The challenge of dementia | Nobel Week Dialogue 2025 | Health For All

0:00 I wanted to start out with the idea of biomarkers for dementia

0:03 and this topic is really going to be focused on the challenge of dementia.

0:07 And so Henrik, you know,

0:08 you have been central to the revolution in fluid biomarkers.

0:12 Your whole career has really been focused on that to some extent.

0:15 So what do you think is the most transformative advance in the field today?

0:20 Barbara and I don't agree on this.

0:21 That's good.

0:23 The whole concept of dementia has changed during the past 10-20 years.

0:29 Everything 10-20 years back it was regarded as a part of aging.

0:34 Now we know that the dementias are caused

0:36 by many different diseases and they are molecular in essence.

0:40 So there are brain tissue changes that we can

0:42 measure and this is where the biomarkers come in.

0:46 20 years ago one had to do an autopsy

0:49 examining the brain of a dead patient, not very helpful.

0:52 But now we can measure the protein changes that occur

0:56 in Alzheimer's disease in biofluids and treating which is your expertise

1:01 in living people and then it has become clear

1:04 that these are relatively distinct diseases that happen in the aging brain.

1:09 It can also happen early in life if you have genetic susceptibility.

1:13 It's measurable.

1:14 It's not something that just will happen to all of us.

1:19 These are diseases that we should try to diagnose

1:23 and try to treat and optimally this is where we discuss a lot try to prevent

1:29 which I think is almost impossible but that's

1:32 going to talk about that too but he he thinks

1:34 there's some contention here that you don't believe in biomarkers.

1:37 That was the implication.

1:39 no.

1:40 [laughter] No, I do believe in biomarkers just to be clear.

1:42 Um but there has been um as Henrik mentioned a a shift in the field

1:47 with regard to how we think about

1:48 dementia and the pathologies that caused dementia.

1:53 And uh for the first time we also

1:55 have disease modifying medications which is a big

1:58 shift in the field and makes the work

2:00 of of biomarker research so much more important.

2:04 Um for over 20 years we didn't have any new uh medicines for Alzheimer's disease

2:10 and now we have promising new treatments that actually

2:13 target specifically the pathologies that underlie Alzheimer's disease.

2:19 So uh that does give us optimism and it's a really nice compliment to the work

2:25 that you see with regard to diagnosing the disease

2:28 with fluid biomarkers or brain imaging or other methods.

2:31 So do you think there's a lot of barriers?

2:32 I'm going to start with the biomarker issue here though.

2:34 Um moving that from the laboratory to the clinic.

2:37 It seems like it's working now.

2:38 You have a translation of biomarker biology into clinical diagnostics.

2:44 Is that solid?

2:46 Yeah, so the you know,

2:47 with regard to um particularly the work that Henrik's doing

2:51 and now we can compliment each other and not fight.

2:54 But the the work that you're doing um

2:56 has really advanced the field because you can measure

2:59 the pathologies using a blood test which is quite

3:02 different um from what we had 10 years ago even.

3:06 Um and so that makes the clinical care easier.

3:11 On the other hand uh the treatments that we have

3:13 for Alzheimer's disease right now um do require delivery in specialized centers.

3:19 So that can be actually a barrier to treatment.

3:23 Uh the new treatments uh that are being used right

3:25 now they require an infusion um due to some safety monitoring.

3:30 They also require uh brain imaging to make sure that you

3:34 can care for the patient and make sure that they

3:36 don't have any uh vascular injury during the treatment and those are

3:40 the kinds of resources that you don't find um globally.

3:45 So just give us a some sense of how many different

3:47 clinical trials are underway and how many uh treatments are available.

3:53 Now there are hundreds of trials that are ongoing and many have

3:57 been focused on Alzheimer's disease which is the most common dementia causing

4:01 disease where beta amyloid clumps in the brain disturb the neural networks

4:06 and make them dysfunctional and eventually

4:08 neurons die off in a neurodegenerative process.

4:12 And there there are that's where we have seen the big progress lately.

4:16 In the Alzheimer's In the Alzheimer's field.

4:18 For the other dementia causing diseases progress has been slower.

4:22 They are likely a little bit more tricky to to address but we have seen

4:27 breakthroughs the past 10 years in neurodegeneration

4:31 in general and there is a very prominent success story in regards to a rare

4:37 disease called spinal muscular atrophy that kills kids

4:41 with mutations in a gene that helps

4:42 the motor neurons of the spinal cord survive.

4:45 There is a cure for that disease which is amazing.

4:48 So for a while pharma and and also researchers thought

4:52 that neurodegeneration was too difficult and that one should try to many

4:58 of the big pharma companies stepped out from out of neurodegeneration

5:02 research a while ago but now there is much more hope.

5:05 Uh so we've seen it in spinal muscular atrophy.

5:09 We have also seen a couple of new

5:11 interesting treatments against ALS which is a terrible disease.

5:15 Uh but you also seem to be able to modify

5:18 the disease onset by having a molecularly target targeted uh drug.

5:23 And is that partly because the disease classification

5:25 is more clear in these cases you've given now?

5:28 It is partly improved diagnostics so that we measure the underlying pathology.

5:35 Uh with Alzheimer's disease if you have a patient with memory

5:38 complaints there could be many reasons for that apart from Alzheimer's disease

5:43 and when using these biomarkers one has to do a complete medical

5:46 evaluation which any doctor should be able to do to examine bodily functions,

5:52 thyroid hormone levels, calcium, of course type 2 diabetes,

5:56 also looking into psychiatry with depression.

5:58 And then you address the neurodegenerative aspects with imaging and biomarkers.

6:03 Well, I wanted to ask Barb what do you what gives you

6:05 hope in terms of the treatment uh the trials and also the options?

6:09 So I think what again where we have optimism is that it has

6:13 been so many years since we have had new treatments for Alzheimer's disease.

6:18 So having new treatments has now brought fresh momentum to the field.

6:23 Um pharmacy is interested in developing treatments.

6:26 We've had some successes and it's really moving towards

6:30 probably we're going to have more treatments that work better,

6:35 that have better safety profiles and with that momentum

6:38 it's going to become possible I think to cure dementia.

6:43 Right now the treatments aren't curative.

6:44 They really are lifelong therapies.

6:47 Is that correct what we see?

6:49 And also the treatments are not I mean to some extent

6:52 I can't help but thinking they are a little bit of miracle

6:54 drugs because they are very effective at removing the amyloid from the brain

6:59 and most of us think that the amyloid is really important.

7:04 But the the clinical benefit has been discussed.

7:07 Uh so one could say that okay these new treatments might slow down the disease

7:12 by 30% and then there is

7:14 in the interindividual variation also in responders and non-responders.

7:18 But as you said Barb there are some

7:22 now tweaks to these anti-amyloid antibodies that will help

7:27 them to cross the blood-brain barrier more efficiently

7:30 and those drugs might turn out to be very useful.

7:33 But we are very far from health for all in this field.

7:38 Well, I wanted to move to things like you know,

7:39 in that respect modifiable risk factors, lifestyle.

7:43 You know, how much can we prevent uh dementia?

7:48 Yeah.

7:49 So genetics most certainly are important.

7:52 Um but I think so an example that really illustrates

7:55 how modifiable risk factors come into play is when you

7:58 think about for example genetically identical twins and there is

8:02 actually um discordance in genetically identical twins who develop dementia.

8:07 So one twin might develop dementia um and then the other person might

8:12 not develop it till 3-5 up to 18 years discordance has been observed.

8:17 So that tells you that there's something about

8:19 um the exposures over the lifetime perhaps or lifestyle

8:22 which kind of fits into this picture that are

8:25 uh affecting people's uh risk for developing dementia.

8:30 Um Are there clues what if these maybe epigenetic

8:33 factors are how the lifestyle can influence the genome?

8:37 Are there is it diet, smoking?

8:39 well there's a really nice um kind of term for this and it's the exposome.

8:43 So it complements the idea of the genome.

8:46 Uh the exposome is all of your exposures from in utero until later life.

8:52 Um just to stick on the topic of genetic twins,

8:54 there was another study that was done in uh

8:58 middle-aged men where they evaluated their lifestyle factors at midlife.

9:02 So smoking, alcohol, uh physical activity, cardiovascular risk factors.

9:08 And then those same men had brain imaging 20 years later and what

9:12 they saw was among the twin um the twins who had less physical activity,

9:18 more that those individuals showed more brain changes.

9:24 So more shrinkage of the brain, more vascular injury.

9:28 So we know that there are these relationships

9:31 between the modifiable risk factors and brain health.

9:35 And there's now also been some very

9:37 large clinical trials using um multifactorial interventions.

9:42 So not just one modifiable risk factor but multiple risk factors.

9:47 Can we change those in later life?

9:50 And then what you see is actually um maintained and improved cognition.

9:54 So So also now have some gold standard uh clinical trial results.

10:00 I I don't believe in this paper.

10:01 Well, I just before I want to I think it's all genes.

10:04 The more you continue on I want to continue

10:06 on the topic of I do want to continue.

10:08 I'm going to let you unpack that, but just a [laughter] curiosity question.

10:12 How reliable are animal models then

10:14 for for for studying in the clinical condition here?

10:17 Because you you have to imagine that dementia takes

10:19 many years to be able to manifest this disease.

10:22 And sometimes it takes a long time to be able to test your hypothesis.

10:25 So can we use animal models in this case or we're using epidemiological data?

10:30 So um epidemiological data has been very helpful in identifying

10:36 some of these factors that could potentially be modified.

10:40 But then, you know, um what what really has I think changed the field now

10:44 is this idea of doing randomized controlled clinical

10:48 trials just like you do with the drugs,

10:50 but in this sense prescribing a lifestyle.

10:53 the lifestyle or health behaviors.

10:55 But he's skeptical.

10:57 Yeah, I I it's like this.

10:59 I have to of course have to look at the data.

11:03 So and I agree that there seems to be modifiable risk factors.

11:07 Okay.

11:07 A little bit.

11:08 You agree.

11:08 A little bit.

11:09 bit.

11:10 So I think that if you are if you have the genetics that tells

11:14 you that you have if you look in in your family for example,

11:17 if you see that people get old get demented,

11:19 then there is a big genetic risk for aging in that way.

11:22 If you get to live that long, that's another that's another challenge.

11:27 Um and then if you maintain your cardiovascular fit the system fit,

11:33 then you will also maintain your cerebral vascular system in a good

11:37 Everything goes back to the heart.

11:38 Everything goes back to the heart.

11:39 So everything that's good for the heart is good for the brain.

11:41 Okay.

11:42 But that's details to me because then I think you will still if

11:46 you have a high genetic risk get the amyloid process of the brain.

11:50 It's like a if you might remember the mad cow disaster

11:56 that happened with infectious proteins

11:57 that propagate propagate along the brain tissue.

12:00 It's a little bit similar with these types of diseases,

12:03 but then you can resist the process better if you

12:08 have a healthy cerebral vascular system and good brain networks.

12:13 like you agree actually.

12:15 Go ahead, Barb.

12:16 There is another important point to be made and that is

12:18 that you can do everything right and still get dementia.

12:23 And we definitely don't place, you know,

12:26 this idea that you you got dementia because you didn't do things right.

12:31 That's that's absolutely not what we what we think.

12:34 Um but in in that sense as well,

12:37 I think um it's important to also consider that um

12:41 only so much of our behavior is actually under our own

12:43 control because there are factors around us all the time

12:47 that are pressing on us and are modifying our behaviors.

12:51 Um it might be also the case that over

12:53 the lifetime you've been exposed to to toxins or pollution,

12:58 which increases risk for cardiovascular

13:00 windows of time in our life where that's really critical.

13:03 Absolutely.

13:03 we heard a little bit about adolescence earlier here um in the preceding talk.

13:07 You know, could be a window of time where we have

13:09 an exposure that actually manifests uh disease phenotype much later in life.

13:14 Absolutely.

13:14 And there I you know, well, when I started in this field,

13:17 there was an idea that midlife was the critical period.

13:21 That that's when trajectories of aging change.

13:24 But we've now seen that that's backed up even further.

13:27 And there's study now studies now that suggest that even

13:31 early life exposures are influencing brain health tens of, you know,

13:36 decades later, which is pretty fascinating.

13:38 All right, we've got 2 minutes.

13:39 You each get a minute.

13:40 What do you think is sort of the big breakthrough that we're waiting for?

13:44 Yeah, I hope for refined refinement of the existing treatments.

13:48 And since we are in Sweden now,

13:49 these treatments are not in clinical practice yet,

13:52 but they are we're getting a lot of knowledge

13:54 from the US and other countries where they are.

13:56 Uh so I hope that that will happen in the European

13:59 countries and in other countries across across the world.

14:02 I also hope that we will tweak

14:04 these drugs and make them accessible through not infusions,

14:07 but that you can give them yourself sub Or maybe tablets.

14:10 Tablets, that would be wonderful.

14:12 There are also some exciting approaches to develop drugs

14:16 that could that could be taken as a pill

14:19 to modify what types of beta amyloid proteins you

14:22 are secreting and thereby delaying onset of the pro process.

14:26 Then we also need to tackle all the other diseases,

14:29 cardiovascular disease, frontotemporal dementia, Lewy body dementia.

14:32 So Those of you want to enter science That's your 5 seconds left.

14:36 Okay, you got you had your minute.

14:38 That's great.

14:38 Now Barb, you get the last word.

14:40 you know, I'll I'll take up from where you

14:41 left off about if you want to enter science,

14:45 there's still a lot of need, a lot of research that needs to be done.

14:49 And we absolutely need to support the next generation.

14:53 And one of the things that I've observed recently is

14:56 that when there's uncertainty around funding for example for research,

15:01 that individuals who are planning to work in these fields

15:05 sometimes also feel uncertainty and might step back.

15:10 And so we definitely don't want to lose this momentum

15:12 right when all of these exciting things are happening.

15:16 So I also I agree with you.

15:17 We need to encourage the next generation.

15:19 All right.

15:20 Well said.

15:21 Thank you very much for that.

15:22 And it's indeed exciting times.

15:24 Thanks.

15:25 Thank you.

15:27 [applause] That's great.