- Welcome to "Healthy Minds."

I'm Dr. Jeff Borenstein.

Everyone is touched by psychiatric conditions, either themselves or a loved one.

Do not suffer in silence, with help there is hope.

(bright music) Today on "Healthy Minds," (bright music) Alzheimer's Disease.

Today I speak with leading expert, Dr. Howard Fillit, the co-founder and chief Science Officer of the Alzheimer Drug Discovery Foundation.

We speak about early diagnosis, symptoms, treatment, potential methods of prevention for Alzheimer's disease.

That's today on "Healthy Minds."

(bright music) This program is brought to you in part by the American Psychiatric Association Foundation, the John and Polly Sparks Foundation and the WoodNext Foundation.

(bright music) Howard, thank you for joining us today.

- Jeff, it's a pleasure to be here with you.

- I wanna jump right in, and ask you to just start off with an overview of Alzheimer's disease.

What are the early symptoms, the progression?

Give us an overview of this illness.

- So, Alzheimer's disease is a neurodegenerative disorder.

It's chronic and uniformly progressive and in the end, uniformly fatal.

It's characterized by basically the loss of mind, and it robs us of everything that makes us human beings - Early on, how does somebody know that they or a loved one might have the condition?

- Well, one of the earliest signs that we talk about most of the time is change in personality, which kind of reflects a lot of different changes besides just memory loss.

People do have some memory problems with aging.

And the job of the clinician is to distinguish between what might be normal aging and memory loss, and what might be the earliest signs of Alzheimer's disease.

In addition, there's something called executive function, which relates to planning and scheduling and being able to manage your financials, abstract reasoning, things like that, that, are more cognitive and complex tasks that also can be impaired very early in the disease.

And probably account for the loss of change in personality that people have.

They can also have changes in mood and become more agitated and more volatile or more subdued.

And that can be the kind of change in personality that we're talking about.

And usually from the first time that a loved one notices symptoms till a person eventually gets a diagnosis is about two years.

But what's going on now is that we have biomarkers and blood tests and brain scans, that can definitively diagnose the disease.

And I think that's gonna make the runway from the time people first notice symptoms to the time primary care doctor first does a blood test for Alzheimer's disease, which is revolutionary, literally will be telescoped quite a bit and we'll be able to begin treatment and care much earlier in disease before things like catastrophic things like fraud, abuse and even hospitalization can be avoided.

- Tell us about some of these new advancements.

'Cause this really is a big change, certainly from not that long ago.

Tell us about the blood tests and brain scans that are being used to help in diagnosis.

- About 25 years ago, I got a call from somebody at University of Pennsylvania who said they had a revolutionary idea, but they couldn't get any funding for it because the funders thought it was too risky.

And he said what he wanted to do was take the same dye that Alzheimer used in 1906 to stain the brain slides of some a 52-year-old woman who had an autopsy and that's where he first saw the plaques and tangles.

This doctor at Penn wanted to use the same dye radial label it and use it as a pet scanning agent to be able to identify whether a living person with let's say early memory loss had plaques and tangles.

And that test was used in a clinical trial to show, and it showed that about 30% of people who were enrolled in a clinical trial of a drug for Alzheimer's disease that Lilly was doing, testing (clears throat) showed that the 30% of the people in that trial did not have a positive brain scan.

They did not have Alzheimer's disease and they didn't have any amyloid in their brain, which was the target of the therapy.

And that was revolutionary because how could you get a positive clinical trial if 30% of the people in the trial didn't even have the target of your drug.

So, that was a big change.

And now today that PET scan is used widely to enroll people into clinical trials for Alzheimer's disease, giving a biomarker confirmed case of the disease.

The other thing that spun off of the biomarker in 2012, I think it was, that biomarker went to the FDA and became the first test that was approved by the FDA for the diagnosis of Alzheimer's disease.

And subsequently the test was then used by Biogen and Eisai, to show that their monoclonal antibodies could remove, literally remove the plaques from the brain.

So, you went from a positive plaque to a negative plaque.

And the last part of the story, which is really triumphant, is that the first drug disease modifying agent ever approved by the FDA in 2014, I think it was, was based on the fact that these drugs could remove the plaque from the brain based on the PET scan that we helped to develop way back in 2000, beginning 2000.

And I think it shows you the power of philanthropy as well as the power of diagnostic tests and how important they are not just in the clinic, but also in ensuring that clinical trials are done in a rigorous way with defined patient groups that actually have the disease that you're looking for.

And the test really has been called revolutionary.

The thing is about the PET scan is that it's neuroimaging.

It requires a microdose of radioactivity, and some people don't like they have claustrophobia, they don't want to go into the machine.

So, what we have now, which is even more remarkable in my mind, is we have blood tests.

And the blood tests that are on the market now are even more revolutionary because, they've been validated on the brain scan.

So, the blood tests predict a positive brain scan, but you don't have to endure the pet scanning procedure and a little bit of microdose of radioactivity, you just get a blood test just like you would for any other disease.

And if you ask me five or 10 years ago, if we'd ever have a blood test for Alzheimer's, I probably would've told you no.

But the blood tests are now available throughout the United States and they're gonna be throughout the world, and that's gonna change everything even more.

And the last thing about the blood test besides having very high accuracy is number one, they're much less expensive than the PET scans, so they'll be much more widely available.

And number two, they've opened up the entire biomarker space of using blood tests to define categories of patients with Alzheimer's disease, which is really incredible.

So, we'll have people that have plaques and tangles and inflammation and we'll be able to find those people and put them on combination therapy just like we do for cancer, based on the framework that we've evolved, which is the biology of aging as a model for developing categories of new drugs for Alzheimer's disease.

And right now the largest category of new drugs for Alzheimer's disease is actually neuroinflammation.

And there's a lot of interesting new drugs in that category that are being used or will be used with the monoclonal antibodies to beta amyloid.

So, we've come a long way in the last 20 years and that postdoc and fellow who helped to develop the brain scan at Penn is now the president of, I think, clinical research or neurological research at Eli Lilly.

So, he's really advanced his career in a very wonderful way.

And we just gave him an award because of his contribution to the field.

- We wanna ask you if somebody is watching now, how this translates to clinical care.

What do they ask their doctor if they have a concern?

What do they say about this blood test?

- Well, it's a blood test like any other.

So, there's no risk, and we expect that the blood tests will be covered by insurance.

And I think, that the process of care will be greatly telescoped because now it's kind of a not a clear process.

You know, we like doctors, we expect doctors to do cognitive tests to see if there's a problem in the first place.

And then if there's a problem, there's a clinical practice guidelines that guide the doctor through the diagnostic algorithm and get a vitamin B12, get a thyroid stimulating hormone test to see if there's thyroid problems that might be causing the memory, if there's depression, if there's polypharmacy, get a brain MRI if there's been a possible vascular disease of the brain or a tumor that might be causing the cognitive impairment.

So, we look for what we call potentially reversible causes of cognitive impairment.

And once those are ruled out at this time, the diagnostic algorithm pretty much ends there.

Some doctors might be ordering FDG PET scans to look at metabolism in the brain and to also look at patterns of FDG, glucose metabolism in the brain on PET scanning to see if it's consistent with the pattern of Alzheimer's disease.

But now I think the whole thing is gonna be much simpler because then the doctor can just simply do a blood test for Alzheimer's disease.

And if that becomes back positive, the most likely cause probably of the patient's cognitive impairment as documented by cognitive testing by the doctor, hopefully that would be enough for a diagnosis of Alzheimer's disease.

And we have different staging categories of the disease, like subjective cognitive decline, which is the earliest stage where loved ones notice symptoms, the patient notices symptoms, but the doctor can't pick it up on brief cognitive testing, let's say in the primary care office.

Although if they sent the patient for neuropsych evaluation, they might be able to pick it up.

And then the next stage, which is really the most common stage where the disease is picked up early enough, is mild cognitive impairment where people just have a mild degree of memory problems and sometimes impairments in executive function.

And from MCI, the blood tests have been tested and they do pick up enough of, a pattern of blood tests that are positive to make a diagnosis of Alzheimer's disease.

Let me just also add, which is really interesting for prevention, that these plaques and tangles, start to develop 20 years before their symptoms.

And we weren't able to tell because these people are asymptomatic, that they had Alzheimer's disease, but because they were asymptomatic, there was no way to tell without a brain biopsy.

And there was no reason to do a brain biopsy for that kind of prevention effort.

But the world is changing now.

Because of these brain scans, we've figured out that the disease starts, as I mentioned, 20 years before, there are symptoms.

And so now we can identify people in the community that have Alzheimer's disease and start prevention interventions to delay the onset of symptoms.

And if we can delay the onset of symptoms through lifestyle management and other kinds of interventions, including medical interventions and careful monitoring and treatment of diabetes and hypertension, that if we can delay the onset of Alzheimer's by five years, we would reduce the number of people suffering from dementia by 50%, which I think is an achievable goal in the next 5 to 10 years - That would be an extraordinary accomplishment basically because Alzheimer's often begins at an older age if it's delayed, people would pass away as a result of other conditions and not have to live with Alzheimer's until that happens.

- Exactly, it would be incredible.

And I think the blood test is really gonna enable prevention trials.

We're already funding an intervention called FINGER, which is a finished geriatric study where people have been shown that if they are very compliant with preventative measures like exercise and diet, Mediterranean diet and stop smoking and don't drink alcohol and get treatment for depression and hearing and vision loss and a number of other measures as well as I mentioned, diabetes and hypertension management, that even with just those lifestyle managements and comorbidity medical management, we can slow down the course of cognitive aging.

And today we're funding a study, which is the FINGER 2.0 study, which combines lifestyle management, just as you would for heart disease, combine lifestyle management, comorbidity management, which is mostly diabetes and hypertension and high cholesterol, hyperlipidemia.

And that's the way we prevent heart disease.

It's basically the same paradigm for Alzheimer's disease and other dementias.

Now it's lifestyle management, comorbidity management.

And we've added on for a big study the use of metformin, which is the leading anti-aging drug.

It's inexpensive and it's safe, and it could be used to prevent Alzheimer's disease if the study that we're funding at the Alzheimer's Drug Discovery Foundation, along with Miia Kivipelto, who was the innovator who developed the FINGER study, which is now being replicated in over 60 countries around the world.

- In many ways, what we've all been told to do for prevention of heart disease, whether it be hypertension, cholesterol, exercise, proper sleep, all of those steps, diet, really, those are things that are also protective for the brain and for developing cognitive impairment and Alzheimer's.

So, if we do that, we are potentially helping in terms of the risk of Alzheimer's disease.

- And I would add to that.

That if you look at the, prevalence of heart disease since let's say the 1950s, in large longitudinal studies of aging, and you look at how the prevalence of heart disease has gone down over these decades, presumably due to the improvements in lifestyle that, you know many people have taken on, as well as the availability of effective drugs for diabetes and hypertension, the decline in prevalence, the decline in prevalence, not incidence, but the decline in prevalence of dementia has paralleled the decline in heart disease.

The incidents with aging of Alzheimer's disease increases because as people get older, the greatest risk factor for Alzheimer's is aging.

So, the number of cases per decade in cohorts is actually continuing to rise because there are more people getting into old age.

But the prevalence is actually going down in parallel with the decrease in prevalence of heart disease, which is really quite interesting and hopeful.

- I wanna shift gears a little bit and speak about the genetics and any risk factors genetically of Alzheimer's disease.

- Well, it used to be that, a clinician that did an interview with a patient would ask, do you have any family members that have the disease?

And if a first degree family member has the disease like a sibling or a parent or even a grandparent, then epidemiological studies showed that the risk of that person getting dementia or Alzheimer's disease in particular, went up significantly two to four times.

You know, and depending on the number of family members, even as much as 10 times.

A couple of decades ago, somebody named Alan Roses discovered that a gene called apolipoprotein E, which is a risk factor for heart disease, actually, was also the main, by far the main risk factor for Alzheimer's disease.

And it's also has a great influence on the efficacy of drugs and the side effects of drugs, the new drugs that are on the market.

So, patients are tested for their apolipoprotein E genes.

And there's three kinds of apolipoprotein E genes.

There's apolipoprotein E2, E3, and E4.

And people get one gene from mom and one gene from dad.

So, you could be like a double E, and that's the most common type of profile for the genetic testing for Alzheimer's.

Or you could be a three, four, and if you're a three, four, you got the bad one, which is the the four, and that increases your risk of getting Alzheimer's about five times.

And if you're a double four, then you're at increased risk for getting Alzheimer's disease by about 10 to 15 times.

So, getting a double four is really not a good profile to have.

The other thing about double fours is that they get it about 10 years earlier than the average person who might have a three.

And so if a clinician sees someone coming in at 65 with symptoms rather than 75, which is the average age at which people come in with memory complaints and the earliest signs of Alzheimer's, if somebody's coming in at age 65, doctor would test for APOE4 or I should say APOE genes to see if they're are two, three or four, because that would also determine a lot of the way they might be treated, if they went into using some of the new drugs because the severity and the frequency of side effects in people who are double four, when they take these new monoclonal antibodies is much greater than if they were double three.

And the thing about the APOE2 is that it's a protective factor.

So, if somebody is a two, four, that two is gonna offset the four and they're gonna have a normal risk, not an increased risk.

And if they're a two, three, they'll have a normal risk.

And if they're a double two for example, they'll actually have a lower risk of getting the Alzheimer's disease.

And if you go to your primary care doctor and go to Quest or LabCorp or any, you know, routine testing organization, the vast majority of the them have a way to test for the APOE gene under appropriate circumstances of it being ordered by the doctor.

There's a very rare form of Alzheimer's, which is genetically driven, which is due to a mutation in the gene for beta amyloid.

And in that case people get Alzheimer's disease in their thirties and forties.

I remember back in the '80s seeing a family from Columbia where in Bogota, this is where some of these initial families were discovered.

I saw a family of five where just about everyone in the family got Alzheimer's disease by the age of 35, 40.

And that study is, excuse me, still going on today, and is one of the landmark studies that kind of led to a lot of the interest that we have today in the beta amyloid theory of Alzheimer's disease, which has actually been proven because we have drugs that when they modify the amount of beta amyloid in the brain, there's a therapeutic benefit.

- I want you to talk a little bit about beta amyloid.

What exactly is it, and then how do these drugs work in terms of treatment?

- We think that beta amyloid maybe plays some role at the synapse where there are connections between neurons and we think it plays a lot of other roles.

We're not really sure of the one specific role that beta amyloid plays, but we do know that as a therapeutic target, it's been proven to be a valid target.

And these monoclonal amyloids, what they do is they bind to, beta amyloid species that are aggregating to form the plaque.

So, the monoclonal antibodies specifically bind beta amyloid in its what's called fibrillar form or the form that's in the plaques, and as I mentioned earlier, when the monoclonal antibodies, these drugs that are on the market, Leqembi and Kisunla they're antibodies just like part of the immune system.

And they're out there doing what's called immune surveillance.

They're looking for garbage in the brain, they're looking for garbage in other parts of the body when they're used like this.

And when they find extracellular deposits of debris, they bind to that debris.

And in this case it's the plaques, and the other end of this molecule tells these inflammatory cells, the microglia that are responsible for eating the debris, you know, Hey, come on over here, we found some stuff that you gotta get rid of, and the microglia, the immune cells bind, attack the plaques and literally eat these extracellular debris that's there, and remove it.

So, it's actually an immune reaction that's being stimulated, but in a good way to remove these deposits.

And so by binding to the beta amyloid and the plaques, that's how the drugs work.

But it also illustrates what the important role is in the disease process because the beta amyloid turns out to be a major component of the plaques.

And it's been found in the last few years that these plaques are one mechanism by which what the neurofibrillary tangles, which we haven't mentioned, are created, which are representative of deposits in a near dysfunctional and dying neurons, which lead to cognitive impairment.

And it appears that the misfolded beta amyloid that appears in the plaques contribute to, neuronal dysfunction and death.

So, the beta amyloid plays an important normal role, which we're not really sure of, and definitely a pathological role in the disease process.

- I wanna ask you, if you look forward 5, 10, 15 years, where do you hope, where do you believe we'll be in terms of Alzheimer's?

- Well, I think we'll definitely have more safe and effective drugs.

I think we'll have combination therapy.

I think that the combination therapy will involve multiple biological pathways that occur in a framework of the biology of aging.

Inflammation, the ability of the cells to get rid of damaged proteins that occur with aging.

Metabolism, the insulin resistance of the brain that occurs with aging in these multiple pathways.

And we'll have biomarkers to phenotype people to characterize them the same way that we do in cancer patients.

We get the cancer cells from the tumors.

We phenotype them, we characterize them according to the impairments and pathways, and then we put 'em on combination therapy.

I think within five years we'll have some combination therapy.

We already do in some ways where we combine a symptomatic therapy with a disease modifying therapy, some of the monoclonal antibodies, along with what are called cholinesterase inhibitors.

So, we already have combination therapy, but it's gonna be the next generation where we'll be combining disease modifying agents to affect the various pathways and biomarkers and we'll have prevention and much earlier diagnosis.

And I hope, because you know, back in the '80s, nobody even heard of Alzheimer's disease.

But now, you know, every spouse is worried that their spouse is getting it.

And there's all kinds of care programs out there.

And I think for the first time in history, they're getting widespread recognition of Alzheimer's disease.

And people have in surveys said that they're more afraid of getting Alzheimer's disease than they are of getting cancer.

And so what I've seen as a geriatrician is going from a time when I would tell people I'm an expert in caring for people with Alzheimer's disease, and they'd look at me cross-eyed and say they never heard of Alzheimer's, what is that?

To a time when you know, this is in Hollywood and everybody knows what Alzheimer's disease is.

And I think what we're gonna be building is the infrastructure in a better way to improve care.

We have brain health clinics out there now and we have doctors that are educated actually in medical school and in training in the diagnosis and treatment and care of patients with Alzheimer's disease, which I think is already changed dramatically, but has a long way to go to really get to quality care.

- Howard, I wanna thank you for joining us today and thank you for all the work that you've done and continue to do in this quest for us to, better understand, treat and prevent Alzheimer's disease.

Thank you.

- Thank you, Jeff.

Thanks for having me, I appreciate it.

(bright music) - [Jeff] Do not suffer in silence, with help, there is hope.

(bright music) This program is brought to you in part by the American Psychiatric Association Foundation, the John and Polly Sparks Foundation and the WoodNext Foundation.

(bright music)