This episode of the Dementia Researcher Podcast continues our coverage from the AD PD Conference 2026 in Copenhagen, one of the largest international meetings focused on Alzheimer’s and Parkinson’s disease.

Hosted by Professor Louise Serpell, the conversation brings together Athina Grigoriou, Dr Lauren O’Neill, and Dr Sofie Let Frandsen, each sharing highlights from across the conference.

The discussion spans a wide range of topics, from the biological role of alpha synuclein and mitochondrial dysfunction, through to emerging therapeutic targets and the growing importance of biomarkers. There is a strong focus on how diseases are more complex and varied than once thought, with increasing attention on stratification, personalised medicine, and early detection.

Alongside the science, the episode also reflects on the importance of patient voices, collaboration across disciplines, and the value of sharing both positive and negative research findings.

This is Part Two of our AD PD 2026 reflections, offering a thoughtful look at where the field is heading next.

ADPD Conference Website - adpd.kenes.com/

Top Takeaways:

• Alpha synuclein may have a normal physiological role, not just a pathological one
• Mitochondrial dysfunction remains central in Parkinson’s mechanisms
• Biomarkers are key for both early detection and patient stratification
• Diseases like Parkinson’s and dementia are highly heterogeneous
• Personalised medicine is becoming a realistic goal, not just an idea
• New therapeutic targets beyond dopamine are emerging
• Early stage and presymptomatic intervention is a major focus
• Patient and carer perspectives remain underrepresented but essential
• Collaboration and openness, including sharing negative results, are vital
• More diverse populations are needed to validate biomarkers globally

A transcript of this show, links and show notes and profile on all our guests are available on our website at www.dementiaresearcher.nihr.ac.uk

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(upbeat music)

- [Voice Over] The Dementia

Researcher Podcast, talking careers,

research, conference highlights,

and so much more.

- Hello and welcome

to the Dementia Researcher Podcast.

Today's episode is coming to you

from ADPD Conference in Copenhagen,

where researchers from around the world

have gathered to share new findings

on Alzheimer's disease,

Parkinson's disease,

and other related

neurodegenerative conditions.

(upbeat music)

I'm Louise Serpell,

a Professor of Biochemistry from

the University of Sussex,

and I'm delighted to be

hosting today's show.

This week, the ADPD Conference

has brought together scientists

working across the full spectrum

of neurodegenerative research

from molecular mechanisms

to biomarkers and clinical trials.

Across the few days,

there have been hundreds of talks

and posters, so rather than

trying to summarise everything,

today, we're going to focus on

a few highlights that really

stood out to our guests

during the meeting.

Joining me are three people

who have been exploring this conference,

Athina, Lauren and Sofie.

And I'm going to ask them each to

introduce themselves and tell you

a little bit about their background.

(upbeat music)

Before we begin, could I ask each

of you to briefly introduce yourselves

and tell listeners what area of

research or work you're involved in.

Athina?

- Hello, I'm Athina Grigoriou

and I'm a second year PhD student

in Dr. David Koss's lab at

the University of Dundee in Scotland.

So we are working on DNA damage,

so basically understanding

the role of DNA damage in dementia

with the Lewy bodies

and then compare it with

other neurodegenerative diseases

such as, Alzheimer's disease.

And specifically, I'm looking

into the role of alpha-synuclein

in DNA damage repair pathways.

And what comes first, basically.

Yeah, that's me, thank you.

- Thank you.

And Lauren?

- Okay, so hi, I am Lauren O'Neill.

I'm also working at the

University of Dundee

alongside Athina in Dr. David Koss's lab.

So my project is looking at elucidating

the mechanisms or specifically,

where alpha-synuclein is gonna

bind on the human genome

in dementia with Lewy bodies

and my background in mitochondrial biology

and also my interest in DNA damage.

I kind of wanna, for my project

ship them these two together to look

at mitochondrial DNA damage specifically

and see if there's alpha-synuclein

you can also bind

in the mitochondrial genome.

- Oh, fantastic.

Sounds really interesting.

And lastly, but not least, Sofie.

- Yeah, hi everyone, I am Sofie Frandsen

and I am a senior research scientist

at a small biotech company

called, Vesper Bio,

which is actually based

here in Copenhagen.

So this year's ADPD Conference

is in my hometown, so that's very nice.

So I am a pharmacist by training

and have done a PhD

focusing on Parkinson's disease.

And right now, I am working at Vesper

who are developing small molecules,

a sortilin inhibitor to increase

the important protein in the brain

called, progranulin, which is

decreased in a lot of

neurodegenerative diseases such as,

FTD, Parkinson's disease,

and also in mood disorders.

So yeah, very nice to be here.

- All right,

thank you very much, Sofie.

So welcome everybody.

So how have you found

the conference so far, enjoyable?

- Very.

- Yes.

- Brilliant.

- A lot of talks,

a lot of good posters.

- Yeah, it is very big.

I think it's one of the biggest

conferences we've been to,

but was talking for myself, yeah.

- Well, just to give the listeners

a bit of a flavour for it,

it's, I think five or

six parallel sessions.

Hundreds and hundreds of posters,

loads of exhibitors, it's a lot.

It's a lot it to try and cover it all.

- Yeah, I think there was over 700 posters

per shift and there's two shifts,

so there's a lot to go around, yeah.

- So you have to pick carefully.

- Yeah.

- Don't you?

- And the prior sessions were like,

there's one in the morning,

there's two in the afternoon,

and I dunno, it was like eight talks

per session, per prior session.

- So I think the app helps a lot

as well because then you can get

an overview of which talks,

you can highlight them as your favourites

because otherwise, there's so many.

- [Prof Louise] Yeah.

- They had an AI summary

as well, so you could go back

and get a report of what the main findings

of the research or each talk.

That was really good.

It was really helpful.

- Yeah, yeah, that's good.

So let's start with Athina.

I would like to know

what you found most interesting.

I think you've picked out one

particular topic you're particularly

interested to do.

- Yeah.

- What about it?

- Sure, I'll go on.

So I really like this talk.

It was by an associate professor

named of Dettmer and he's

a associate professor like I said

at Harvard Medical School

and in the States.

And what he presented is

because it's relevant to my work,

that's why I really liked it.

But what he presented is that

he argued that the phosphorylation

of alpha-synuclein serine 1:9,

which we all know

is the pathological protein found

in dementia with Lewy bodies,

may actually have a normal reversible

physiological role

during synaptic activity.

So he showed a number of,

well, a lot of figures,

a lot of data, and one of the things,

but what they use and is published now

is in cortical neurons,

they showed they're increasing

the network activity using picrotoxin,

it raised this phosphorylation

at serine 1:9

without damaging the total protein,

total alpha-synuclein levels.

They've done this in vivo

and what they've shown again is that,

under environmental enrichment

also increased phosphorylation

of the alpha-synuclein serine 1:9.

And that anyway concluded that there

is a physiological role

of the phosphorylation.

Doesn't mean it doesn't play any role

in disease, but it shows

that there is normal activity.

Then they went and tried knock-ins,

knock-downs, and mutations

and what they showed is that

in a knock-in mouse model where

it prevented the phosphorylation,

it showed that there was a redaction

in an impaired hypercomplexity

and cognitive deficits against suggesting

this physiological phosphorylation,

it contributes to the normal synaptic

transmission and plasticity.

Then he also showed some very,

it's new and published data,

which was really interesting to see.

And what they did is that

they introduced a phosphomimic.

So it was mimicking phosphorylation

and again, they could see all these

impairments in the hippocampal

and the long-term potentiation

and the Y-maze performance.

He said that it raises

two interpretations.

One that there is a dynamic

reversibility of phosphorylation

that is required or whether

the mimic that they use,

it does not function as a true

phosphomimic in cells and it behaves

more like a loss of function.

Yeah, and then I'll keep on going,

how about that.

There's some last things I wanna say

about it is that then they

used the the PLK2 inhibitor,

which we know that is an inhibitor

that it could inhibit the phosphorylation

of serine 1:9 of alpha-synuclein.

And again, they showed that

when they did this,

they actually restored the function

and the neural network

and everything, which was really cool.

So overall what they concluded is

that alpha-synuclein serine

once an phosphorylation

has an important physiological

activity dependent role of the synapses

and it's distinct from its pathological

accumulation in Lewy bodies.

- That's so interesting.

- And it is amazing.

- It's really interesting to think

that the proteins that misfold

in neurodegenerative diseases

also have an important function

and perhaps, you know,

this hyperphosphorylation

or phosphorylation of alpha-synuclein,

and tau, that actually it's part of

a functional role and then somehow,

that regulation goes wrong

and that's maybe what

leads to the pathology.

So it is fascinating.

- Yeah, exactly, that's why

we liked it because

compared the pathological role

and the physiological role.

So it actually shows that

it will be good to look into another way.

Like we just look things in a different

perspective when we are doing this.

Not think that this is just pathology,

you know, there might be

something else there that we don't know.

So it would be good to be

looking both the positive, I think,

and the negatives the same where

that makes sense.

- This is going to be

so important of course when we go

to therapeutics, if you're just going

to clear out this particular phospho

type of alpha-synuclein

and then actually, it's really important,

it sounds like.

And that sounds like they did some

really robust experiments to show that

that actually has a

really functional role.

- Yeah, exactly.

And he was just saying that

this is just preliminary,

but just preliminary data

and published preliminary data

showing this, it means that

there is more to come, you can see that

there is a trajectory there.

- Thank you, Athina,

that really came across

how excited you were about it.

- Yeah.

- That's fantastic, thank you.

So Lauren, do you want to tell us

a bit about what you found really

interesting at the meeting?

- Yeah, of course.

So as I mentioned before,

I come from a mitochondrial background.

So one of the symposiums was looking

at mitochondrial pathways

and so I was instantly drawn towards

that session, one talk in particular

who was by Professor Sarah Berman,

she's a assistant professor

at the University of Pittsburgh.

She was looking at essentially

this complex one PET-binding protein,

it binds to complex one

in the mitochondrial respiratory chain.

So the first complex

oxidative phosphorylation

and essentially, using this

radioligand that binds to complex one,

they're able to see the relative abundance

of complex one in

Parkinson's disease patients

and people who have dementia Lewy bodies.

So this was answering the research

question of disease stratification.

So I think typically, I mean,

I definitely thought this years ago

prior to my PhD, you know,

Parkinson's disease is

Parkinson's disease,

but it seems that you have these

different phenotypes that,

you know, they're all different

types, but under the same umbrella

of Parkinson's disease

of the shared pathology.

So this talk was quite interesting

because it really did kind of,

it really questioned that narrative of,

you know, different types of Parkinson's

disease with different

specific phenotypes.

So the approach that they used was

using this 18FBCPPEF PET,

I know, the radioligand,

so I'll just say that.

And the binding is relative

to the abundance of complex one.

And what they found is

as the disease duration

of Parkinson's disease and dementia

with Lewy bodies ensued in these patients,

the binding of complex

one actually reduced.

So that's kind of supporting

a lot of the literature that

we've known for many years now knowing

that we have complex one dysfunction

in these alpha-synuclein endocrinopathies.

But it was interesting that

it was dependent on disease duration

and it was also particularly

interesting that they found that

those that were actually

complex one deficient were less likely

to like be tremor heavy

for their phenotype.

Whereas, those who weren't deficient

in complex one were more tremor

heavy in their phenotype.

So it's two kind of distinct phenotypes

based on their complex one pathology,

which I found particularly interesting.

And something that I found that really,

it struck me quite strongly

because it does kind of relate

to some of the things that

I did for my PhD project as well,

is that in the earlier stages,

they found that there was actually,

an initial increase

in a peak in complex one binding.

So it's telling us that

there could be an initial compensator

mechanism going on first

and then as pathology ensues,

the mitochondria become overwhelmed.

And you know, as we get an increase

in reactive oxygen species

and a lot of stress, it just starts

to downfall as pathology progresses.

- Really interesting.

So what I remember

and Parkinson's disease

is not my area of expertise,

but complex one was highlighted

particularly because of

the drug-related induced

Parkinson's disease, wasn't it?

- Yes, so I think they found that

in human, I think it was like

an accidental sort of thing.

So there were these people

who had been taking this,

it was like a opioid, it was the MPTP

and then the metabolite MPP+,

it was actually a complex one

inhibitor and it mimicked

and created these Parkinsonian

phenotypes in the people

who've taken this drug.

And we also know that from animal models

and cellular models, they add in rotenone,

which is a complex one inhibitor

also induces this mitochondrial

phenotype associated with Parkinson's

disease, but also, the motor symptoms

in these animal models as well.

- And so are they motor dysfunction heavy,

those particular models or less so?

- I don't actually know.

So this is something that

I found really interesting from this talk

'cause I hadn't come across that before.

Just the case of something

so small as a mitochondrial complex,

the deficiency in that can cause

just such a difference

in the phenotypic presentation.

Yeah, I thought that was amazing.

- It's really fascinating, isn't it?

And I think what you

said at the beginning about

Parkinson's disease, not really

just being one condition

is so important at the moment

because I think there's been a lot of

publicity about understanding

these neurodegenerative diseases

as heterogeneous conditions

with different protein misfolding

and different mechanisms within them

that we really need to try and pinpoint.

So personal medicine is gonna be

so important to sort of work out

and stratify people into

the right categories.

- And just to add on that,

I think that's also very general theme

at ADPD is these biomarkers

that is advancing a lot.

- Yeah.

- But it's both to stratify the patient

and to identify them early

but also, to understand the complexity

of the Parkinson's disease

and Alzheimer's disease.

And there are actually a lot more

comorbidity as well across these disorders

and also just with neuropsychiatry

and so on, so I really think

it's important that we understand.

- Yeah, I was just about to say,

there's a lot of like co-pathologies

and that every single protein,

for example, alpha-synuclein,

you can have the alpha-synuclein

how it forms and aggregates

within dementia, with Lewy bodies,

it's different and Parkinson's

is different in AD.

So there's actually understanding

the different co-pathologies

and those proteins is,

it will be really important for

future treatments, I guess, yeah.

- And as you mentioned,

I think the way forward is

personalised medicine

so hopefully, someday, yeah.

- Yes, maybe in time

for you young people.

- Yeah.

- Hopefully hope, we really, really hope.

Yeah, yeah.

So Sofie, would you like to

tell us what you learned?

- Yes.

So as I mentioned, I really have

always been into Parkinson's disease

and that's been my PhD focus and so on.

So I would just take a step back

and first talk about a talk by

Daniel Kremens who is a co-director

of Parkinson's Disease

and Movement Disorder Centre.

And he talked about the clinical

needs in Parkinson's disease

and how many unmet needs there are

and we're not really treating everything.

And especially, he talked about these

non-motor symptoms

that are not treated in patients

and mentioned the cognitive impairment

and a lot of patients,

they also have hallucinations and so on.

And this is just not treated,

right now, levodopa is still

the golden standard and has

been that for 50 years

and it works good initially,

but it doesn't with time

and may also be related to gut

dysfunction, which is very common

in Parkinson's disease patients.

So I really think he put

like good perspective that

we need some disease modifying treatments

and we need to understand the treatment

better and we need new targets

and we need to not only treat symptomatic.

And in that regards,

I also found both a poster

and also, a talk on a non-dopaminergic

target called, the p75 receptor,

which is also a target we are looking at

at Vesper Bio, so maybe,

I'm also biassed about this,

but the question is that targeting

this neurotrophic or DAF receptor

signalling improved neurodegenerative

diseases and I was very glad

and happy to see that it actually

has some positive outcomes.

So there was a talk from a lab

in Montreal, so in Canada

and then there was also a talk by

Frank Longo who works

at Stanford University

and as I recall it, I hope it's correct,

but he's developed small molecules

to this target, himself

and he has shown that

very positive signals on cognition

and motor behaviour in mice,

but also, saw some reduced tau pathology.

So also has some good indications

in both Alzheimer's disease

and Parkinson's disease

and also, some good effects

on somatic proteins.

So I think it just really gives us some,

yeah, that we can find some new mechanisms

and some hope that we can treat

more disease modifying

and also in the progression stage

and not just symptomatically.

- It makes me wonder, you know,

what p75, is it p75?

- [Sofie] Yes.

- What it does because

is it something like p62 or...

- It actually is,

you can call it a DAF complex

it actually sits in a complex

with sortilin, which is our target.

And so it actually causes apoptosis.

So if you go and inhibit it,

you of course, reduce apoptosis

and then you mature

the pro-neurotrophins or neurotrophins

and then you induce the cell survival.

Yeah, so it can be an indication

of both FTD, Parkinson's disease,

Alzheimer's disease and so on.

So again, this very broad

target for neurodegenerative disorders.

- And do you know what triggers

that pathway that goes

through sortilin and p75 yet?

I mean, is it the protein misfold,

which is what I go to or...

- It could be.

Yeah, yeah, so it's pro-neurotrophins

that bind to this sortilin p75 complex.

So yeah.

Yes.

- Really interesting.

So you're basically

rescuing the cell survival.

- Exactly, yeah.

So you're reducing the apoptosis,

but you're also inducing

the cell survival.

So I think that's a good way to go.

- That sounds like a really

interesting strategy,

completely different maybe

from some of the other ones.

- Exactly, but I think

that's very promising to see

that all these very new

promising mechanisms

and targets to help these diseases.

- Yeah, so I was thinking,

one of the things that struck me

at this meeting has been the emphasis

on biomarkers been fascinating.

And there were a few talks

where they talked about diversity

and whether those biomarkers,

I mean, the one that's been

very publicised is tau p2 and p7.

- Yeah, yeah.

- And whether those

are suitable for biomarkers

in other populations 'cause

there is an emphasis on

western populations generally.

And I just wondered if any of you

have picked up anything about that

in terms of other cohort studies

where they're looking at that.

- I think we've been to a couple talks.

So yeah, like you just said,

they focus on p-tau217, but

this was another talk,

it was on the same biomarkers

like session, but they picked up

on other phosphorylation sites

on the tau protein that they say

that that could be used as a biomarker.

So I think the other one was p264,

if I'm not mistaken.

Dunno if you remember.

- I can't remember

exactly which one it was.

- I think it was 264,

if I'm not mistaken.

- Sounds familiar.

- Yeah, well, it is on a different

side of the protein,

but they showed the use

and number of techniques,

I can't recall all of them right now,

but they showed that that could also

be used with a biomarker

and that it comes early in disease.

You can see there's a lot of people

who are shifting and trying

to find other biomarkers or like

use other different like experiments,

yeah, to understand anyway always.

- Yeah, so that's gonna really

help us with this personalised medicine,

isn't it?

- Yeah.

- But we are really at an

early point in biomarkers,

but it's quite exciting.

- Yeah.

- They found this

particular one that seems to work

really well for at least,

western population.

- Like a very important

point that you did raise though,

you know, we're looking

just at the west right now,

it's very important to make sure

that this is kind of

an overarching thing that

could help everyone around the world.

And if it isn't then,

you know, we need to work harder

for this personalised medicine

to really make sure that,

you know, it's not prioritising

the people that we've just

focused on this particular

mutation and modification,

you need to be helping

everyone who's suffering.

- Yeah, and from a mechanistic point

of view, it's actually really interesting

'cause if you've got a biomarker

that seems to work in one population

and not in another,

then it's really surprising, isn't it?

Because then you think, well,

actually maybe that isn't the mechanism

of the disease and you need to

open your mind a little bit more.

Like you were saying about

these other targets where you

can think about upstream targets

that are really important.

- Yeah, and I think,

it's hopeful to see that the techniques

are also evolving in biomarkers.

There's a lot of multi-omics posters

up there, a lot of talks

on fluid biomarkers.

So I think the field is also evolving,

which is great because it really

gives us a better understanding

of the disease and also just,

yeah, identifying the patients early.

And we need to do that because right now,

we identified them very too late

when they have already evolved

the motor symptoms, for example,

in Parkinson's disease,

but we know they actually

evolved or the disease occurs

initially 10 years or approximately

before they have the motor symptoms, so.

- Yeah, it was also just to

kind of build upon the point

that you'd mentioned before,

kind of how we were talking

about there's not always

just kind of one type of disease.

You have different types.

So I wonder if that kind of

comes into, maybe, it could be that

say p-tau217 is, you know,

kind of common in the west for say

like GWAS studies of what we see,

but then it could be that, you know,

there's another particular phenotype

or like sub-Parkinson's disease

or DLB that is more associated

with other genes that are seen

in other parts of the world as well.

So really highlighting that.

Yeah, it's very different,

but very important to address all.

- And just to add on that,

there were actually some talks,

obviously, there were a lot to go to,

but I've seen the titles

and there were a lot of studies

that they were based,

for example, on the east.

So also there was specific

like Chinese studies or like Amsterdam

or well, Amsterdam is, yeah,

still west, but there were like

in Africa and all this.

So there are initiatives now that

they're making all these studies

in other populations to try

and understand whether

what we see in the west

and whether that relates

back to those populations.

So there is stuff going out there.

- [Prof Louise] Yeah.

- Yeah, it's just

bringing it all together.

- Yeah, and then that also

makes me think about,

there were a few talks focusing

on women in terms of particularly,

Alzheimer's disease.

I'm not sure if there's

a change in preference

in terms of Parkinson's disease.

And I wonder if you found that

there were any talks on that,

because it seems really important

that we're focusing on sort of

classifying people and stratifying

the data to try and work out,

you know, that hormones

may have an effect.

- Yeah, so we know from,

so I mean, there probably was

for dementia Lewy bodies

and Parkinson's disease,

but in dementia Lewy bodies,

there's an increased prevalence

in the male population.

So I think there was one talk, actually,

I can't remember specifically what it was,

but it kind of raised the idea that

there could actually just be

sex differences in synaptic activity,

which could then predispose

to different pathologies

because we know that there's links

between hyperexcitability,

near inflammation, downstream,

mitochondrial dysfunction

that can then be this vicious cycle.

So it's really,

I think very, very interesting,

especially because a lot of the work

that has probably been done years

and years ago would've been on male mice

and you know, it wouldn't have

been fully representative

of the female population,

obviously, Alzheimer's disease being

most prevalent in women, yeah.

- I think that's

still the case,

I think you are more aware of it,

but it's mostly male mice

that are used in research.

And I think we really need to shift

and have both female and male

because as you mentioned, more females,

they get Alzheimer's disease.

- Yeah, yeah.

- Yeah, but also, yeah,

talking about patients and so on.

Just taking a step back,

what I thought a lot about

during this conference is that

there's a lot of cool science

and advanced techniques and so on,

but we are not really thinking

about the patient perspective.

And I actually came across a poster

yesterday by Jacqueline Shapiro

from something called, Cure GRM,

which is patient advocacy organisation

who raises focus on

FTD patients with the GRM mutation.

And she actually had a poster

where she told her family story

and had a lot of photos with

her family and who had unfortunately,

had FTD also because it's very genetic

disease and I think it was so strong

and it was a very personal storytelling.

And I just think we need to remember

that without the patient voices,

they really drive the awareness,

but also the research because

we need them to donate a lot.

And I think sometimes,

I talk to her and she was like,

"I just feel like a number sometimes."

And I really think we need to focus

or just remember

why are we doing what we're doing

because of course, we know it's important.

I think she had a very important point.

- That is a really excellent point.

I was going to ask you

about programme, Lauren,

'cause you mentioned it, didn't you?

And I know, yes, that there's

a variant form that causes FTD.

- Exactly.

- And yeah, I'm surprised

that there aren't more patients

or carers sort of

involved in this meeting,

but then it is quite

sort of in depth high science.

- Yeah.

- It is, but I think it's important

'cause you know, there were sessions

that were like spread out

or there was other, you know,

obviously, we had some breaks,

so it would be really nice,

if on those breaks, we had carers

talking or even patients

like being around.

I think that will make everyone

understand and basically,

recall why I'm doing this,

why I'm doing research.

And yeah, it's really nice

'cause we've seen thousands exhibits,

there were a lot of exhibitions

like that we went to during the breaks

where it be really good

if you had one stand.

If it's just, yeah, just one stand there

where people talking

about their experience,

especially the carers, I guess,

it's really hard for them,

let's just not forget them.

It's not just the patients,

the carers as well.

- I think it's important

that they have a voice, especially

for public engagement

and patient engagement.

You know, letting them have a say,

you don't want them to feel

like a number statistic, you know.

- [Prof Louise] Yeah, yeah.

- You wanna keep them

updated with where the research is going.

- And the genetic forms are obviously,

incredibly difficult because people

actually follow their parents

being ill and declining,

but then know that they have the gene too.

So it's really shocking

to have to live with that.

I can't even imagine, so yeah.

- Yeah.

- And yeah, that makes

it so important then, doesn't it?

- Yeah, a 100%.

And I think you also mentioned

this Sofie, about, you know,

catching, well, not catching,

but you know, determined

presymptomatically,

that is the most

important part to look at.

And it is interesting that even

for Parkinson's disease, Alzheimer's,

dementia Lewy bodies,

you see these changes that go

unnoticed like decades before.

And even, especially

when you were talking about

the gut and the microbiome,

how that can actually have a big role

in actually the onset

of Parkinson's disease especially.

Yeah, considering how many years

it is prior, I think it's very important

to really hone in on these presymptomatic

and prodromal diseases.

- Absolutely, and then we might

be able to identify people

we can treat early enough.

- Yeah, that's the goal.

Yeah, there was a striking code,

I actually took Lauren a photo,

it was the Michael J. Fox Foundation

and they had Michael J. Fox on the poster

and he said, the Parkinson's disease

and cure, we're gonna find

the Parkinson's disease cure

brain in order to do that is

because we're all gonna work together.

So he said, "The reason why

we're gonna find the cure is

because we're all working together."

And that striked me.

I was like, okay, this is really nice.

So I guess, that actually made us

think that we need to publish

what we're publishing,

we need to tell other scientists

and scientists, you know,

need to talk with each other

in order to, you know, share the insights,

and share the thoughts

and how we can like go forward

with this so we can get closer-

- I think that's very important, yeah.

- And also just to communicate

the negative data as well.

- Yeah.

- Because I think that's

also been a problem in the field.

And I think in regards to that,

I think the Novo Nordisk,

the Evoke talks, they were also very good.

I think it was very inspiring

and very clear communicated,

but also very transparent how

they communicated negative results

and were just very honest.

And I think that's so

important for the field as well,

because we also learn a lot

from negative results.

- Yeah, exactly.

- I've also been to a talk yesterday,

it was not my area,

but it was about how A beta 42

and A beta 40, they get

degraded in the liver.

And the first slide the girl had on,

it was all the studies

and all the papers that came out.

Some of them were saying,

"Oh yes, that is true."

And then it was like,

"Oh no, it's not.

And then, "Oh yes."

So you could see like

the different papers.

And then she went on to talk

about her research

and how she found that A beta 42

gets the greater faster in the liver

compared to A beta 40 and all this,

but she showed that

there's still this debate out there.

Yeah, which is really good

because this is how we're gonna

address the questions, I guess.

- Yes, so that openness,

I was really, really informed

by the Evoke study on

the GLP-1 inhibitors.

I just thought that the way,

it was a real exemplar of how

a company who presumably

have put an enormous amount of money

into these trials have actually

offered to share the data,

to publicise exactly what they've done.

And perhaps, this will lead to

something in the future,

we don't know, but for them

to have really talked about it,

I think it's fascinating.

I mean, it seems sort of

plausible that it might be a good target,

but obviously, not in that trial.

And so interesting to see

what will happen next in that area.

I just hope that they keep being open.

- Yes, I agree.

- Yeah, I mean,

the best thing would be, you know,

like a repurpose in a drug

that already exists, I suppose,

you know, there's actually evidence for,

I think it's metformin,

the diabetes drug and it's actually

reduced in those who have diabetes

and that are on metformin

there's a reduced incidence

of Alzheimer's disease.

So I think even if it's not just

neuroscience, but everyone collaborating

and everything that we know,

you know, and yeah.

- Yeah, so the talk we went

this morning by Doug Orsland, yeah,

he was-

- Who was it?

- Doug Orsland, I think, yeah.

I think, yeah, so yeah.

Well, I've seen his talk before

once in another conference

and it was really interesting.

So we just rushed this morning

to get here to see his talk.

But he was talking about

the new perspectives in dementia

with Lewy bodies and Parkinson's disease

and all the clinical trials

that this happening.

And I think they've also used,

was it Metformin that they were using?

- Yeah, I think.

- It was, yeah.

So they're using this drug,

so for DLB and they showed some

cognitive advances and that is great.

So just said that

the Reese clinical trials coming out

for these diseases that is dementia

with Lewy bodies, but we need more.

Yeah, so it was really good.

It was really, really good.

- Really exciting meeting.

So we probably should be wrapping up.

So I'm just thinking,

was there any particular research area

that any of you just think,

you know, is the future

where this field should be really

focusing their ideas

and where think we

should all be going next?

- Big question.

- That's a big question.

- Yeah, yeah.

I think we all have

our own preferences and buying.

- Yeah.

- You know, our backgrounds.

- I think the bio is a very,

yeah, theme that goes again along

in many talks, I think yeah,

understanding, but for just

a researcher as we are,

I think just coming to these

conferences and getting inspired

on what's moving in the field

and which models to use

to be more translatable,

for example, to the diseases.

And I've learned a lot on

which in vivo models also to use

in the field and they get more and more,

yeah, specific also to, for example,

if you have lysosomal dysfunction

and Parkinson's disease,

you can actually create a mouse model

that is linked to a

GBA mutation and so on.

And also just to see that a lot of

complex cell models also evolving

and being validated well.

And I think that's really

a good way to go in the research field

to have these complex models

that really represent the human body

and the disease the best way.

- Yeah, yeah, good point, I agree.

And I suppose, I thought maybe

you meant in terms of like the theme

of like where research is mainly going.

I'd say there was a lot of focus on

neuroinflammation a few years ago,

but I'd say, I think because

of the link between, you know,

where we talk about metformin

and how, I think there's a lot

to speak about when

it comes to like hormonal changes.

You know, if you have diabetes,

all these different other factors

like epigenetic modifications.

I just think it's really important

that it's kind of seen more

as kind of a whole,

I know it's easy to really

hone in on just one particular thing,

especially when we're researchers

and we're looking at literally

like molecular basis, but yeah,

I think maybe if there's

more collaboration between clinicians

and the researchers to kind of have

more of those discussions,

I think that would help the way forward.

- And that reminds us about

being patient-centered, doesn't it?

- Yeah.

- Because one of the things

that I've talked about is

that Alzheimer's disease, for example,

takes your whole life to develop

and it's about, you know,

the experiences and the genetics

and the environment of the person

and what leads to that

outcome and presumably,

the same for Parkinson's disease.

So just thinking about

exactly the hormones and the effects.

One thing I thought was missing actually,

which I was a bit surprised about,

was there was nothing about infection.

So I think a few years ago,

there was an idea that if you

are protected against herpes virus,

that you would

have a resilience to Alzheimer's disease.

And I didn't see anything

about that this time.

- I didn't really catch

anything like that.

- No, no.

- It was quite interesting

'cause I do think that if you are to get

a severe infection then, you know,

it sort of makes sense, doesn't it?

That it could trigger changes

and dysfunction, so it's quite

interesting that that didn't come up.

- No, that's true

and that it's actually also

true with the neuroinflammation.

I think there's been a lot

of talks focusing on the lipids

and the lysosomes especially,

in both Alzheimer's and Parkinson's.

(upbeat music)

- So it's been a really

fantastic conversation.

I've really enjoyed talking to you all.

And I just wondered if any of you

presented posters or talks

at this meeting and whether you

wanted to say a little bit

about what you did.

- You can go.

- Oh yeah, yeah.

I did have a poster.

I was on the first shift 'cause

there was two shifts for

the whole conference.

And my poster focused more on

the cytoplasmic to nuclear translocation

that I see in dementia with Lewy bodies

and Alzheimer's disease cases.

So I am using postmortem brain tissue

as well as, brain slides

from the frontal cortex of patients

from the control cases,

prodromal Alzheimer's disease

and dementia with Lewy bodies.

And specifically, for the postmortem

brain tissue, what I do is,

I fractionate the tissue into the nucleus

and the cytoplasmic fractions.

And what I saw was really interesting,

we still don't understand it

when we're still in the process

of increasing our end numbers,

is that we do see there's differences

in the cytoplasmic

and the nuclear fractions on dementia,

sorry, in DNA damage repair proteins

'cause like I said before,

I'm interested in the role

of these proteins and in disease

and we do see that there

is a downregulation

of this proteins of the Ku70

and the APEX1 protein

in the cytoplasmic fraction.

And there is a potential

upregulation in the nuclear fraction.

We're still trying to understand,

there's a lot of variability especially

in dementia with Lewy bodies.

Which brings back to the question

actually, and these disease dementia

with Lewy bodies actually might

not be pure that all these

co-pathologies that we were talking

before actually contribute to all

the changes that we observe

and this variability that we observe.

But then I've also used brain tissue sites

to stain for Ku70 and APEX1 proteins.

And again, I do see this shift

from the cytoplasm into

the nucleus in Alzheimer's disease

and dementia with Lewy bodies cases,

which is really striking.

So then something else that

I am working on is cellular models.

So we try to have a shift

and get a step back to understand

the mechanism of why

we're seeing what we're seeing.

So I am using the SH-SY5Y cells,

some differentiate in

neuron like phenotypes.

And in order to induce DNA damage,

I use etoposide,

which is a top mastocytosis 2 inhibitor

and something that's really striking.

And what we observe is that

when we induce DNA damage using

this chemotherapeutic drug etoposide,

I see that there is an increase

of phosphorylated nucleus in

with increase in concentrations

of the drug without any changes

in the total levels of alpha-synuclein

and the total levels of tau.

And I don't see any

phosphorylation of tau.

That's why I really love that talk

as well 'cause they do see

like similar things.

And also, so we're in the process

of doing further experiments on this

and like splitting into

the nuclear cytoplasmic fractions.

And also, we've also produced

generated some preformed fibrils

from alpha-synuclein using

the Michael J. Fox Foundation protocol.

And we wanna use these preexisting

pathology, the preformed fibrils

with and without the DNA damage

inducing agent atococyte

to see what comes first.

So try and understand basically,

the basics behind what we see.

Yeah, so it's an exciting work.

But yeah, that is all me.

That's what my poster was about.

- Well, that sounds really interesting.

So I really look forward to

hearing what happens in the end.

- Thank you very much.

Yeah, yeah.

- [Prof Louise] So exciting.

- Thank you.

- [Prof Louise] What about you, Lauren?

- So I also had a poster.

So I actually have only recently

started my postdoctoral position

at the University of Dundee,

but I have my finalised work

for my PhD at Newcastle University.

So that's what I presented in the poster.

So what I've shown using

a transgenic mouse model

of ultrasound endocrinopathies,

A30P mouse, I looked at

a presymptomatic age range

between two and four months.

And I specifically wanted to look

at the hippocampus

and the hippocampal neurons.

And it was actually kind of like

an accident as to how I found this

is when I zoomed in on the images

and the parietal layer,

I saw that there was kind of

differential expression of

alpha-synuclein in the A30P mouse

between cells of the same mouse.

And I thought it was quite strange.

I did a frequency distribution

and I categorise these cells

that are having low, medium,

high levels of alpha-synuclein.

And I went to look at

how the mitochondrial

respiratory chain subunits

are impacted when there is either

low, medium or high

levels of alpha-synuclein.

And interestingly, we found that

in the cells that had the very

high levels of alpha-synuclein,

there was a significant increase

in mitochondrial complex one subunit

and also, mitochondrial complex four.

Which is interesting because

from what Sarah Berman shown in

patient data that there

was actually initial increase.

So I thought it kind

of linked very nicely,

I know that I was using a mouse model,

but it's reassuring that, you know,

it's actually seen in some patient data

as well that it might be a commonality of

this compensatory response initially.

- That's what conferences

are for really, isn't it,

when you really get some sort of

backup on what you think

and then you start thinking about

how that compares to other people.

That sounds fantastic.

- Yeah.

- Really exciting stuff.

- Thanks.

- What about you, Sofie?

- Yes, yes.

So I-

- You gave a talk

for a YouTube video.

- Yes, that's true, yes.

So I did present a poster as well.

And that was for Vesper Bio,

which I just mentioned before.

We developed small molecules,

sortilin inhibitors,

and we actually have one called,

(indistinct) which has just finalised

or completed a Phase 1b/2a trial.

And we have a talk later today

on the safety and the efficacy of that.

And I can spoil alert, it's good.

But I did present

more the preclinical stuff.

So as I mentioned, we increase

by blocking the sortilin receptor,

we increase the very important

progranulin protein in the brain.

And we do it both extracellularly,

but also intracellularly.

So by that, we improve the lysosomal

function, it's neuroprotective,

but also, anti-inflammatory.

So that's very good.

And then I talked a lot about

the potential we have in Parkinson's

disease because that we

are in a very preclinical stage.

And that's especially with

the DAF complex I mentioned before.

So the sortilin p75 DAF complex,

which especially is on

the dopaminergic neurons in

the substantia nigra pars compacta.

So very important

for Parkinson's disease patients.

So when we block that,

we increase the cell survival.

And right now,

we're in a very beginning stage.

So we've actually tried with

the AV, the viral

alpha-synuclein mouse model.

Unfortunately, it was a very harsh model.

So we saw 90% loss of

the dopaminergic cells, which is a lot.

So unfortunately, we couldn't really

rescue anything that wasn't there.

So I mean, we've also really

learned a lot from this conference

and got a lot of good feedback

on what the next steps are.

And we are very lucky to have

a funding from the Michael J. Fox

as well, which are really incredible

to work with and have also

had a lot of good talks with them

here at at the conference.

(upbeat music)

- So that brings us to

the end of our ADPD Conference,

reflections from Copenhagen.

Thank you all so much for

your fantastic input and discussion.

I really enjoyed it.

I hope you did too.

Good luck on going home,

although, don't have to go far.

- Not so far.

- If you want to learn more about

the research we discussed today,

you can find links and further

information in the show notes.

On our YouTube channel,

you'll find many of the

posters short recordings.

I've listened to them and watched them

and they are really fantastic.

I'm so impressed with the way

that people are able to communicate

their research as you've seen today.

So the researchers will share

short summaries of their work

presented at the conference.

But for now, I'm Professor Louise Serpell

and you've been listening

to the Dementia Researcher Podcast.

Goodbye.

- Bye.

(upbeat music)

- [Voice Over] The Dementia Researcher

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from the UK National Institute

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