Alzheimer’s Foundation Head Discusses Breakthroughs: Can Biomarkers & Vaccines Offer Hope?

Dr. Howard Fillit

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Marianne O’Hare : Welcome to Conversations on Health Care. This week we are joined
by Dr. Howard Fillit, Co - Founder and Chief Science Officer of the
Alzhei mer's Drug Discovery Foundation, accelerating the pace of
discovery for drugs that will preven t, treat, and cure Alzheimer’s and
other dementias.

Dr. Howard Fillit: Repurposing d iabetes drugs for the treatment of Alzheimer's disease
is a very exciting field right now.

Marianne O’Hare: FactCheck.org’s Managing Editor, Lori Robertson stops by and we end
with a bright idea improving everyday lives. Now, here are your hosts
Mark Masselli and Margaret Flinter.

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Mark Masselli: As we catch up with loved ones during the H oliday season we might
notice our elderly parents or relatives have aged a bit m ore . The
experts say the H olidays are an important time to recognize such
changes.

Margaret Flinter: Alzheimer's disease is the most common form of dementia now, but
more than ever there's hope, because of promising innovations. Here
to share his insights is Dr. Howard Fillit. He is the Co - Founder and
Chief Science Officer of the Alzheimer's Drug Discovery Foundation .

Mark Masselli: Dr. Fillit, welcome to Conversations on Health Care.

Dr. Howard Fillit: Hi everybody , nice to be here with you.

Mark Masselli: You know, I was shocked at the number 6.5 million Americans aged 65
and ol der are living with Alzheimer's. Why was the Alzheimer's Drug
Discovery Foundation s tarted and what does it focus in on?

Dr. Howard Fillit: Well, we are a unique foundation in the s ense that we have a very
clear and very fine - tune d mission, which is to accelerate the
development of new drugs for Alzheimer's disease. And basically,
that's all we do since 1998, when we were established by the Estée
Lauder family, who saw the great need for translating basic research
into Alzheimer's disease that had gone on for the prior 20 years or so
to begin funding the risky effort in developing new drugs . It's
obviously hard, but we're making a lot of progress.

Margaret Flinter: Well, Dr. Fillit, N ovember is Alzheimer's Awareness Month and so
often, I think both in our daily lives and in healthcare we hear elderly
people say that they don't want an official diagnosis because there is
no cure. But share with us why is getting a diagnosis and maybe a n
early diagnosis so important.

Dr. Howard Fillit: I'm a geriatrician, so I specialize in the care of elderly people. For the

Dr. Howard Fillit

past 40 years or so the majority of my practice efforts are in people
with Alzheimer's disease. And I like to say that I've never m et a
patient or a family with Alzheimer’s disease that I couldn't help. I
think that despite the fact that we don't have really effective
therapeutics, I do believe we're going to have them in the next five
years or so , but even if we do, we're going to st ill need to care for
people. And a good example of what happens when people don't get
an early diagnosis is that very often catastrophic things happened. So
people that are undiagnosed can wander, they can get lost. They end
up in the hospital for a variet y of reasons, such as poor management
of diabetes, and hypertension and infections , and also caregiver
stress. Let's not forget that . Well , there are roughly 6 million people
with Alzheimer's . There' are probably 15 to 20 million caregivers. And
part of ou r job as physicians, I do believe is counseling families on
how to take care of their loved ones, so that the caregivers
themselves don't become depressed a nd at risk for hospitalization.

The other thing is that early di agnosis is critically important for our
research efforts. Less than 5% of people with Alzheimer's disease,
participate in clinical trials, it's very hard to find people. But with new
diagnostic tests, we can identify people with Alzheimer's disease 20
years before they become symptomatic. A nd what that means is that
today, we can do prevention . There are clinical trials going on right
now for prevention of Alzheimer's disease, studying people that have
the pathology in their brain based on new diagnostic tests that our
foundation has helped to develop, and then entering those people
into clinical trials to prevent the onset of symptoms. So there's really
a lot of excitement in the field right now over 120 drugs in
development, and about over 350 clinical trials going on around the
wor ld. It's a very exciting time. We have diagnostic tests on the
market.

Mark Masselli: You know your organization is an enthusiastic supporter and investor
in blood based biomarker research. What exactly is that? How does it
work and where is it available?

Dr. Howa rd Fillit: Well, biomarkers are critical to clinical care and drug development
and I’d like to take the example of cholesterol . Cholesterol in the
1950s was discovered as a risk factor for heart disease. Nobody knew
how it worked. And then it took about 30 years for the first statins to
come to market. And those statins actually were developed because
they were designed to lower cholesterol with the theory that if you
lowered cholesterol, you could prevent a second heart a ttack and that
worked actually. So the development of the first statins would have
been impossible, if it wasn't for the development and the recognition
of cholesterol as a risk factor for heart disease.

We're at the same stage today. We discovered that the plaques in the

Dr. Howard Fillit

brains of people with Alzheimer's disease have a protein called beta
amyloid. Beta amyloid became one of the first targets of drugs for
Alzheimer's back in the 1980s. We've been working on it about 30
years, just like heart disease. And just in the last few months, we had
the first accelerated approval by the FDA for drugs to modify the
disease and remove the beta amyloid. What we needed was better
biomarkers because the only way that we could detect beta amyloid
in the brain was either by brain biopsy or autopsy, and most of my
patients didn't want an a utopsy just to get a diagnosis.

But we were involved in the development of the first diagnostic test
brought to market and approved by the FDA, which is an amyloid
brain scan. And that amyloid brain scan is used almost unifo rmly
around the world now in clinical trials to develop new drugs. And we
also have for the first time during the past year or two, the marketing
of a blood test for Alzheimer’s , which is incredible. If you had said to
me five years ago or ten years ago, t hat there would be a blood test
for Alzheimer ’ s disease, I would have been astounded. The blood test
is now available in 49 S tates. And there are many new blood tests that
are going to be coming to market, making the diagnosis of Alzheimer's
disease more p recise, less expensive, and more accessib le and less
invasive to people. The blood tests will be part of clinical care of
people wit h memory disorders and old age.

Margaret Flinter: You know, Mark and I are very engaged in the primary care space and
partic ularly community health centers. And of course, health
disparities are a front and center concern for us and we understand
that there are really very significant health disparities among different
racial and ethnic groups w hen it comes to Alzheimer's disea se . I think
we've read Black Americans twice as likely as whit e Americans to have
Alzheimer's, Hispanics 1.5 times more likely, but how are you
organizing the research agenda to address them within the c linical
work that you're doing?

Dr. Howard Fillit: Th e most honest answer is we don't know how or why Blacks and
Latinos for example, or Hispanic communities are at greater risk. But
we do know there is greater risk. I think, probably it's related to
common medical comorbidities that are risk factors for Alz heimer's
disease, and cognitive decline in old age, and particularly diabetes and
hypertension. We know that hypertension is clearly a risk factor for
cognitive impairment and Alzheimer's disease in old age, as is
diabetes . These common comorbidities and s omething like 65% of
people over 65 have hypertension, and 30% have diabetes , and the
combination of the two is particularly devastating to the brain. And in
underserved communities, these comorbidities they're actually kind
of difficult to manage effectiv ely in underserved communities .

It's very clear that effective management of diabetes and

Dr. Howard Fillit

hypertension can reduce the risk of dementia and Alzheimer's
disease. And so what we need to do is improve our primary care, as
you mentioned, to make sure that thes e common comorbidities, that
if we can improve the management of those then we would reduce
the risk of dementia and Alzheimer's disease particularly, as we've
seen in the U.S. that the declining incidence of heart disease in
America has been associated wi th a decline in the incidence of
dementia and Alzheimer's, which kind of proves that by managing
vascular risk factors, we can have an impact on the occurrence of
dementia. And I think another big thing is we need to better recruit
underserved communities into clinical trials because you know, the
vast majority of people in clinical trials have been Caucasian people.

Mark Masselli: Our organization is part of the “ All of Us” research project to try to get
the population that looks like the rest of America i nto these clinical
trials. But I want to focus in on some things that have happened over
the past couple of years. The FDA approved an Alzheimer's drug, but
it's been denied Medicare coverage. However, another group of
companies reported encouraging result s for their drug. There's also
some progress with a nasal vaccine for Alzheimer's. I wonder if you
could take us through where we are on the pharmaceutical front,
both successes and stumbles along the way .

Dr. Howard Fillit: Well, we've had many failures s ince 1980. And the last full drug
approval that we had for Alzheimer's was in 2003. The drug you're
referring to a ducanumab or Aduhelm from Biogen did go through a
controversial review process. It ultimately received what's called an
accelerated approval f rom the FDA, which is kind of an interim
decision based on the idea that the drug clearly showed that it could
remove the amyloid plaques from the brai n a nd so we showed that
the Biogen, for example, showed that the drug actually worked to do
what it was s upposed to do, which was to remove the a myloid
plaques from the brain, as measured on these brain scans, and the
other drugs that are in development drugs from Lilly called
d onanemab, drugs from Eisai and Biogen called l ecanemab , drugs
from Roche called g a ntenerumab , they all do something similar,
which is to remove these a myloid plaques from the brain. The big
question about what's called the Amyloid hypothesis is if you remove
the plaques from the brain, does it slow the rate of decline of
cognitive impai rment? And it's looking to me like it does . The question
is the slowing of the rate of decline that we're seeing with these drugs
is clinically meaningful. And for that reason, I think the drug got
accelerated approval based on the idea that removing the p laques
reasonably predicts that patients would have a slower rate of decline ,
but it's not a definitive answer. And I think what we're going to see is
these other drugs coming down the pipeline that I mentioned,
probably getting a ccelerated a pproval and ma ybe if the results are
even more robust, m aybe will get a full approval.

Dr. Howard Fillit

This is, imagine wh ere cancer was in 1950. You know, we didn't have
any approved drugs . We were experimenting . We didn't know what
to do , and today, cancer is a chronic disease that' s manageable in
most cases. We're just on the cusp of a new era of drugs for
Alzheimer's disease, these approvals are really exciting because, you
know, if we slow it down by 30%, well, we want to slow it down by
100%. But that's where we're going. We're g oing to be using
Biomarkers, what we call precision medicine, like in cancer. I think the
Medicare that the Centers for Medicare and Medicaid did not
approve payment for the drug is somewhat unfortunate, and
somewhat understandable. I think the issue that Medicare had was
one about, as I mentioned, clinical meaningfulness when it wasn't
clear how effective they were and there were side effects . I think gave
caution to Medicare to give what's called the coverage with evidence
development. They're saying to t he companies, we want you to prove
that these drugs really work and that they're effective, and they're
safe enough for us to pay for it. It was unprecedented that Medicare
refused to pay for a drug that was FDA approved , but that's a whole
a nother discuss ion that we need to have.

Margaret Flinter: Well, Dr. Phillip Mark mentioned the “All of Us” project a few months
ago, and you just referenced precision medicine. So want to talk
about genetics a little bit. We understand you're investing in a unique
treat ment approach that targets the underlying genetics of
Alzheimer's disease, and that this approach could generate levels of a
gene that might be protective for those with a pre - existing genetic
risk for Alzheimer's. Share with us the latest on this research .

Dr. Howard Fillit: Sure . Well, it's been known for many, many decades that if you have a
close family member with Alzheimer's, then you have increased risk of
parent or sibling and it wasn't really understood till about 30 years
ago, a gene and a protein called a polipoprotein E was discovered to
be a majo r risk factor and remains today really the major genetic risk
factor for what we call Sporadic Alzheimer's disease and there's three
kinds of this gene APOE2, A POE3, and APOE4. About 70% of people in
the community have APOE3 . So that's thought of as the neutral risk of
this gene, which by the way, plays a critical role in cholesterol
metabolism, and does a whole host of other things modulating
inflammation in the brain. About 20% of people in their communi ty
have an APOE4 gene , either one from mom or dad, or two one from
mom and one from dad. And the people that have one APOE4 have
about a five times increased risk of Alzheimer's disease in old age. And
people that have two APOE4s have about a 15 times incr eased risk of
Alzheimer's disease in old age and that's huge. So even though only
about 20% of people in the community have an AP OE4, about 60% of
people with Alzheimer's disease have an AP OE4.

Now people that have an APOE2 actually have a reduced risk of

Dr. Howard Fillit

Alzheimer's disease. So it's telling us that something really important
is going on in this biology of a polipoprotein E . But because APO E plays
so many different roles in the brain, targeting any one of those roles is
probably not going to be good enough. So we worked with
investigators, particularly Dr. Ron Crystal, who's the Chairman of
Department of Genetics at Weill Cornell here in New York and he is an
expert in developing gene therapy and they're developing gene
therapy to treat this APOE4 problem by putting the AP OE2 gene
which is protective into a non - infectious virus, and then injecting that
non - infectious virus into the brain of people who are APOE4 and
seeing if that injection of that virus stimulates the production of
APOE2 . So the theory is tha t if we could turn these APOE4 people into
being able to produce APOE2 , we would offset the risk of APOE4. And
this has been approved by the FDA, a small number of people have
been treated with this virus gene therapy , and it's been shown that
these people actually make APOE2 in their spinal fluid. So it's a really
exciting approach , and we're very hopeful that this will move forward
and have a big impact on preventing and treating Alzheimer's disease.

Mark Masselli: Well, that's very exciting. And I know t here are probably more exciting
things coming up because there's a major conference coming right up
after Thanksgiving, the Clinical Trials on Alzheimer's disease
conference . Tell us about what you'll be presenting and if there are
additional outcomes of t his conference that you're looking forward to .

Dr. Howard Fillit: Being a geriatrician, I've been interested in aging , and I thought early
on that Alzheimer's disease is a disease of aging and all day and we've
known, there's been research going on about t he biology of aging for
over 100 years, but we didn't ever really translate that knowledge into
developing therapeutics for Alzheimer's. So things like inflammation is
also seen in the aging brain and in Alzheimer’s disease , and indeed,
inflammation is rec ognized as one of the causes of the progression of
Alzheimer's disease and for the first time we're going to start seeing
at this conference, a result of that therapeutics research , and I'm
chairing a section for example, called Beyond a myloid . We want to go
beyond the drugs that had been tens of billions of dollars in
development to remove the a myloid, which is one theory beyond the
tau , which is the other pathology and look at things like neuro -
inflammation and vascular problems, and metabolic problems li ke
diabetes that we mentioned and how we can improve that in the
aging brain. We're going to hear at this conference coming up with
these novel trials and the results, the early results trying to reduce the
amount of neuro - inflammation in the brain. There' s a gene called
TRIM 2 , which has been recognized and so that's one I think, exciting
reports that we're going to start to he ar about metabolic
disturbances, repurposing Diabetes drugs for the treatment of
Alzheimer's disease is a very exciting field right now . The brain is
dependent on glucose. If we have reduced glucose availability in the

Dr. Howard Fillit

brain, then neurons get sick and die. There's insulin resistance with
aging . It's part of aging , and so drugs like Metformin, for example,
which is the leading drug for d iabetes is now being repurposed for the
treatment and prevention of Alzheimer's and heart foundation is
supporting a large prevention trial out of Finland, where lifestyle
intervention, comorbidity management of d iabetes , hypertension,
and the addition of Metformin as a drug sort of parallels the way we
prevent heart disease, these days, lifestyle and exercise, diet and
sleep and so on reduce stress, manage your d iabetes and
h ypertension, and take a statin, using that model will be a randomized
clinical tr ial of prevention thing that Metformin adds on to that by
reducing insulin resistance.

So for the first time, it's going to be a meeting where we're going to
have positive results from clinical trial, we're going to see a lot of
clinical trials that are n on - a myloid , non - tau, non - traditional
interventions from many different companies, small biotechs, and
academia. There's a lot of excitement in the field and we're going to
see a lot of reports.

Margaret Flinter: Let me just ask you about one group early on set. Is the search for
solutions any different for this group than it is for the older
population? Is there a different biomarker that we're looking at?
What is different about this group?

Dr. Howard Fillit: It's rare to see Alzheimer's disease under 65 an d I had families from
South America come visit me where everyone in the family got
Alzheimer's in their 30s and 40s , and these are genetic mutations.
They're rare. But in many of the mutations are in the beta Amyloid
gene. So they're teaching us that these proteins play a role because
alterations mutations in the genes that code for these proteins cause
Alzheimer's disease, but it's not the same illness as sporadic illness in
old age, in my opinion, because the sporadic form of the disease have
multiple cau ses, particularly lifestyle and comorbidity whereas you're
taking the healthy 30 - 40 year old and seeing them develop the
cognitive decline. There's one issue there, which is the mutation. So
you can't necessarily translate what's going on in these genetic
mutations. But I think we have learned a lot from people that have
these mutations around the world , and so it is unfortunate and I've
seen people in my practice in their 40s and 50s with Alzheimer's, it's
very, very tragic , but it's actually quite rare .

M ark Masselli: As we started off the show, we mentioned that we're in the H oliday
seasons, what ’s some good advice for noticing and dealing with any
changes we might see in our relatives around the Thanksgiving time.

Dr. Howard Fillit : You know, of course, memory, but the way it manifests, for example,
a t Thanksgiving dinner is that mom might ask you like, what are we
doing tomorrow? And you'll say, Well, we're getting together over

Dr. Howard Fillit

sister's house tomorrow and then 5 or 10 minutes later, mom might
say, what are we doing tomorrow? You know, that's kind of out of the
ordinary. That's, you know, very obvious sort of memory problems,
particularly short term memory, mom will remember when sister was
two years old, and that wonderful day that they had, but she migh t
not remember what you told her five minutes ago, mom might be the
person who's hosting Thanksgiving dinner and now suddenly, she's
having trouble cooking , these kind of functional deficits that we see
they're so obvious.

Another thing is loss of emotiona l control and executive function,
which is very common in the early stages of the disease at a stage
where we call -- that we call now mild cognitive impairment or MCI.
And MCI is characteristically a stage where there's memory disorders,
but also loss in what we call frontal executive functions, loss of
emotional control, change in personality. So in the past, mom might
have been the peacemaker at the dinner table when everybody else is
fighting . And now she's kind of lost control of her own emotions. And
that's a change in personality for mom or dad.

And I think that would be another sign that I would be worried. And if
you combine them, usually these things occur together. Word finding
is common with old age, remembering names is common, but
forgetting t he name of your daughter, who would not be common. So
there's a difference. People always ask me, Well, I'm having trouble
retrieving words , that happens with old age. But when it gets into the
ability to recognize or remember the name of a loved one that you've
known for 40 / 50 years, that would be a problematic sign for me.

And I think under any of these circumstances, a person should
probably be brought to primary care or to neurology care, just to get
some simple cognitive testing that can take 10 / 15 min utes and se e if
there's something going on, so we can get the early recognition. We
can do the advanced care planning, but most importantly, we can
understand what's going on with mom and help her to get through
this horrible disease.

Margaret Flinter: We ll, thank you, Dr. Fillit for your very important work. You can learn
more about Conversations on Health Care and sign up for our updates
at www.chcradio.com . Thank you again, so much for all that you're
doing and fo r joining us today on Conversations on Health Care .

Dr. Howard Fillit : Nice to be here with you.

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Mark Masselli: At Conversations on Health Care, we want our audience to be truly in
the know when it comes to the facts about health care reform and
po licy. Lori Robertson is an award winning journalist and Managing

Dr. Howard Fillit

Editor of FactCheck.org, a nonpartisan, nonprofit, consumer advocate
for voters that aim to reduce the level of deception in U . S . politics.
Lori, what have you got for us this week?

Lori Robe rtson: COVID - 19 vaccination has been shown in multiple studies to reduce
the risk of stillbirth by protecting pregnant people and their babies
from the Coronavirus. There is no link between COVID - 19 vaccination
and an increased risk of stillbirth despite s uch claims being made
online and on social media. These posts have been circulating a
leaked memo from a Fresno California Hospital to incorrectly suggest
that vaccination increases the risk of stillbirth.

The memo reportedly came from a staff member at a Fresno hospital,
who claimed that the stillbirth rate had skyrocketed after the COVID -
19 vaccine rollout. The employee shared an e - mail from a managing
nurse that referred to an apparent uptick in the number of so called
demise patients, including 22 demis es in August, but the memo
makes no mention of COVID - 19 vaccination and is primarily focused
on informing nursing staff how to properly handle the demise
specimens.

Moreover, the e - mail never states that its figures are only for
stillbirths. Fetal death or a fetal demise refers to death at any time in
pregnancy. Deaths before 20 weeks of gestation are miscarriages,
while deaths after 20 weeks are considered stillbirths, conflating
stillbirth with fetal death erroneously exaggerates the number of
stillbirths . A mong 16 studies that have assessed COVID - 19 vaccination
safety with respect to stillbirth, none has found an increased risk of
stillbirth following vacci nation. On the contrary, a meta - analysis
reviewing some of those studies found that vaccination redu ces the
risk of stillbirth.

A Centers for Disease Control and Prevention study looked at 1.2
million delivery hospitalizations in the U.S. between March 2020 And
September 2021. It found that women with COVID - 19 had nearly
double the risk of a stillbirth c ompared with those who did not have
COVID - 19. And that's my fact check for this week. I'm Lori Robertson,
Managing Editor of F act Check.org.

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Marianne O’Hare : FactCheck.org is committed to factual accuracy from the country’s
major political players a nd is a project of the Annenberg Public Policy
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like check ed , e - mail us at www.chcradio.com . We’ll have
FactCheck.org’s Lori Robertson check it o ut for you here on
Conversations on Health Care.

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Dr. Howard Fillit

Marianne O’Hare : Each week Conversation ’ s highlights a bright idea about how to make
wellness a part of our communities and everyday lives.

Heart disease is the leading cause of death for both men an d women
in this country. And while it's known that women often present with
cardiac disease differently than men, the standard treatment
protocols are based on studies done mostly on men for whom
blockages are the primary cause of heart attacks. But not so for
women whose cardiac events often have different causes and
different symptoms. Not just chest pain, but often pain in the jaw or
in the stomach.

Dr. Samit Sha h : When women come in, it's not always so clear and women are less
likely to have blockages i n their blood vessels and so we see heart
attack without blockages in the blood vessels.

Marianne O’Hare : And according to a recent study done by Yale New Haven Hospital,
I nterventional C ardiologist, Dr. Samit Shah , an accurate diagnosis can
sometimes take years .

Dr. Samit Sha h : The average time to diagnosis is more than six years , most people
have had two heart catheterization without a diagnosis multiple stress
test s , and it reflects how you know what the patient is going through.

Marianne O’Hare : Dr. S ha h’s findings showed that when a woman presents with a
cardiac event in the ER, the standard testing protocols to look for
blockages in the large vessels. But that baseline test does not pick up
on problems in smaller vessels were the cause of heart attacks in
women may lie .

Dr. Samit Sha h : And it's all part of what we call the comprehensive coronary
physiology program. What we want to tell our patients is that we
have more testing that we can do , that can really get to the bottom of
these problems were othe rwise it's like chasing a goat .

Marianne O’Hare : Sh ah found it by doing a second more comprehensive scan, you may
identify what's causing the heart attack in women taking the skin
deeper into the smaller vessels where more nuanced problems can be
detected.

Dr. Samit Sha h : So , you know the conditions specifically that I look for is something
called coronary microvascular disease and then the other big one is
coronary vasospasm. There are problems that aren't related to
cholesterol plaque.

Marianne O’Hare : Dr . Sha h is expanding his study to nine teaching hospitals around the
country to include this comprehensive coronary physiology program
in their treatment protocols to automatically progress to the next
scan if a blockage isn't found. He believes the larger national dataset
from multiple hospitals will yield the necessary impetus that should

Dr. Howard Fillit

lead to a change in the national protocol for diagnosing heart disease
in women, which he says will not only save lives, but insurance
companies will see the wisdom of sa ving money in the long run . The
Comprehensive Coronary Physiology program, seeking to standardize
a new protocol for cardiac care for women that will yield a healthier
outcome from this leading killer of women. Now that's a bright idea.

[Music]

Mark Massel li: I'm Mark Masselli.

Margaret Flinter: And I'm Margaret Flinter.

Mark Masselli: Peace and H ealth .

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Marianne O’Hare: Conversations on Health Care is recorded in the Knowledge and
Technology Center Studios in Middletown, Connecticut, and is
brought to you by the Community Health Center , now celebrating 50
years of providing quality care to the underserved where healthcare is
a right not a privilege , www.chc1.com and www.chcrad io.com .

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