learn the stories of their families. Because even when their parents are being diagnosed, it was when familiar Alzheimer’s disease was being discovered. One of the people I see, it was their mother who wrote a letter to John Hardy, having seen a notice in the Alzheimer’s society newsletter back in the ’90’s and saying there’s something wrong with my family. This keeps happening. And she continued to see them and to have that history and to know how it’s evolved and everyone who comes, they’re not only a research participant but a lot of them are carers for their family members. And you get a real insight into not only the difficulties of living at risk or with the knowledge that you’re a mutation carrier, but also the fear. The dealing with being a carer. So it’s a real overview of the condition.

Megan Calvert-O’Hare:

Yeah. And finally, where would you like to take your research given infinite funding and time?

Ivanna Pavisic:

I think making sure that there is enough accessible support for people while we try to find a treatment. I think more of the funding should probably go there. And also of course, just more money for clinical trials that would hopefully work and be disease modifying and not only sometimes.

Megan Calvert-O’Hare:

Because neither of you actually work on treatments, do you? You’re both looking at the-

Dr Antoinette O’Connor:

I, as part of my role do some assessments on a treatment trial that’s ongoing, it’s the DIAN too, treatment trial for familial Alzheimer’s disease. But I’m a teeny tiny cog in a very large machine for that. But yeah I think, having seen the devastating effect of this condition on families, I really hope that my research contributes at least a little bit towards the search for a cure proper and proper trial design at a presymptomatic stage that will lead to an effective treatment.

Ivanna Pavisic:

And we’ve got a great window of opportunity. Hopefully someone can use it properly, yeah. Soon.

Megan Calvert-O’Hare:

Well, thank you both very much. I hope you’ve enjoyed chatting today.

Ivanna Pavisic:

Yes.

Dr Antoinette O’Connor:

I have, thank you.

Megan Calvert-O’Hare:

You are welcome. So it’s time to end today’s podcast. I would like to thank our panellists, Ivanna and Antoinette and you can visit our website to look at the profiles. And if you have anything to add on this topic, please do post your comments. And finally, please remember to subscribe to this podcast. Through SoundCloud and iTunes and Spotify. Please also share and post your review. Thank you.

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