Horizons from PBS News

I'm William Brangham and this is "Horizons."

Over 55 million people worldwide are living with the devastating reality of dementia.

But researchers have now identified some individuals who share a rare genetic predisposition to developing a type of this tragic disease.

Could studying these families unlock new ways to predict, treat, or even prevent Alzheimer's and dementia?

Coming up next.

♪ Narrator: Support for "Horizons" has been provided by Steve and Marilyn Kerman and the Gordon and Betty Moore Foundation.

Additional support is provided by Friends of the News Hour.

♪ This program was made possible by contributions to your PBS station from viewers like you.

Thank you.

From the David M. Rubenstein Studio at WETA in Washington, here is William Brangham.

Welcome to "Horizons."

Dementia is often called "the thief" for the way it steals memory from people.

In time, dementia also steals that person away from their loved ones.

Among the millions worldwide who suffer from dementia, the majority of them have Alzheimer's disease.

And even though scientists have identified the proteins in the brain that, when they mutate and deform, are the hallmarks of Alzheimer's, there's still no way to prevent, let alone cure, it or dementia.

So the thief continues to steal.

There are other much rarer types of dementia.

One is called frontotemporal dementia, or FTD.

And it robs people in an especially pernicious way.

Not only does it strike much earlier in life, as early as their mid-40s, but it also alters people's personality first, impairing their judgment, stripping away inhibitions, and changing them in essential foundational ways.

A new book tells the heartbreaking story of one family who have a genetic mutation that makes them vulnerable to developing FTD.

But it also details how their condition could hold a clue to prevent and treat all forms of dementia.

The book is called "The Vanishing Family, "Love, Fate, and the Quest to End Dementia."

And its author, Robert Kolker, is here today.

Kolker is a contributing writer to the New York Times Magazine, and he was the author of the 2020 bestseller "Hidden Valley Road."

Bob Kolker, so good to have you.

I cannot tell you what a tremendous piece of writing... This book is just such a powerful story that you tell.

It is, as I mentioned, telling the story of a family from Pennsylvania, and members of the family start to recognize that something is wrong with Mom, Jean.

Can you just tell us, what did they start to see about Mom?

Thank you, William.

I'm really glad to be here.

This is a family with nine children and very much an ordinary middle-class family in suburban Pennsylvania.

And the trouble starts in the 80s when a lot of the kids have already left the nest, but some are left behind to see their mother, Jean, go through something strange.

She used to be a very put-together person, kind of a pillar of the community, reading to her kids, and suddenly she doesn't care about any of that anymore.

And her personality begins to change.

She becomes a hard drinker, and she becomes checked out and less invested in parenting her children.

And the family searches for answers, and they find some pretty easy ones.

Her marriage is falling apart.

Perhaps she's an alcoholic.

She hasn't taken good care of herself.

Maybe she's menopausal.

Brangham: All the classic, like, 80s excuses for why an upstanding woman might seem to hit the skids a little bit.

Exactly, and it's a mixture of things, right?

It's no one wants to assume the worst, and also nobody wants to be that family where the worst is happening, so you try to keep living the way you always have.

But it gets worse and worse.

They have an intervention for her.

Eventually, cancer takes her before they even know what's wrong with her.

And so the family continues on well into the 90s not realizing that there's something neurological going on.

And then something happens to one of the eldest daughters, Christy, in a similar sort of dissolution.

Over the course of the book, you detail the long investigation they go through to try to figure out what this actually is.

And as I mentioned, it is this specific type of dementia, FTD.

What is it?

What is it that is afflicting them?

It's so interesting, William, because genetically it's kind of a cousin to Alzheimer's and might even be a backdoor to understanding and treating Alzheimer's one day.

But symptomatically, in the beginning, it's very different.

Instead of hitting your memory or your cognition, the way that we think about Alzheimer's, it hits your impulsivity and your apathy and your personality.

It hits your frontal lobes, which, you know, the shorthand for frontal lobes is executive function, right?

But really, it's more than executive function.

It's also triaging all the information that comes into your brain and deciding whether those social cues even matter.

So it's not like the people who have it become narcissistic or become evil.

It's simply that they become less capable of understanding that other people have wants and needs.

So they almost become like children at first.

They do what they want to do when they want to do it and don't think about social consequences, and they care less about the people around them.

It's really a shock to everyone around them, perhaps except them, because they don't believe anything is happening.

And as you document so sort of tragically and beautifully, that the way in which the family members are interacting, the people who are afflicted by this, and again, not really knowing what's going on, it's not like they're being violent or they're being offensive to people.

It's just that they are slowly stepping away and fading away in a way that no one in the family can quite figure out what's going on.

And I've met lots of families who have suffered afflictions like this, and the diagnosis always takes years and years, because everybody thinks it might be something else, and everybody thinks that the person will snap out of it sooner or later.

But what's happening is something neurological, neurodegenerative, and because, as a culture, we really equate neurodegeneration with senility or with Alzheimer's or garden-variety dementia, we don't realize just how broad and widespread the conditions can be.

Think about people, for instance, living on the street who really can't take care of themselves.

A good number of them, researchers say, may simply have neurological conditions that then lead to things like homelessness and addiction.

It really is quite something.

I mean, you could imagine many members of this family, as you detail, if they did not have the extraordinary support network that this family can provide, principally through one of the daughters, that they would be living on the street.

They would absolutely not be able to function.

I write a lot about families.

This is my third book about families, and the interesting thing about families is you see every possibility come to life, particularly with a large family.

There are people here who were Fortune 500 executives or were scientists and engineers whose lives are completely transformed.

There is one who becomes homeless for a while.

There's another who runs away from the family and, you know, severs all connections.

And then there are people who rise to the occasion and become the most amazing caregivers and crusaders.

The family stories are always inspirational to me.

The family goes through this long search, and the frustrations and the misdiagnoses and the tests that go nowhere finally culminate in them understanding that they do have this genetic mutation.

I can't remember what the acronym for it is, V337M, something like that.

And that it gives everyone in the family potentially a 50-50 chance of having this.

Can you just talk a little bit about what that is like?

If you know that you have this chance of developing something that will basically send your life into a nosedive over many years, what that burden is like?

You've got two big blows to the family at once.

The first is they know exactly what it is, which in a way is good news.

They know the mutation.

People with Alzheimer's don't know what genetic mutation causes it most of the time, or nearly all the time.

People with schizophrenia, there's no genetic mutation, no single one that's a smoking gun.

This family has it, and yet there's nothing they can do about it yet.

We're in the era of gene editing, and you'd think we'd be able to lick this problem tomorrow, but not so much.

That's the first problem, but the bigger one is now you can be tested.

Do you even want to know?

There's a family member who's 32 years old or so when she's offered the opportunity to be tested for the first time.

She's married, she has a career, she has kids.

Does she want to live for the next 10, 15, 20 years, hopefully knowing this is going to happen for sure?

How will that change her parenting?

How will that change her career?

How will it change her marriage?

And so, even though she was desperate to know the answers, she decides not to know for the time being.

Every single member of the family, as I said before, families are amazing this way.

They answer the question in very different ways.

Some don't want to know.

Some want to know right away.

Some give themselves a deadline.

Some go on and have kids without knowing.

One person has a vasectomy.

It's really... The reader will read this and wonder, "Well, what would I do "if they were in their shoes?"

Right.

I was wondering that constantly, reading this.

Because it is one of those things that, yes, how could you not change your behavior?

But I don't know.

Maybe you hold out hope on some level.

I know many members of the family do.

They just think, "I'll just wait until my 30s or 40s.

"I'll get old enough and then I'll know "whether or not I've got it or not.

"But I don't really want that test for confirmation."

You mentioned this before.

But the way in which this manifests itself as changes in their personality does seem to make it especially hard because it just flies under the radar for so long.

It's not like... This is not to minimize what Alzheimer's does, but there's a concreteness to the way that that progresses and the way that it manifests itself.

Whereas with this form of FTD, it just flies under the radar because people think there's surely some other reason going on here.

Something amazing happened in science throughout the world in the 70s into the 80s.

And that's, researchers said, "Wait a minute, "what we've been calling senility or just dementia, "all of it basically is Alzheimer's.

"And if we call it Alzheimer's, "then it'll be "the third or fourth biggest killer out there.

"And the entire scientific community "can organize and put resources into it.

"It can be like cancer, something that we can beat."

And that worked, but in a way, there were unintended consequences.

All the other dementias out there got overlooked, misdiagnosed, for many, many years.

It polluted the patient pools for people who were being studied for cures for Alzheimer's.

Brangham: Simply because it was so hard to say who was who and which was which?

Yeah.

I mean, let's remember, there was no way to know if you really had Alzheimer's until you died and there would be a postmortem examination of your brain to really know for sure.

I grew up in the 80s and that's when people would say, "Oh, my grandparent, she has Alzheimer's."

And people would nod and say, "Oh my goodness, "Alzheimer's, that's terrible."

But in fact, there'd be no way of knowing if it was Alzheimer's for real until later.

Brangham: Right.

And then part of this mutation, everyone knows, once you get tested, that also dictates whether your children would then be similarly have inherited that from you.

Again, this idea of the legacy that you're passing on to your children, perhaps not knowing is a way of preserving your sense of how your children's future will be.

Absolutely.

Let's say you grew up with a mother like Jean who was changing and you had to watch her change.

And then one day you finally learn why and you realize it might happen to you.

That's one tragedy.

Then you look at your kids, who are entering their teen years, and you realize that if you do have it, they're going to have to watch you the same way that you watched your mother.

That's the second tragedy.

And then you look at your kids and you say, "If I have this mutation, "that means they each have a 50-50 chance.

"They have to flip the coin to find out their futures too."

That's a third tragedy all in one realization.

At several different moments in the book, you talk about how this type of dementia cuts to the very question of who we are as individuals, that if your personality starts to change in fundamental ways, it calls into question, like, well, what is it that makes you Bob and me William and how we are different and how my sense of identity...?

Can you just talk a little bit about that, the way in which this dementia brings up those essential questions?

Sure.

All neurodegenerative disorders are tragedies, obviously.

They're all difficult for the people who have them and the people around them.

Disorders like FTD interest researchers in a specific way in that, because they hit the personality so hard, it makes you wonder what a personality is to begin with.

One researcher said this is where neurology bumps up against psychiatry.

This is where it really overlaps.

What makes us who we are?

The members of this family, they look back and they honestly can't say for sure about some behavior that their loved ones had.

Was this really them or was this the disease starting?

Did the marriage end because of FTD or did FTD end after the marriage ended?

Come after the marriage?

It's a mystery.

It becomes something that the researchers all grapple with, not just with the patients, but with the state of the mind, with the... where the mind actually meets the brain.

Neurologically, we look historically and we see the way that science has sort of kind of helped the brain assume the spotlight in a way that it didn't for hundreds and hundreds of years.

You know, we... We always... For many centuries, we thought there was the mind and then the body like Descartes would say.

Brangham: Two clearly separate entities.

Kolker: Then in the late 1800s, we learn about the brain being in charge of how we form language and our reflexes and our nerves and we start to see, wait a minute, the brain really is in charge.

Even Freud was a neurologist before he became to be and he was influenced by the idea of inhibition and disinhibition, which is a brain function.

That's where he eventually came up with the id and the superego.

And so we've gone on in that way thinking the more we learn about the brain, the more we'll realize that it can control our personality and that personality may actually be nothing but a bunch of wires and switches inside our heads.

And, yet, of course, there's this whole other school of thought that says, "Wait a minute, "we'll never solve the problem of consciousness.

"We'll never know exactly why humans "have this amazing ability.

"Looking in the brain won't solve that problem."

So the FTD patients are, in a way, an amazing place to study this issue and to have those arguments.

Brangham: Do people who are suffering with this, I know we hear from different family members, are they aware of the changes that they're undergoing?

They aren't.

They have something called anosognosia, which a lot of people with schizophrenia have and other disorders as well.

That means that you really don't know you're sick.

And in a way, that's kind of the cruelest irony of this condition, which is that the people who end up suffering the most are the people who love you, the people who are around you, caring for you, because they're watching the changes happen and they know they're happening.

You mention in the book that despite FTD being so rare, that because there is this genetic marker that says, if you have that marker, you're going to get it, and if you don't, you're not.

That this might be a clue, a pathway to finding a way to prevent or treat or identify.

Explain how that mechanism might work.

Okay.

To dip into the science a little bit here, when people who have talked about Alzheimer's or learned about Alzheimer's, they might know about plaques and tangles.

Plaques and tangles are what load up in your brain and overload your brain that everyone believes is what causes Alzheimer's disease.

They're both proteins.

The plaques are the beta amyloid protein and the tangles are the tau protein.

And for decades, we've been going after the beta amyloid protein.

Brangham: They were considered the prime suspect that if you could direct research, treatment, pharmaceuticals, that would be the way to get at this.

Yeah.

There were certain proven genetic links that suggested that it was amyloid's fingerprints that were on the knife, that they were what we really needed to go after.

Meanwhile, tau has sort of been thought of as an after effect, sort of a, you know, whatever, it's there to... it closes the deal maybe, but it's not the problem.

But all of these other rare dementias, including FTD, there are just more and more over the years were discovered to really be tau disorders.

And now that we've sort of reached a point where we've done what we can with amyloid, the entire research community seems to be pivoting and discovering tau.

Now, if you were a researcher who wanted to try to reduce the amount of tau in someone's brain and you really wanted to make sure it worked, I think you might be tempted to try it with a family that has a confirmed tau condition.

Brangham: And FTD is in the tau camp.

Kolker: Oh, that's right.

Exactly.

This family in particular, there are all sorts of FTDs and there are all sorts of genes, but a great number of people with FTD have tau disorders.

And so do people with progressive supranuclear palsy and Lewy body dementia.

There are a lot of them.

Wouldn't you want to test them to see if your drug worked?

Wouldn't you want to try and get an easy win on the books before you really put all that money and time into Alzheimer's?

And that's the argument that tau families are making in every disease, including FTD, including this family.

Brangham: But as you document so clearly in the book that Alzheimer's, because it is the majority of dementias, it's considered the big fish and the big prize.

And all the research and the money in the pharmaceutical effort has gone in that direction and not in this.

And so you've got these families waving their hands saying, "What about us?"

But they're not getting nearly the attention that they feel they ought to be getting.

Yeah.

We have an amazing free enterprise system that's built up an amazing pharmaceutical industry that's capable of amazing things.

But a lot of the investment is built around big swings, like things that are going to lead to big cures, because that's going to get the biggest profits.

So it's natural for somebody who wants to invest in any brain science to try and find some sort of one-and-done drug out there, some sort of pill that people can take that can really help the most number of people.

So they feel uncomfortable asking shareholders to put time and effort into something that helps 50,000, 100,000 people, when there's something like Alzheimer's that has millions of people suffering and they could probably try and go after them.

So they are highly motivated to ignore rare diseases.

That's why there are so many rare diseases that organize and lobby Congress to not be forgotten, because they, again, these could be easy wins.

These could be ways to help people in a material way.

And it could be a way to test cures for a larger population, too.

What would the interventions look like?

I mean, what are the most promising ways that these families and the researchers who are studying them think could be a way in?

To alter a genetic mutation, to repair a genetic mutation, the temptation is to use something like a gene editing treatment.

Brangham: Like CRISPR.

Like CRISPR, could be, something like that.

There is a team at University of California, San Francisco, that's working on a CRISPR treatment.

There are also other treatments that could go in and do genetic editing that don't rise to the level of CRISPR.

The reason why they're trying lots of different things is that getting into the brain is hard.

There's something called the blood-brain barrier, which is a membrane that has, you know, that you want to have it.

You don't want diseases.

Brangham: So it's a really valuable function.

But if you want to get medication into your brain for any reason, you've got to get past it.

So the treatments so far look like, to answer your question, look like spinal taps.

Perhaps they're trying to get into your cerebral spinal fluid to try and get into the brain.

There's one new amazing treatment for Huntington's where they actually know what part of the brain or think they know where the trouble is.

So they drill and get a very small needle to go right to that spot to kill the mutated cells and that's been successful so far.

Getting past the blood-brain barrier may be actually the trickier thing to do than the actual gene mutation repair itself.

Barb, who is one of the central characters, really the kind of the thread throughout your book, one of them, she is quite hopeful that this... that they will... their family could be part of the catalyst to make this cure.

I mean, given all of the research you did for this project, do you share that same level of hope?

Do you think that they might be a key?

I think certainly they're a perfect family to test for a tau-reducing drug.

There are a lot of people with tau-related FTD who can make the same argument.

I am hopeful.

I think that we're making progress about the blood-brain barrier.

I think that that part of it may be something that we get past in the near term, not in the long term.

And if that happens, then all bets are off.

There are all sorts of ways to perhaps bolster brain health and delay the onset of any disorder, but also repair genes.

So we're really at the beginning of an amazing period, I think.

Brangham: Do... The family, obviously many different members of the family, have got different outlooks on all of this.

But overall, how would you characterize the way in which this remarkable genetic mutation has rippled through this family and how that they have dealt with this over their lifetimes?

I'd say that they're inspirational, certainly to me.

I think that there were at least five, maybe more, moments when I was reporting this book over the last few years where I genuinely had my breath taken away by what somebody did for someone else, about what sacrifice someone made for someone else, about a spouse making a certain commitment when it really needed to happen, and then a sibling moving cities just to make it happen.

It was stunning to me.

I mean, we live in a time now where families are portable, where you don't necessarily expect that everyone's going to live in the same town and where you can choose your own family almost and decide who not to hang out with.

And this family, against all odds, has sort of recommitted to each other in some significant ways.

And that's just been an amazing thing to see.

I mean, it is hard to imagine if you suddenly got the call to say one of your close siblings has suddenly got this disorder and they will need full time care.

And it's not like this is a wealthy family that has endless amounts of funds.

Who could make that decision to say, as someone here does, "Okay, I will step up and do this?"

It's incredible.

Yeah.

They've learned in a very real way that whoever dodges the bullet has a responsibility and a commitment to support the others.

And so the disease really is affecting them all.

It's not who gets it and who doesn't.

I mean, in a way, they all have their lives changed because of it.

Brangham: The book is called "The Vanishing Family, "Love, Fate, and the Quest to End Dementia."

Bob Kolker, thank you so much for being here.

Such a delight.

And thank you for this tremendous piece of work.

Thank you so much, William.

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