Dr. Howard Fillit: The Future of Precision Medicine in Alzheimer’s Disease Treatment

Precision medicine is a medical approach that considers a patient’s genes, environment, and lifestyle. In the realm of Alzheimer’s disease, experts are pushing for using this approach to improve diagnosis, treatment, and our understanding of the condition. But what does precision medicine for people with Alzheimer’s disease and other dementias look like? 

As the Alzheimer’s Drug Discovery Foundation (ADDF) Co-founder and Chief Science Officer Dr. Howard Fillit has seen how the latest innovations in Alzheimer’s disease research, like biomarker blood tests and monoclonal antibody drugs, can allow more primary care physicians and specialists to approach the disease on a more customized level. Fillit joined Being Patient founder Deborah Kan in a conversation about precision medicine and how Alzheimer’s treatment and care will evolve in the future. 

Fillit is an award-winning geriatrician, neuroscientist, and innovative philanthropy executive who has led the ADDF since its founding. He has authored or co-authored over 300 publications and is the senior editor of Brocklehurst’s Textbook of Geriatric Medicine and Gerontology. He has held faculty positions at Rockefeller University, the SUNY-Stony Brook School of Medicine, and the Cornell University School of Medicine. Fillit also maintains a limited private practice in consultative geriatric medicine focusing on Alzheimer’s disease and related dementias.

Read or watch the conversation below to learn his insights about precision medicine and its potential for Alzheimer’s disease diagnosis, treatment, and care.

Being Patient: What is precision medicine?

Dr. Howard Fillit: Precision medicine is the ability to use biomarkers like blood tests or spinal fluid tests, neuroimaging, brain scans, digital tests, or eye tests to define the diagnosis that a person has and to identify a [treatable] drug target, using the biomarker, and seeing if it’s going in the right direction. 

For example, a person comes in, and they have a family history of heart disease where their father died of a heart attack. So, the doctor’s going to do a cholesterol [test], and if it’s high, [they will] put the person on a statin and then use that blood test to make sure the drug is at the right dose to drive the blood cholesterol or the LDL down to where we want it to be to prevent a heart attack.

Being Patient: What comorbidities are associated with Alzheimer’s disease, and what do we need to be monitoring to minimize predisposition to getting the disease?

Fillit: There are a few ways to look at it. There are genetic risk factors, like apolipoprotein E, particularly apolipoprotein E4. If you have one copy of it from a parent, you have about a five times increased risk of Alzheimer’s disease. If you have two copies, one from mom and one from dad, then your risk of getting Alzheimer’s is about 10 or 15 times [than] the average person. [A genetic test] can be done at any time in life. 

If people have diabetes or hypertension, these are also two risk factors for cognitive decline, aging, and Alzheimer’s disease. We want to manage those diseases pretty aggressively to prevent [and] delay the onset of cognitive impairment. 

The big breakthrough now is that we have blood tests and brain scans that can tell us, like the cholesterol of Alzheimer’s disease, except for Alzheimer’s, we call it beta-amyloid. [It] is this protein that gets deposited in the brains and the plaques of people with Alzheimer’s, and it’s thought to be neurotoxic, killing brain cells and just disconnecting circuits in the brain. 

We know that the disease starts about 20 years before people get symptoms, just like a person can have high cholesterol and start developing plaques in their coronary arteries when they are a teenager, but they don’t get that first heart attack till they’re 50, 60, or 70. [It] is the same thing in Alzheimer’s. 

We’ve been able to detect the onset of the plaques and tangles, which would be the beginning of the pathology of the disease, 20 years before people get symptoms. That gives us a big window for prevention. 

Being Patient: How can someone minimize their chance of getting amyloid plaque?

Fillit: To my knowledge, [it] hasn’t been shown yet that we can delay the deposition of plaques. What’s going on now is we have these new drugs that actually remove the plaques from the brain. It’s incredible. You do a brain scan, you see all these plaques on the PET scan, and then you give people these two new drugs that are on the market, Leqembi and Kisunla, and depends on the person, but by 18 months, about 80 percent of people have their brains completely cleared of amyloid. Now, that’s in people [with] symptoms from the disease, so they have the symptomatic disease, not just the pathology. 

“We’ve been able to detect the onset of the
plaques and tangles, which would be the
beginning of the pathology of the disease,
20 years before people get symptoms. That
gives us a big window for prevention.”

When you do that, when you remove the plaques in that setting, and people who are already diagnosed with mild cognitive impairment or mild dementia, you can slow it down by about 30 or 35 percent. [The] way those studies are being designed is screening people in the community, initially with brain scans. It was done, but it was very expensive and time-consuming. 

Now, we could screen people with blood tests in the community, which is a revolution in how we can do prevention because these blood tests are much less expensive and invasive. You screen people in the community to see if they have an elevated what’s called p tau, phospho-tau-217, for example, and if they do, then that means that they’re cooking the disease, but they don’t have symptoms. 

Confirm that with a brain scan, then put them on these drugs that remove the plaques in the pre-clinical stage of the disease, and see if you can delay the onset of symptoms in that context. So, that’s how the clinical prevention trials are being designed, and it’s still how they’re being done. 

It’s an exciting time because we can combine lifestyle management with drug treatment in the same way we do in heart disease. We combine lifestyle management, comorbidity management, and add a statin to the process. We’re funding a big clinical trial out of the Imperial College of London, the Karolinska Institute FINGER study, and it has five major outputs— exercise, socialization, cognitive stimulation, and management of diabetes and hypertension. 

“It’s an exciting time because we can combine
lifestyle management with drug treatment in the
same way we do in heart disease.”

Dr Kivipelto, who started this whole FINGER thing— she’s shown that if you manage those five risk factors, you can delay the onset or slow the rate of cognitive decline in aging people and in people with mild cognitive impairment. We’re adding to that in FINGER 2.0. FINGER is being replicated in about 62 countries around the world, so it’s a very powerful prevention model. 

We’re in FINGER 2.0, where we’re doing the five fingers, plus we’re adding Metformin, which is the leading anti-aging drug and also has been shown to have some effect on people with mild cognitive impairment. Already, there’s a big clinical trial going on. We’re starting to get into that era where we’re combining lifestyle management with drug treatment to delay the onset of symptoms from Alzheimer’s. 

An achievable goal is a study modeled [on] what it would be like if we could delay the onset of symptoms from Alzheimer’s disease by just five years. And if we did that, we reduced the number of cases of Alzheimer’s by 50 percent. 

The way I look at it, it makes sense because the average age of onset of dementia or symptoms from Alzheimer’s is about 75, and, arguably, the average age of death is about 80. So, if you could delay the onset of symptoms by five years, people could benefit. That’s why I think it’s a very doable goal to reduce the number of cases by 50 percent through prevention.

Being Patient: How many more people need to go on these monoclonal antibody drugs before we have conclusive evidence of the role these drugs play in the entire puzzle of Alzheimer’s treatment and prevention?

Fillit: I think we already have the answer to that. There have been a few thousand people that have been tested in clinical trials. The data from those studies are pretty clear. There’s about a 30 to 35 percent slowing of the rate of cognitive decline. In the case of Kisunla, there was about a 45 percent slowing in the rate of functional decline. 

Now, we usually consider something a drug clinically significant and clinically meaningful if the slowing of the rate of decline of a chronic disease is about 30 percent or better. We’re kind of in the range where these drugs have clinical efficacy, and there are other ways to analyze their efficacy. 

For example, if people stay in the same stage for a year in a chronically, inevitably progressive disease, if people stay in the same place that they are— [in] mild cognitive impairment for an extra year— then we’re giving people an extra year of quality of life. I think each person has to decide for themselves whether that’s meaningful. 

Most 80-year-olds, for example, would value having an extra year recognizing their grandchildren and being able to function independently. That’s kind of the difference when people take the drug in the clinical trials. The way the models show the data is that you get an extra year or so of stability before you progress to the next stage. That means people going from mild cognitive impairment, where there’s just memory loss, not a lot of functional impairment, to the next stage of the disease, which is mild dementia, where there is functional impairment, and people need a lot more caregiving. 

“Most 80-year-olds, for example, would
value having an extra year recognizing their
grandchildren and being able to function independently.”

Being Patient: After the amyloid plaque is cleared, the disease still progresses. Do monoclonal antibody drugs also remove tau in the brain along with the amyloids? Could these drugs help dementias like CTE?

Fillit: These drugs would not treat CTE because there’s no amyloid in CTE. Amyloid is characteristic of Alzheimer’s disease, and it’s a requirement that you have a positive amyloid scan or maybe a positive blood test for beta-amyloid to get on the drugs and to get Medicare to approve the payment for these drugs.  

It would be like treating somebody with a statin without having measured their cholesterol. That’s what the beta-amyloid is about. After about 18 months, about 80 percent of people have their brains completely cleared of amyloid, and while we haven’t clearly shown an effect on tau, you’re right that the disease does seem to continue to progress, which is really interesting. For many years, people were thinking that amyloid was the whole story, but it’s very clear that while amyloid plays a role in the story, the plaques, and so on, it’s not the whole answer, and there are other mechanisms going on. 

That’s what’s exciting about today’s research endeavors because it’s becoming clear that we’re going to need combination therapy. We’re going to need precision medicine with combination therapy. Five, six, and seven years ago, 75 percent of the drugs in development were just trying to figure out how to remove the amyloid plaques. Now, 75 percent of the drugs in development are not directed against amyloid, they’re directed against brain inflammation and other mechanisms that are related to the biology of aging. 

“It’s becoming clear that we’re going to need combination therapy. We’re going to need precision medicine with combination therapy.”

[That’s] because of all the risk factors for Alzheimer’s disease, by far the leading risk factor is aging. What we haven’t done is apply all [our knowledge] about aging and what we call gerontology, the biology of aging, to the development of new drugs for Alzheimer’s disease. 

People do go on to progress even when their brains are cleared and it’s been shown that the clearance of the amyloid in the brain remains for at least four years before people re-accumulate the amyloid. I’ve heard even longer times. 

It’s sort of the equivalent of being put into remission, where you clear the amyloid from the brain that takes out that major risk factor and mechanism of the disease, and then you get quite a bit of time before it comes back. During that period, we could use other drugs in combination, like anti-inflammatories, for example.

Being Patient: Are there types of dementia, like CTE, that have tau and not amyloid plaques?

Fillit: A lot of tauopathies, frontotemporal dementia, and all of its subgroups are basically diseases of tau in one way or another. About half of them are tauopathies, and half of them are related to other proteins. Tangles are a critical part of the disease, and antibodies and drugs are directed against the tangles and the tau in the cells that are aggregating and causing neuronal death and dysfunction. 

Cancer patients, they’re on two, three, four, and sometimes five drugs at a time because to get at killing these cancer cells, you really have to use a number of drugs. I can imagine a day when Alzheimer’s patients will be on two, three, and four drugs [for the disease]. 

They’re already on two drugs if they’re taking the monoclonal antibodies and they’re on one of the cholinesterase inhibitors. If they get put on Memantine, that’s the third drug we use in combination. There are combination products already on the market. We’re, we’re about somewhere between 20 and 50 years behind cancer, but we’re catching up, and that’s why combination therapy and precision medicine are so exciting right now.

Being Patient: How close are we to getting a monoclonal antibody drug for tau?

Fillit: It’s not proven yet. None of the anti-tau antibodies, to my knowledge, have proven efficacious in slowing the disease, and some of them have been pulled from their development. I think the whole issue with tau right now is we don’t really know if attacking tau is going to have therapeutic benefits or not. 

Being Patient: With the existence of blood tests and some clinicians using them, let’s reimagine the Alzheimer’s patient journey. What should people concerned about dementia be asking their doctors for at this point in time?

Fillit: Most people [concerned about] memory are going to be going to their primary care doctor, and that’s very different from going to a neurology specialist. I think the role of primary care in this setting is to determine who needs to be referred to a specialist for further evaluation. A primary care doctor can easily do a 10-minute cognitive assessment as the first thing to see if there’s something wrong.

“Most people [concerned about] memory are going to be going to their primary care doctor, and that’s very different from going to a neurology specialist. I think the role of primary care in this setting is to determine who needs to be referred to a specialist for further evaluation.”

The most widely used ones are 10-minute exams that are highly validated for detecting cognitive impairment. If a person has cognitive impairment, then the next question is, what’s the cause of the cognitive impairment? Is it polypharmacy? Are they on too many drugs that might be causing cognitive impairment? Are they not sleeping? Are they not depressed? Are they vitamin B-12 deficient? Do they have thyroid disease? 

There’s a very simple algorithm that primary care doctors can go through to determine, initially, what the cause of the cognitive impairment might be. Then, once it’s all ruled out, if it’s none of the above, the next question is— is it Alzheimer’s? How can we, in a positive way, define it?

There’s a revolution because we [now] have blood tests that are highly predictive of plaques in your brain. They’re predictive of a positive brain scan. They lower the cost of that element of the diagnosis. A brain scan costs about $8,000, [and] a blood test might cost $500 to $1,000 with almost similar accuracy. 

So, the primary care doctor can use a blood test, which is part of the normal work stream of a primary care doctor. For diabetes, they’re going to get hemoglobin and A1C, for heart disease, they’re going to get cholesterol; and now, for Alzheimer’s, they can order a blood test, actually a panel of blood tests. If that’s positive, then that might be the time to make the specialty referral to the neurologist for further cognitive testing. 

Sometimes there are unusual causes of cognitive impairment that are neurologic in nature, like hippocampal sclerosis or frontotemporal dementia. Also, it’s going to be the neurologist if the patient is going to be put on these monoclonal antibodies. It’s going to be the neurologist who’s been educated and practices the use of these monoclonal antibodies because there is a very specific protocol that doctors need to apply in the treatment and management of these drugs to minimize side effects and maximize efficacy.

Being Patient: In terms of polypharmacy and monoclonal antibody drugs, are there drugs you shouldn’t be on while getting this treatment?

Fillit: I’d say the only one is anti-coagulants that I know of because they do cause some minor, tiny little bleeds in the brain, probably due to the inflammation that’s triggered by the monoclonals. That’s how they work. They’re promoting inflammatory cells to come in and eat the plaques. But if that goes a little bit too much, they can cause a local inflammation that can lead to a little bit of a bleed. 

[There are] people that have had really serious side effects from the monoclonals, and it’s very rare. It’s like one percent of the population that gets treated are usually people that have been getting or are on anticoagulants, in addition to the people that are double ApoE4 that have a more serious side effect reaction to the drugs. 

I would say, if your loved one is on an anti-coagulant for atrial fibrillation and they want to go on one of the monoclonals, I’d be very careful about that patient’s risk. 

“I would say, if your loved one is on an
anti-coagulant for atrial fibrillation and
they want to go on one of the monoclonals,
I’d be very careful about that patient’s risk.”

Being Patient: What is the best practice for people with two copies of ApoE4 who do not have symptoms yet in terms of monoclonal antibody drugs? How should they approach prevention?

Fillit: I would say that the use of the monoclonals for that prevention scenario, whether they’re ApoE4 positive or not, whether they are E4 carriers or not, has not been blessed by data and by the FDA as an indication. I think given some of the risks of the monoclonals, I would want to treat ApoE4 homozygotes who have symptoms, early symptoms, to catch them as early as possible. 

Not everybody with plaques and even tangles gets cognitive impairment. It’s an interesting phenomenon, but it’s certainly true. There are 95-year-olds that have died. They’re robust, they’re still working, and they go to autopsy, and their brains are filled with plaques, and they have no cognitive impairment. So, why would I want to treat them with a drug that has potentially serious side effects? 

On the other hand, that’s why doing a cognitive assessment is so important as part of the workup to see if people have symptoms. I think if [I had] double ApoE4 and I was symptomatic, then I would have this shared decision-making discussion with my doctor about the risks and benefits. 

It might be a difficult decision, but it’s one that individuals can make and decide what their risks, benefits, and ethics are and their personal opinions, what they are. We did a study 20 years ago asking people if there was a drug that could stop Alzheimer’s disease in its tracks. 

[We asked:] Would they be willing to tolerate a side effect of death or major strokes? A majority of people said that if there were a drug that could stop Alzheimer’s in its tracks, they’d be willing to risk death or strokes, which tells you people are more afraid of Alzheimer’s than they are of cancer. You think about cancer drugs and try to put them on an equivalent basis. 

“A majority of people said that if there were a
drug that could stop Alzheimer’s in its tracks,
they’d be willing to risk death or strokes, which
tells you people are more afraid of Alzheimer’s
than they are of cancer.”

Cancer drugs might delay the time to progression of the disease by six months, and during that time, you’re vomiting, and your hair’s falling out. I mean, these drugs can give you a year of stability to the next phase of the disease. What you [have to] do, for the majority of patients, is to go for serial MRIs to make sure you’re not getting these side effects. If you put it in that context, in my opinion, the drugs have a better therapeutic profile than a lot of cancer drugs.

Being Patient: What are your views on glucose metabolism and Alzheimer’s risk?

Fillit: Well, the body is dependent on glucose for energy. Every cell in the body needs glucose. Insulin is what helps glucose get inside the cell. The brain is about two percent of the body weight, and it consumes, at any moment, 20 percent of the body’s energy through glucose.

“The brain is about two percent of the body weight, and it consumes, at any moment, 20 percent of the body’s energy through glucose.” 

If somebody is diabetic and they take too much insulin and their glucose level drops below about 60 in the blood, the first thing that happens almost immediately is they go unconscious, and then you give them glucose, and they wake up. That’s how dependent the brain is acutely on the availability of glucose for energy because it’s so metabolically active. If you think about that in a chronic setting of a diabetic or even a pre-diabetic, you could imagine that a subclinical level of glucose energy inefficiency would contribute to neurodegeneration. 

I think that’s what’s so interesting about the current study that no one noticed is doing with GLP-1 agonists. They’re studying Ozempic or semaglutide for Alzheimer’s disease because this is such a clear hypothesis, and there’s preliminary data that metformin, liraglutide, and other glutides are beneficial in preventing and treating, predominantly preventing as a risk factor, cognitive impairment, cognitive decline, and even Alzheimer’s disease. 

This is another way that the biology of aging is being translated into new therapeutics for Alzheimer’s because it’s not just, as you said, the anti-inflammatories. [Still,] it’s also this metabolic dysfunction that occurs with aging that predisposes people to neurodegeneration. When there’s neurodegeneration, there’s plaque formation and all of that.

Being Patient: 10 years from now, what is your prediction about where we’re going to be in terms of Alzheimer’s treatment and prevention? What’s going to change in the next decade?

Fillit: There’s been a revolution in Alzheimer’s diagnostics and treatment, and we have the first disease-modifying drugs on the market in the history of the world. We have a simple blood test that can tell you with about 90 percent certainty if you have Alzheimer’s disease. This is really a revolution, and as doctors become more familiar with these tests and drugs, I think it’s going to become more commonplace for primary care doctors. 

“We have a simple blood test that can tell you with about 90 percent certainty if you have Alzheimer’s disease. This is really a revolution, and as doctors become more familiar with these tests and drugs, I think it’s going to become more commonplace for primary care doctors.”

When I trained, I never heard the word Alzheimer’s disease. I’ve been doing this for 45 years. When I [would] meet somebody at a cocktail party, they’d say, “What do you do?” I’d say, “Well, I do research on Alzheimer’s, and I take care of people,” they’d look at me cross-eyed and say, “Alzheimer’s, I never heard of it.” It wasn’t in my textbooks. 

I’m just trying to say we’ve come so far, and in 10 years, I think we’re going to be rapidly changing the world. It’s not just going to be blood tests for amyloid. There already are blood tests for tau. There’ll be imaging tests for tau. We’re going to be able to make a precise diagnosis. We’ll have blood tests for the right inflammation to see if inflammation is contributing to that person’s dementia or cognitive impairment. We’ll use these metabolic tests and [look] at other pathways, which I won’t go into. 

You’ll get a profile like you would in cancer, and then we’ll tailor the drugs to your biomarker profile, your blood test profile. I think that’s going to have a big impact on the prevention and treatment of the disease. 

I think the world is really changing with this whole thing. This is becoming a mainstream illness for neurologists and other doctors. Everybody’s heard of it, everybody’s scared of it, and we have treatments now and ways to get a definitive diagnosis that are non-invasive. It’s a completely different world. 

“Everybody’s heard of it, everybody’s scared of it, and
we have treatments now and ways to get a
definitive diagnosis that are non-invasive.
It’s a completely different world.”

10 years from now, it’s just going to be gonna have multi-modal treatments and diagnostics. We’re going to be able to treat and manage it in a pretty good way. Will we be able to cure it completely? I don’t know about that so much, but, certainly, we’ll be able to, the same way that we’ve come to see cancer. [It used to be seen] as a death warrant, and now, this is a chronic disease that we manage through precision medicine. That’s what’s going to happen with Alzheimer’s and related dementias. 

Katy Koop is a writer and theater artist based in Raleigh, NC.