ALZHEIMER'S PREVENTION
I’m a brain scientist, so most of the questions I ask myself today are related to brain health, which is very important to me. That’s also because of my family, who has history of Alzheimer’s disease. Alzheimer’s disease is the most common form of dementia affecting 5.6 million people in the United States alone. The fact that it runs in my family is a concern for me.
My grandmother developed dementia, as did her two younger sisters, but their brother did not. It’s female-based in my family, as in many other families. My family shaped my career trajectory as a scientist, a clinical scientist, through to my current position as the associate director of the Alzheimer’s Prevention Clinic at Weill Cornell.
What I did not know is that Alzheimer’s affects more women than men all over the world, or at least in all the countries for which we have data. I just launched the Women’s Brain Initiative at Weill Cornell so we can focus on women’s brain health, specifically on preventing Alzheimer’s disease and dementia in women. It’s not just Alzheimer’s prevention, but optimizing cognitive health in women. That's important to me.
The #MeToo movement in 2018 was such a big deal, and in some ways it replaced the Lean In movement. The Lean In movement was about how women can do everything by themselves, and then #MeToo was about how that's not exactly the case for the vast majority of women, because women are abused, neglected, mansplained; women are overlooked legally, financially, societally, and culturally in so many ways. Women have been overlooked in medicine as well, especially in my field of neurology.
My goal is to prevent Alzheimer’s. Most of my research is based on the understanding that if you wait until patients have Alzheimer’s disease, your options are more limited. If you address any issues preventatively, you have much more power.
The brain is a very special organ, but it's pretty much the only organ in the body that does not regenerate. All our cells in the body are continuously replaced and renewed. For example, we shed hair all the time, but it regrows. Even our skeleton is renewed. Every year you get ten percent of a new skeleton. Our blood also changes all the time. The reason that so many diets can work in a short amount of time is because our cells change very quickly. That doesn’t happen in the brain. The neurons that make up most of our brain, the astroglia and microglia, are born with us and stay with us for a lifetime. Neurogenesis, which is the birth of new neurons, is very limited and circumscribed to specific brain regions. By and large, our brains age with us, so you have to keep your brain healthy for the long term. It’s much easier to support the healthy neuron than regrow a sick one.
Right now, we don’t have therapies that regrow neurons. Alzheimer’s is a disease that kills your neurons over time, so once they’re gone they’re pretty much gone. There are things that one can do pharmaceutically to ameliorate the symptoms. For example, there are FDA-approved drugs such as acetylcholinesterase inhibitors or memantine, which do lessen or stabilize symptoms for a few years, but they can’t stop disease progression. What we’re interested in is disease modification, stopping it before it’s too severe or too advanced.
At the Alzheimer’s Prevention Clinic, we try to tell people what to do in a preventative way. There are a lot of other people and clinicians that are actively engaging in prevention as well. It’s new in my field, especially in the field of neurology. Until four years ago nobody would dare use the word “prevention” out loud because so many doctors and clinicians would just label you as a quack right away and you would lose credibility overnight. I find scientists are much more open to this now.
Four years ago the National Institutes of Health and the Alzheimer’s Association got together and led a council. They called together many scientists who were leaders in the field and came to the conclusion that Alzheimer’s disease is preventable in many cases. That was largely based on a fantastic paper that came out a few years ago, a population-based estimate of risk, which showed very clearly that at least a third of all Alzheimer’s cases are not caused by genetic mutations, but rather by the way we live our lives. That’s a very powerful message.
It’s also important to clarify that when I started in this field, which was in college, everybody thought of Alzheimer’s as something that was caused by bad genetic mutations, or aging, or both. Over time, it turned out that neither of these alternatives were the case. There are genetic mutations that cause Alzheimer’s, but they’re found in less than one percent of the general population. It’s a much lower number than we previously thought.
It’s important to me to understand, in my own family history for example, why three women got sick and the men did not. I don't know if there’s a genetic mutation involved in my family. If there is, it’s not aggressive. The reason I’m saying that is because we know that there are three genetic mutations that cause a very aggressive form of Alzheimer’s disease, which is called an early-onset form. Usually people get sick when they’re in their thirties and forties, sometimes fifties. It’s an early-onset form of Alzheimer’s that is defined by very high penetrance. If you have the mutation, your chances of developing dementia are close to one hundred percent.
There are other mutations that are recessive, and there are different patterns of transmission found in the late-onset form of Alzheimer’s after age sixty or sixty-five. My grandmother and her sisters got sick when they were in their eighties—a late-onset form of the disease. However, there’s a sex effect there: the three women got sick, and the man did not. I’m concerned about that. A lot of my research has been about maternal transmission of Alzheimer’s and how that affects risk in the children and the generations to come. More importantly, it is essential to understand that what you need to do to prevent Alzheimer’s disease differs if you’re a man or a woman. This is very new. It’s maybe in the last year or two that doctors have had enough data to come to conclusions that are reliable and effective.
Men and women tend to develop Alzheimer’s for different reasons. If you exclude those with clear genetic mutations, the risk factors that trigger Alzheimer’s or promote Alzheimer’s disease in men and women are different. The process for diagnosing Alzheimer’s differs depending on the symptoms. Let's say a patient comes to the clinic and it's very clear that there’s a cognitive impairment, then we would follow one protocol. If instead the patient or the participant in a way is not affected, does not have any cognitive impairment but is at risk for Alzheimer’s because the parents had Alzheimer’s or because of other reasons, then we would follow a different protocol.
In general, we start with a medical evaluation and a neurological exam because we need to make sure that whatever issues the patient comes to the clinic for are not caused by something else. The screening process is very thorough. We need to look for thyroid disease, vitamin deficiencies, and anything that can be going on in the brain such as a stroke, vascular issues, brain tumors, or normal pressure hydrocephalus—all these things we can screen for using different tools. We do blood tests, we do a lot of screenings, and we do brain scans. It is a very specialized examination, not what your typical doctor would do. They do check for some parameters like thyroid function, cholesterol levels, and triglycerides—the basic tests are usually done by a GP, but then we add a whole other level.
The clinical process for the diagnosis of Alzheimer’s is upsetting for most patients because what happens is you’re not feeling good, you can’t remember names as easily as you used to, you’re misplacing your possessions, or there are concerns about memory. What do you do? Who do you talk to? Most people would go to their general practitioner, but usually a GP is not trained or equipped to diagnose Alzheimer’s. The GP will do some basic screening tests such as thyroid function, cholesterol levels, an EKG can be done easily, maybe some memory testing if the GP is high class. Once those are done, if you test negative for these findings, or even if you test positive, what happens instead is they would send you to a specialist. Depending on your doctor they may send you to a gerontologist, a doctor for older people, or they could send you to a neurologist, which is the right thing to do in case of a suspect diagnosis of Alzheimer’s. A radiologist would also be a good person to see because maybe there’s a stroke or something else going on in the brain. Cancer can cause that or malformations of some sort. A neuropsychologist is another viable option, to test for deficits in memory, attention, and language.
As a clinician, and as somebody who specializes in Alzheimer's prevention, I believe that one day everybody will be tested for an increased risk of Alzheimer’s so that prevention can be implemented very early on in life. Right now, the United States as a country is not big on prevention. One of the major limitations, and one of the reasons that there aren’t as many Alzheimer’s prevention clinics as one would hope, is that you get no money back. Insurance won’t cover anything done preventatively. Colonoscopies are covered, the flu shots are covered, mammograms are covered, but that’s about it. Anything that is more high-level prevention that is not packaged into an Alzheimer’s prevention CPT code, we get no money for it.
For patients who are interested in Alzheimer’s prevention and want to come to the clinic, there are inclusion criteria, so at the moment we only take on patients who are potentially at risk for Alzheimer’s—meaning, a family history of Alzheimer’s. Many people are now doing genetic tests through companies such as 23andMe or Ancestry.com. There’s an option to find out a specific genotype, called the APOE gene; it comes in three forms naturally, one of which increases risk of Alzheimer’s, and that's called the ApoE4 gene. Many patients would just come to us and say, “I got this test result, and I understand that my risk of Alzheimer’s is higher than people who don’t have the same gene. Can you help out?” If you do qualify, it costs you nothing because we take insurance. We work on assignment, so we take whatever your insurance gives us. I believe there’s a co-pay, though I don’t remember exactly how much it is. It’s basically the same as going to a doctor; you just get a lot of tests.
For some of our patients we’re also doing brain scans at no cost to participants because I am funded by the NIH. I’m the very lucky recipient of three grants from the NIH, which are all focused on understanding these factors of Alzheimer's in men and women. The NIH pays for all the brain scans. All the people who end up working with me receive brain scans as well, and they’re fascinating. They’re wonderful tests, and I hope that one day everybody will get their brain scanned.
There are some tests that are FDA-approved and some that are not, which means we can only disclose the results of the tests that are FDA-approved, including some brain scans like the MRI scans. The reason we can't disclose results that are not FDA-approved is because those are considered research tests, so there is no universal way to interpret them. It’s not like a blood test where you have a reference range. Some brain scans are a little bit more difficult to interpret.
At this point I’m working with three neurologists, a nurse practitioner, several research assistants, two radiologists—it's a huge team of people. We review all the results together, and then one of the neurologists will take the lead in talking to the participant, in explaining the results and the risk factors that we need to address for prevention. Then we start treatment.
Our preference, and what we recommend, is that we work with our patients continuously over time. Everybody comes back for follow-ups every six months. We do a shortened version of the big thing. I repeat brain scans every year and a half to two years. It would make no sense to do it more often than that, but just checking in every six months is very helpful. Most patients appreciate it because when you usually go to your doctor, you spend about seven minutes with them, they give you a prescription, and then you’re on your own. We don’t do that. Our patients spend hours with us whether they want to or not. They have to spend a certain amount of time with us and understand what we’re doing. There’s an educational component. Then the treatment plans are custom-tailored for each person.
The procedure I just described is for people with no symptoms but whom we've identified as at-risk. The key is to address those immediately so that they don't get Alzheimer’s down the line, hopefully. For patients who have been diagnosed with Alzheimer’s, the process is different. We refer these patients to clinicians who specialize in Alzheimer’s treatment after their diagnosis. So, we are on the preventative side.
The recommendations range widely from case to case because we believe that prevention should be individualized. There is no one-size-fits-all approach that makes sense. That’s always been medicine, frankly. Clinical trials give the same drug to a number of people, but for preventative care, also clinical care, it should be individualized to the person who is in front of you. It depends on your risk factors. Let’s say you have high homocysteine. Homocysteine is a protein that is found in blood. If your homocysteine is too high, it increases your risk of heart disease, and heart disease is a major risk factor for dementia in life. The thing about homocysteine is that it’s regulated by B vitamins, so if your B vitamins are low, your homocysteine goes up. If you bring the B vitamins up, the homocysteine goes down. The way you manage your B vitamins is through diet and supplementation, and that’s where precision medicine comes into play.
Everybody knows that genetics, your DNA, is important, and there are some things that can be quantified very reliably. We do actual genetic testing. For instance, many people have mutations on the MTHFR gene, which is a gene that regulates the way your body processes B vitamins. If you have a specific type of MTHFR gene, then your body is not as good at using these B vitamins. So, we give supplements that are methylated, which means they’re pre-metabolized so they have a much stronger effect on the homocysteine levels in people with high homocysteine levels. This is a whole process for everything that is a risk factor for Alzheimer’s. I’m particularly interested in how that plays out differently by gender.
What’s important for me as a scientist and the director of the Women’s Brain Initiative at Cornell is to understand the risk factors that are more important to address for men and for women. We know now what’s important for men, but we’re just learning what’s important for women. One of the most important factors for women is measuring hormones and addressing hormonal health. As a brain scientist, one might think it's strange for me to be talking about hormones, because in Western medicine we look at everything slightly separately. If I’m looking at your brain, I shouldn't quite care about your ovaries, but it’s important to acknowledge that the brain is not an isolated organ; it's in charge of the body, and every organ in the body will report back to brain. There are constant feedback loops and different mechanisms by which your brain impacts the rest of you, but the rest of you also impacts your brain back. It’s a more holistic ecological approach.
What we have found using brain scans is that for women going through menopause, it is a shock to the brain as well as to the rest of the body. That’s quite new. We just published that in 2017. As women go through menopause, it’s not just overnight. What happens is that you’re pre-menopausal and your estrogen and your hormones start changing; then you go through peri-menopause, which is when you start missing your cycle; and then you're post-menopausal or menopausal a full year after your last menstrual cycle, which is usually around age fifty-one for most women in the United States, but also in the rest of the world. The brain shows a similar pattern of change.
If we look at brain activity in men and women ranging from forty to sixty, which is what we did, men are fine. You take a man who’s forty and a man who’s sixty and their brain energy levels are roughly the same. We look for the presence of Alzheimer’s plaques, and there are no plaques. And then we look at women. I’ve looked at hundreds and hundreds of women, and this is what happens. If you’re pre-menopausal, your brain energy is just as high as that of a man who is your same age. When you’re peri-menopausal, your brain energy goes down by a good twenty to thirty percent. Once you’re post-menopausal, it goes even lower. For some women it’s up to a fifty percent energy reduction, and that seems to trigger the neurological symptoms of menopause.
When women say, “I’m having hot flashes. I’m having night sweats. I’m feeling depressed all of a sudden. I can’t think straight. I can’t sleep at night,” that doesn’t start in your ovaries; it starts inside your brain. These are brain symptoms of menopause that are usually completely overlooked because the women with the symptoms would go to a gynecologist, not to a neurologist. There's a gap in clinical care that is due to the fact that we don’t think of hormones as something that affects your brain. Most importantly, what we have shown is that as the energy levels go down, that’s when women start accumulating Alzheimer’s plaques. Usually, Alzheimer’s disease in women begins when we are in our late forties and fifties, which is quite shocking.
Another question that came up recently is what happens to women who take hormones to change their gender to men? So, females with female DNA who just feel like they should have been born male. From a purely medical perspective, I wonder about the impact of taking all these hormones and androgens that you need in order to change your appearance. Also, all the procedures that some people undertake to change their appearances further, what kind of impact could that have on your brain?
I’m not aware of any solid research that looks into that, so it’s something I would personally be very interested in doing. As more and more people begin embracing different genders, it’s important to be aware of what happens to your brain, as well as the rest of you. I find that's something that nobody talks about. It’s important to raise awareness that we need to understand what happens on that level as well.
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I’m obviously Italian, as I’m sure transpires through my accent. I was born and raised in Florence, Italy. Both of my parents are nuclear physicists, which is quite unusual. They’re not the stereotypical nuclear physicists, but they are nuclear physicists intellectually and also behaviorally. As a result, I was definitely the weirdest kid in school. For a long time, I had no idea who Cinderella was. I knew who Einstein was, but not Cinderella. And we had no television. I grew up in a very socially unusual environment, and I was exposed to research from a very early age. I also started cooking when I was very little. I believe I was five when my mom first put me in front of a stove, and I enjoyed that enormously.
Then I went to a French high school and spent a lot of time in France. I loved Paris of all places. That had a big influence on me. I’m a scientist, but I’m also interested in lifestyle and nutrition and diet. I wanted to be a psychiatrist when I went to college, but then I spoke to a couple of psychiatrists and realized the amount of time you spend one-on-one with your patients was a lot more than what I was prepared to do. I was so interested in the brain all the time, so I decided to go into neuroscience. It was the first year that specific curriculum had opened in Florence, so only a certain amount of people could get in. I took an exam and passed, so I went to college.
My mom was teaching nuclear physics and transitioned to medicine, specifically to nuclear medicine, which is a branch of radiology where you use radioactive isotopes to look at your body and your brain. It’s those pictures of the brain where some parts are blue and green and red—that’s nuclear medicine. I went on to do my thesis in neurophysiology. I was looking at the brain using event-related potentials, which is a very cool technique. So, I have a dual PhD in neuroscience and nuclear medicine.
I moved to New York in 2004 and have been here since. NYU hired me immediately as an assistant professor, and then I became the director of the Family History of Alzheimer’s Disease Research program at NYU. But I became so interested in how your lifestyle affects your brain above and beyond your DNA, so I went back to school and now I’m also a board certified integrative nutritionist. Then I opened my own lab at NYU called the Nutrition and Brain Fitness Lab. In 2016, I was recruited by Cornell, where I'm now the associate director of the Alzheimer’s Disease Prevention Clinic and the director of the Women’s Brain Initiative.
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There's so much confusion around what to do to help women, especially those going through menopause. Now, we understand it is not just that you’re not able to have kids anymore, but your brain may or may not suffer. Twenty percent of women have no brain symptoms of menopause, but eighty percent of women do, and all women go through menopause. This is something we need to address. The most obvious course of action is hormone replacement therapy, but there’s so much confusion around it.
Some studies show that estrogen replacement therapy increases your risk of cancer, of heart disease, of dementia. Now, we’re starting to understand that it depends on what you do and when you do it. It depends on a woman’s age, on whether or not a woman still has a uterus, doesn’t have a uterus, it depends on family history. It speaks to precision medicine and how every woman should be treated as an individual rather than the as the average woman all over the world.
Pretty much everybody agrees that there’s a window of opportunity during which hormonal replacement therapy would have the greatest chance of success, but that is also individual. It’s different ages for different women, but nobody knows how to choose the right age. The reason for that, believe it or not, is that we have no tools to measure estrogen activity in the brain. We’re in 2019 and we still measure estrogen in blood, which pretty much has nothing to do with the estrogen inside your brain. It’s not a linear relationship. I had no idea that there were no tools to do that. I’m a brain imaging person, so I went to my colleagues in radiology and told them I wanted a tracer to look at estrogen in the brain. I did a lot of research into this and we discovered that, yes, it' doable. I got a grant from Maria Shriver to develop the tracer and test it in people. We are halfway through tracer development, and we’re going to start looking at estrogen in the brain of people hopefully in April. I’m super excited by it. It’s the first time ever. I’m going to be the first brain to be scanned.
Tracer development is tricky. Nobody has done it for the brain. There are different ways to do brain scans. There is a very complicated way and an easier way, and you always have to start with a very complicated way to then understand how to do it with more ease. I’m the first person who is going to get an injection to measure inside my head. That means I have to be inside the scanner for sixty to ninety minutes so I can be injected when I’m in the machine. And then we can see everything that happens inside the brain as the tracer goes inside my brain and starts accumulating and shooting out gamma rays for at least ninety minutes.
