Risk Factors For Alzheimer's - with Molly Fox, PhD | The Empowering Neurologist EP. 31

Hello everyone, I'm Dr. David Perlmutter and welcome again to The Empowering Neurologist. Over the past few years, I have been incorporating into my presentations to professionals a series of slides that talk about the work of our guest today, Dr. Molly Fox. This is work that really has centered on her recognition that changes in the diversity of the organisms that live within the gut may lead to changes within the body like inflammation that might explain why in certain countries where there's less diversity and higher levels of parasites, or rather lower levels of parasites as it were, there is increased risk for Alzheimer's disease. I would suspect her work really is translatable to other inflammatory conditions, and we're going to talk about that today. But first, let me tell you a little bit more about Molly Fox. Molly Fox is a PhD, and what she states about herself is that within the frameworks of evolutionary and developmental biology, my research focuses on maternal and grandmaternal transgenerational transmission of genes phenotypes, life history patterns, and disease risk. I synthesize information from molecular, clinical, and epidemiological, as well as anthropological research towards understanding the evolutionary context of human health and disease, family and social structure, and addressing global health challenges. Wow, that means we're in for a very interesting interview. She has several academic appointments, including Serving as an assistant professor in the Department of Anthropology at UCLA. She has been there just recently. She also has an appointment at the Department of Pediatrics at University of California at Irvine in the School of Medicine beginning in 2015 until now. She was at Cambridge between 2008 and 2013 where the research that I have been following originally took place. Her PhD in biological anthropology was granted at Gonville and Caius College, where she was a Gates Cambridge Scholar. Her PhD thesis was entitled The Evolution of Postmenopausal Longevity and the Preservation of Cognitive Function. She's done some really interesting work related to a reduced risk of Alzheimer's disease, for example, in women who have breastfed, and we'll talk about that today. She's a graduate of Yale University, 2004 to 2008, with a BA in anthropology and theater studies, a really intriguing combination. Maybe we'll touch upon that as well. So let's just jump right into our interview with Dr. Fox. Well, hello, Dr. Fox. In the intro, I was going through all of your credentials, and you really have done some interesting things. So you first You were a theater major and also then branched out into anthropology, or how did that work?

You know too much about me.

I know a lot about you.

Yeah, I double majored when I was an undergrad at Yale. I was originally just a theater major, and all of my elective courses were in human evolution. I just found it too fascinating to avoid.

So you've done, even in your research moving after that, you've done some very diverse types of research. But, you know, one central theme recently has been— you're looking at Alzheimer's in terms of some of your papers anyway. And one of the ones that I really found interesting is that you found a decreased risk in the downstream development of Alzheimer's in women who breastfed earlier in their lives. What made you think that might be something you would find when you looked at that data? And then maybe we can talk about perhaps a mechanism.

Hmm. Um, so there were a bunch of different converging ideas that led me to this. You know, as a biological anthropologist, which is the field that I come from, we're really interested in human evolutionary history. So looking at our species over a long time span and globally as well. And one of the major ways in which human biology has changed in the modern era has been the timing and implementation of women's reproduction. And probably within that realm, the most major change has actually been in breastfeeding in terms of duration, like how many months women breastfeed for after each pregnancy, and in terms of frequency, whether they breastfeed at all. So breastfeeding is actually a really fascinating biological phenomenon that might exert, I think, long-term effects on women's biology. And it involves major reorganization of the immune system. It involves reorganization and effects on endocrinology. And these are all systems that have been implicated in geriatric disease, specifically Alzheimer's.

I have to say, when I first was reading your bio and looked at the name of that publication. I could do everything. I did it very quickly. And the first takeaway till you stop and read it again is perhaps there is some kind of protective mechanism in the children who were breastfed, which could certainly speak to issues with reference to their developing microbiome and their risk for inflammatory disorders down the line. And that, I think, that error on my part segues nicely to another bit of research that you did that I have been using in lectures over the past several years, and that is I want to talk about the study that you did looking at the microbial diversity and parasitic load in various countries plotted against the risk, basically risk for Alzheimer's, not necessarily demonstrating causality, but at the very least correlation.

Yeah, so that project again is Similarly, sort of inspired by a long-scale view of human history and human biology and human diversity. And another one of these major ways in which the human biology and life experience has changed has been in our microbial exposures, or our exposure to bacteria and viruses and other microorganisms, parasites. Mm-hmm. And this is— It's all part of a concept that we usually call either the Old Friends Hypothesis or the Hygiene Hypothesis. Track 10. Yeah. The Old Friends Hypothesis name really emphasizes the fact that mammals have spent our evolutionary history living in concert with all of these little microorganisms that live in our bodies and in our environments and in our food and through constant exposure, the way natural selection has shaped our biology has basically been under the assumption that we are infected with these little guys. And so in very, very recent history, when we look at an evolutionary timeframe, really the last 200 years since industrialization, we have done 2 weird things. We've eliminated a lot of these microbes from our environment. So you send your kids to play out in the mud, they're not going to get infected with a lot of those microbes because we've eliminated them through these sort of large-scale industrial sanitation measures as one way. We've also selected for different sets of pathogens because we just live in a totally different landscape than we used to. Yeah. The other major change, of course, is in our own bodies. It's not just our environments, but our own bodies don't have these microorganisms living in us anymore. The idea of the hygiene hypothesis is that these changes might explain some of the modern acceleration in inflammatory disease that we see. And might help us understand rates of inflammatory disease that are accelerating in different world regions. So that's things like allergy and asthma and also autoimmunity or autoimmune diseases. So I think Alzheimer's should potentially be added to that list.

Well, it's a leap, and I know it's a leap because I've been, you know, trying to connect those dots for a long time as well, you know, recognizing that I think it's pretty clear between at least scientific researchers that Alzheimer's has all of the hallmarks of a prototypic inflammatory disorder, whether it's at a biochemical level or even at an imaging level when we can image activated microglial cells and see the brain on fire. But I think getting that message across to clinicians and certainly to the mainstream has been a bit of a challenge. And I was surprised with your study because— and I'm telling you, I love your study, but I was surprised because, you know, that you maybe didn't choose something that was a little bit more obvious in terms of inflammatory. I'm thrilled to no end that you've been so helpful in connecting dysbiosis or changes in the gut bacteria through the mechanism of inflammation to Alzheimer's. And if we want to just connect a few more dots there, it might well be that those changes imparted on the gut by our modern lifestyle, our drugs, our dietary changes, etc., ultimately induce the changes in the microbiome to the extent that the gut becomes permeable. We then stimulate these immune cells, create these inflammatory chemicals that affect the body from stem to stern, from top to bottom. So I was thrilled by that. And I think, you know, the message is that— hard to say, but dirt is good, or being exposed to bugs is a good thing for us. And How do you get away with saying something like that?

Well, that's the thing is that it's— the problem is that we're really balancing 2 major sources of disease and destruction of the body. If we think back to before humans lived in industrialized cities, before humans even lived in cities, before we were—

Which was yesterday.

Before we were even farming, we go back more than 10,000 years ago. Yeah. We spent the vast majority of human history living as hunter-gatherers. We were living mostly outdoors. We were in very sparse population structures. If you think about life from the perspective of a bacterium, they, from a natural selection— in a natural selection context, had evolutionary incentive to keep their hosts alive for a long time so that those people would come into contact with someone else and infect more people. So pathogens in that context would be under selection pressure to be what we call less virulent. But once humans started living in really dense populations and living indoors, a pathogen that infects us and causes illness and sort of from an evolutionary point of view wants to reproduce Can do a lot of damage to the host very quickly and kill the host very rapidly and still be reproductively successful because that person will very likely come into contact with other people. And the reason that I bring that up is because the nature of our pathogenic environment has changed really dramatically with our own change in lifestyle. So if you try to enact some of these exposures in our modern world where we have really dangerous infectious disease that might have been at least somewhat absent in the pre-modern world, you're going to run into a lot of problems. I would definitely not encourage people to deal with our increasing understanding of the benefits of microbial exposure against inflammatory disease by seeking microbial exposure because the nature of those microbes has changed.

That said, if you chose Alzheimer's on the basis of your understanding that it was an inflammatory— is an inflammatory disorder and relating degrees of loss of bacterial or microbial diversity to increased risk for Problems related to immune modulation as well as inflammatory issues, not that they're different. Could— do you believe that your data might be extrapolated to other disease processes?

I would say in some ways the opposite, that my understanding of other disease processes led me to investigating Alzheimer's. Okay. For sure, other diseases that have similar biological hallmarks of a similar type of immune dysregulation should fall into that category, but the similarities with autoimmunity specifically between autoimmunity and Alzheimer's were really what led me to potentially include Alzheimer's in that category. What's funny or what's interesting is that Our understanding of this hygiene hypothesis concept really came from these large-scale epidemiological observations, and then we sort of boiled down to looking at individual bodies. But it started by looking at what's happening in Europe over the last 100 years, or what's happening, you know, at that large-scale population level. And so that's where I started with Alzheimer's, saying, does it even have a Is there a similar population-level trend going on?

In looking at population trends here in America and other Western countries, especially in cosmopolitan areas, we are really seeing an explosion of very prototypic autoimmune conditions. Hashimoto's thyroiditis being, I guess, at the top of the list, but celiac disease, type 1 diabetes as well, and certainly lupus. I think that, you know, Dr. Strachan, who popularized this hygiene hypothesis back in 1989, I think there is probably, although it is, you know, just observational, I think now that we have such a more robust, although it's still fairly primitive, understanding of the metabolic effects, immune-regulating effects of the microbiome, that now we're starting just, you know, we're at a nascent stage of really putting these pieces in place where we're starting— to understand these relationships and maybe just be able to pave the way for some therapeutic interventions. What do you think?

I think that understanding the pathways and mechanisms will lead, hopefully, to research in therapeutic interventions, and I think that there are a few different points at which we might be able to intervene. It may not be necessarily infecting people with particular microbes, but rather trying to mimic the effects of those microbes on the immune system in order to help people develop a healthy immune system. The other thing is looking at the full lifespan and figuring out the timing of intervention because the immune system develops over an individual's life course beginning in prenatal life, beginning in embryonic and fetal development. Early life is generally what biologists point to as the critical phase of opportunity to intervene in these types of inflammation that we've been talking about. However, I think that I'm very interested in early life as a phase of intervention, but there are other points in the lifespan where we see immunological development of these systems that have not been studied sufficiently. We see Another surge of developments that occurs at adolescence, and in women, we see major changes during reproductive events as well.

So, I think to maybe extrapolate a little bit from what you've just mentioned, there might be then a correlation between early life events, i.e., the set point of inflammation as dictated by the structure of the microbiome, And risk for what we consider to be a later life event, which is Alzheimer's. That's kind of revolutionary talk there.

Yeah, well, we're—

And I'm loving it, by the way, so you know.

Yeah, we're starting to understand more and more how human biology is really flexible and very sensitive to environmental exposures during early life, during early prenatal and postnatal life. This is existent both in things that latch onto us, like the microbiome, and also just in the way our own biology develops. Our genes really allow for a wide range of possibilities. Our genes, especially for traits related to health, don't seem to have this direct one-to-one relationship like they do— like our genes for eye color, for instance, seem much more directly related to the trait we develop. But a lot of our genes related to health seem to allow for a wide range of possibilities to develop. Adaptability.

Yeah.

Yeah, and that kind of flexibility or plasticity is dependent on environmental exposures. Yes.

Well, as you say that, I'm thinking of perhaps through the lens of the microbiome in terms of how the microbiome itself is influenced by the environment and perhaps The most potent environmental cue for the microbiome being what we're able to eat. Yes. It seems to me that that's really our biggest relationship with the environment, looking upon food as information and then really affecting the metabolome, the metabolites of the microbiome that then act as messenger molecules and influence the expression of our genome. epigenetically and then lead to changes that allow us adaptability. You know, one of the biggest issues that I find with loss of diversity is loss, loss of the ability to adapt to different environmental conditions. Right. I recently interviewed a Dr. Mark Plotkin, and we were discussing this, but on a different level. He spent the last 30 years in the Amazon Basin characterizing loss of species diversity and saying this has global consequences for the globe, the world, to be able to adapt to our changing environment. I think, you know, the same thing is happening in us. I mean, here you are demonstrating that in sub-Saharan Africa, where individuals are colonized with more diverse organisms, with parasites, which we've all thought for years are, you know, the worst thing, we've got to get rid of every parasite there is, and yet these individuals If I may extrapolate from your work, are robust and adaptable and are able to respond to environmental changes in such a way that it doesn't light a fire in their brain.

Yeah, well, exactly. Exposure to microbial diversity itself is what we're really coming to understand is very valuable, and that relates back to what I was talking about, about this Yeah. This problem that we've seemed to wipe out a lot of the diversity in our environments, and the way that the immune system develops in what we would think of maybe as a healthy way really requires low-level stimulation from a wide variety of benign microbes, so microbes that don't cause us harm. Without that stimulation, Right. From that kind of variety in early life especially, like we were saying, a lot of the cells that were supposed to differentiate and turn into a type of cell that helps to regulate inflammation for the rest of our lives instead remain undifferentiated or naive, which opens up the possibility that when we do get some sort of infection by that one microorganism to which we're exposed later in life, it could cause excessive inflammation or general dysregulation of immunity.

What you're, I think, describing is the important role of the microbiome in terms of educating our immune system and really makes us that metaorganism that we are so interdependent with our 3 pound load of microbes within us that actually are educating our immune system. It brings me to a place of wanting to ask you, you know, there's been so much work done looking at the changes in microbiome and risk for immune-related issues in children who are born by C-section versus those who have been born vaginally. What are your comments?

Yes, I actually am doing a study right now of Mm-hmm. Newborn and infant gut microbiome development. I think that's a really interesting issue. My perspective on it is that we don't have a great comprehension yet of what a healthy gut microbiome should look like. I mean, we're really in the beginning stages. We observe differences between C-section and vaginally delivered infants. Yeah. But a lot of those differences seem to resolve by the end of the first year of life. So we're not— it's not clear how persistent those effects are because the differences in what bacterial phyla are represented in the gut in those babies doesn't seem to last forever. And so there are a few issues. One is just because a certain microbial profile is associated with a disease That doesn't necessarily mean that it's causing that disease state. It might actually be our body's or our metabody system of responding to a disease state and trying to heal itself, just the way that a fever isn't, in evolutionary terms, a disease itself. It's our body's way of trying to respond to an invasive element and get back to a healthy state. There's so little that we know about microbial diversity in the human body in terms of what it does functionally. That is just where the state of things are right now.

It is so compelling.

I think there's been a lot of focus on the C-section versus vaginal delivery issue. Partly, I think that's because it's easy math to do. You have 2 groups of babies and it's very easy to compare them when the math is so complicated in terms of looking at the populations and environments and comparisons of different types of bacteria in the gut.

Sure.

There's a lot of work to be done in that realm.

So, you know, you're, I'm sure, familiar with the work of Dr. Maria Dominguez-Bello up at NYU, and she has popularized the technique of putting a sponge in the birth canal, harvesting these, the microbiome in the birth canal, and basically then inoculating that child after birth. And in a recent study that she put out in Nature, she demonstrated, in fact, preservation of some unique species that were, in fact, recovered months later from the newborn. I think your point is very well taken. Basically, that's great, but really, what does it mean? I would encourage our listeners to really get your arms around the fact that we are still at a very, very nascent stage in our understanding. The amount of data here is so incredible, so hard to get your arms around. One individual, Dr. Larry Smarr, there at University of California in San Diego working with Dr. Knight, is just doing his very best to utilize their supercomputer to start looking at just some nuances of what may be primordial trends. I mean, even at that stage, but it's great to be back at, I think, at square one and having sort of revisited the whole germ theory that there's a germ lurking around every corner that's going to jump on you and all germs are bad. I mean, I think your work has been quite clear that it's just the opposite. Most germs seem to be doing us good.

Yeah, that they're both healthy and necessary players in the process of human development and human physiological function. Yeah. And, you know, with babies and infant development, I will also say that a huge future area of research will probably be No doubt.

Then that's, you know, on both sides of that issue, mother and child. Well, I just want to tell you, it's great to meet you virtually. And again, I've been so taken by your work, and it really connected a lot of really important dots for me in the work that I do. So I really want to thank you for that. And I look forward to reading more of your research as we move forward.

Thank you so much for having me. It's a real pleasure.

My pleasure. Thanks again. Bye-bye.

All right. Take care.

Wow. That was a very, very intriguing interview. What an interesting individual. Her work, from my perspective, is interesting as it relates changes in the microbiome to the mechanism of inflammation, and as she clearly demonstrated, a relationship, at least, A correlation with risk for Alzheimer's. So again, it does seem to feed back to the microbiome. And again, what an empowering notion in that we can change our microbiomes based upon our food choices. But what a wide range of experience Dr. Foxe has had and brings to bear on her outlook. What a really interesting individual she is. Well, I hope you enjoyed today's interview. I sure did. I'm Dr. David Perlmutter. Thank you. Thanks for watching The Empowering Neurologist.