How are things going awry, and what is the root cause if it's not the beta amyloid?

Well, the root cause, and I think that this is where the science is, as you and I have this conversation, there are changes in these microglial cells that rather than existing in what is called their M2 supportive configuration, what I call brain defenders, where they are nurturing the neuron, they are nurturing the synapses, they're keeping the blood-brain barrier working effectively, that they can shift, and we'll talk about what causes that shift, to being the what's called M1 configuration that actually destroys synapses, threatens the neurons, and destabilizes the blood-brain barrier.

All of those things are bad.

The fact that these immune cells are gobbling up our synapses is very relevant as it relates to Alzheimer's, because Alzheimer's is really a disease characterized by the loss of connectivity.

The loss of connectivity of one neuron to the next neuron, which happens at the level of the synapse.

So at a microscopic level, that's what's going on.

At a macroscopic level, people become disconnected as well with themselves, with their environments, with people around them.

But my question is the gobbling that they do, the pruning that they do, is it both, is it like pruning, is it good pruning? Like when you're growing and developing your brain and getting rid of cells that you don't need, is it getting rid of infections? Is it like, what starts it? And does every microglia cell become at some point an M1 or an M2 or some only an M2 or some only an M1? How fast do they turn over? What is the day in the life of a microglia cell?

So what was happening in your conventional neurology practice that made you willing to walk away from the mainstream and take this step? Yeah, I'm glad you pointed that out because...

I have to say, a lot of times when I do these interviews, people are really interested in, well, you know, it's all about the brain's immune system and how we influence it.

But you're right.

That's the opening lines of the book.

And, you know, what's the worst that could happen? And what I was already 10 years practicing mainstream neurology, you know, up every third night in the emergency room, dealing with strokes and all kinds of things.

And then in my practice, really dealing with a lot of neurodegenerative conditions like Parkinson's and Alzheimer's.

And I suddenly began to wonder, and I think partly because of my wife's prompting, what was the cause of these issues? What was going on? And back then, there was really no dedication to trying to understand the cause.

How do these microglia fit into that picture of the immune system? Are they completely separate or…

Why are we talking about Sideways? Why is it required viewing?

Well, let me start out by pointing out something about this film that I rarely do and I rarely refer to.

I, I leave that to you.

Let's talk box office, okay? This film, in 2004, cost $16 million to make.

I was looking up some of the history and, and the, the deal with the director was that you've gotta keep it under 10 million.

We know that that's the one promise in Hollywood about you gotta keep the budget under something.

That is the mo- Among the many broken p- dreams and broken promises on the streets of Hollywood, that's, that's one of them.

He is like we are not in a lot of ways specialized in one specific thing, which is adult character dramedy, and they work like gangbusters.

So for the person listening to this podcast, because the title is Well Beyond 40, who is thinking, "Well, shoot, I'm not 30 or 40, I'm 50, 60 or 70, is it too late for me?"

No, and in fact, let's play on your title a little bit.

Well Beyond 40.

Okay, if you wanna be well beyond 40, and you know, I'm 31 years beyond 40, if you wanna be well beyond 40, you've gotta make the changes when you're 40 and not wait till you're 60 and wait till you're 70 because, uh, a lot of, uh, there's a lot that passes under the bridge between being 30 and being 71, as it is in my case, uh, that you, you know, that are to some degree not as easily reversed.

So it's really all about what you've been talking about.

And you know, your new book, for example, talks about this fundamental importance of not becoming sarcopenic.

What does that mean? Not losing muscle mass.

Yeah.

So what I, like, what can we women do specifically to prevent this, you know, turning these evil twins on in our brain?

Let me just emphasize the point you just made.

And that is that women are twice at risk compared to men.

Why do I have to write that in a book or you have to talk about it on a podcast? That should be something that is screamed from the mountaintops.

And yet women have been neglected in this regard for years.

And I praise the work of Maria Shriver, for example, with her Alzheimer's Initiative to really get this message out there to make funds available for the research and to really ask that question that you just asked, which is so fundamentally important.

Are there hormonal differences between men and women? Yeah, gratefully there are.

firing on all cylinders.

Mm-hmm.

Because the...

And the definition of an endocrine gland is an area in the body, a gland or an organ, that produces chemicals that go elsewhere and target other organs and do things.

Like the thyroid targets your brain and your muscles and everything else.

And the muscles do that.

They secrete chemicals that target the heart, that target the blood vessels, that target the pancreas, liver, and even, yes, the brain.

So let's take full advantage of that.

The correlation.

that one, actually.

Yeah, I was surprised to see that too.

The issue that should be considered, let's talk about the potential downside, has to do with sleep-wake cycle chronobiology.

And I think that Remember, the half-life of caffeine is six hours, which means that if you have a double espresso at three o'clock in the afternoon, there's still that single espresso because of a half-life on board at 9 p.m.

So six hours later, you still have half the amount of caffeine floating around your bloodstream and no one would recommend drinking an espresso at 9 p.m.

So I like to embrace the notion of a caffeine curfew.

Meaning, what is the latest time of day that you're able to consume a cup of coffee and get away with it? We'll talk about getting away with it in just a moment.

This is the glymphatic system and it's relatively newly discovered, right?

Hmm.

When their metabolism shifts, that is what characterizes them becoming destructive, and the key player in their metabolism is the function of their energy producers called the mitochondria.

So in a very real sense, what is upstream of all of these issues, of all the neurodegenerative conditions, of lack of hormone functionality in menopause, of cardiometabolic conditions, cardiovascular disease, all chronic degenerative conditions of the body that the World Health Organization ranks as the number one cause of death on the planet are ca- are fundamentally issues with how the mitochondria are producing energy.

Yeah

... you're right, but the idea of going into ketosis from time to time isn't just for improving momentarily the brain energetics at that moment, but it's to target these other issues like inflammation, like insulin functionality.

Uh, you know, we, we recognize that insulin is a real player in the brain.

Uh, people know that insulin is really a critical hormone that allows our cells then to utilize glucose appropriately.

It's why, uh, it, it's how insulin works.

There's a lot

of questions here.

So let me back up a little bit.

And yesterday I was sent a list of questions from Vogue magazine.

And they said, ultimately, what was the number one thing people can do action right now that would be the best thing they could be doing for their brain health and you know what dr cassie you just talked about well is it sleep is it exercise is it diet all those things all matter of course they matter they matter a lot but the number one thing is to embrace the fact that you are in charge of your brain health That's the most important thing you can do because if you don't do that, then the other things aren't gonna happen and therefore you're not gonna put into play any of those salubrious activities that you just mentioned.

So job one is to rewrite that narrative that it's not offloaded to a third party to mop up the disaster once it's occurred and your brain health is suddenly declining, that's at the very end stage.

Even when you're starting to have senior moments well before even mild cognitive impairment, or even before that subjective cognitive impairment, long before the diagnosis of Alzheimer's, if you're already at that stage, where you're noticing that you're going into a room, you don't know why, and things are becoming more challenging, that's well into the continuum.

And my heart doctor said it's going to people who are put in these situations which by the way her mom had dementia and one of her biggest complaints to me was i'm hot i have vaginal dryness and have utis all the time but i do not want to have dementia like my mom did that was her biggest thing i don't want dementia and it's like man you know her fsh is 150 her lipoprotein a is a little high she's got some metabolic issues but like in her estrogen from what i have seen in practice and the studies i'm reading now maybe beneficial maybe even a little bit of testosterone as long as we do the right dose the right frequency etc so what are your thoughts on hormones are they really bad will they help does it help if beta amyloid plaque has already started does it help just prevent it like let's talk about hormones and brain health from your perspective

Mm.

And how effective are they, are they, and how safe are they? This was, you know, looking at, uh, 20,342 individuals across 17 studies for 18 months per study.

And it found that the drugs don't work.

The, the, uh, the word that they used was trivial in terms of their effectiveness, and in the face of significant risk, more than 20% of these people get brain hemorrhages and/or brain swelling.

Uh, and it's, you know, an IV two, every two weeks at a cost of $40,000 a year that Medicare is covering.

Uh, and, uh, I, I actually had this discussion with the Director of Medicare and Medicaid for the United States-

Mm.

But when gamma is disrupted, it sets the stage for brain degeneration.

But alcohol is something you explore in the book as well, and maybe you can touch on it.

Yeah, it's funny 'cause I did an interview for Newsweek just yesterday, but [chuckles] it actually came out yesterday morning.

They said, "What are the things that this neurologist, the six things that, that you would never do?" And alcohol is one of those.

Not that I wouldn't have a glass of wine from time to time, but alcohol is an issue at multiple levels.

A, it is a direct neurotoxin.

It is toxic to neurons, no matter how you slice it, i.e., whether it's scotch or red wine.

We used to say, well, the epidemiology studies demonstrated that one glass of red wine for women, two glasses per day, actually was associated with a, a reduced risk for Alzheimer's disease.

The last thing I did wanna ask you about is the GLP-1s and what your thought is about them and everything we've been discussing.

But from the standpoint of brain health, why is sleep so valuable?

So lack of restorative sleep is a powerful risk factor for brain degeneration.

Maybe that's a soundbite right there, and people need to think about that.

Because I think there's a trend these days to, well, I want to be more productive.

I'm going to stay up later and do something.

Or I'll binge watch whatever it may be, Homeland, until who knows what time.

But you've got to get enough restorative sleep.

And do I avoid gluten 100%? I do not.

What is the mechanism of how they end up supporting the body and the immune system that you've been describing, and how much of it do we need to actually stay healthy?

Well, let me answer the last question first.

How much do we need to actually stay healthy? The very important point is that any exercise is gonna immediately benefit the brain.

That means that, uh, if walking to the mailbox is something new for you, that's gonna actually help your brain.

One study published in the Journal of the American Medical Association looked at, followed people for a number of years, giving them, in those days was a pedometer.

Uh, it was a, a thing you'd wear that would click every time you took a step.

And it found that the b- the benefits began by just taking a few steps a day, adding that to your program.

Sure.

That's B-O-N-C-H-A-R-G-E.com/hyman, and you'll get 15% off.

To wanna take it a little deeper, let's look perhaps at your C-reactive protein.

And as I describe in the book, there are a, uh, a suite of very brain-specific blood tests that we can get, like, uh, p-tau 217, which we, we could talk about.

But The main players are, uh, those blood tests that I mentioned that look at your blood, uh, metabolic markers, know your blood pressure, and, and buy a very, uh, very sophisticated and expensive tool called a tape measure, and put it around your belly and put it around your waist.

And then do the math and determine your waist-to-hip ratio.

And, you know, this is an extremely valuable way of understanding what is your risk.

How does that relate? Well, w- when your belly is big, you have more visceral fat and you're increasing inflammation.

Yeah, yeah.

Yeah

...

in things like mood disorders.

Uh, and that is certainly upstream of any change in the neurotransmitters.

And what's really exciting is that this is the same kind of, uh, issue mechanistically that goes on in Alzheimer's and Parkinson's and PTSD and long COVID, and all the neurodegenerative conditions are all united by the fact that these changes in the brain's immune system, uh, that can be brought on by a number of inroads, like inflammation in, in depression, for example, all filter through, uh, the changes in the immune system that then leads to, uh, changes in brain functionality.

So now we have kind of a, a global entree for brain health a- across multiple domains of risks, of illnesses, for example.

Things like depression, uh, things like Alzheimer's and Parkinson's, all united by a similar mechanism.

Mm-hmm.

Um, for those who don't understand, can you just explain some of the basic terms? Like, what is a neuron and what is a microglia, and, a- and why should we be more focused now on the importance of the microglia for understanding these diseases?

Well, the neuron is the workhorse of the brain.

You know, the neuron is, is d- is doing the heavy lifting.

It is transmitting the information, uh, to its neighbor, uh, and through networks when neighbors all get together for a community meeting.

And so, you know, it, it's really the hardware of the brain, if you will, the connectivity of the brain.

Uh, but the reality is that the functionality of that neuron and the survivability and the resistance that neuron has to degenerating is the purview of these other cells we've talked about, the microglial cells.

When we characterize these microglial cells as being immune cells in the brain, or part of the brain's innate immune system, people immediately default to the notion of, well, immunity, that's something that comes into play when I have an infection.

So when it comes to diet, um, should those who want optimal brain health, who are concerned for themselves or their patients, should they be recommending a Mediterranean low glycemic diet, a keto diet, a MIND diet? What, what would be the best diet, or does it depend on the person?

But when it comes to metabolism, how important of a role is diet to have a healthy metabolism? And then touch on metabolic flexibility.

Well, the answer to the question how important it is, it's one of the pillars.

It is fundamental.

And, you know, as we've watched the degradation of what was called the American diet, then became the Western diet, and now is the global diet in terms of these ultra-processed foods, we've seen metabolism go down the tubes and Alzheimer's increase, as I mentioned earlier, in lockstep.

One recent study, uh, demonstrate- was an evaluation, uh, followed individuals, 1,325 individuals for 12.7 years.

Average age was 67.

And followed them and had them keep a food diary, and they retrospectively looked at their food diaries, diaries and compared them with their risk of developing Alzheimer's.

Mm-hmm

Mm

... a good body go bad, really to me gets down to what I call environmental evolutionary mismatch.

In other words, that we have a genome.

Our DNA, the collection of our DNA, has been honed and perfected, almost to perfection, over tens of thousands of years to allow us to survive and reproduce, really in the face of certain environmental cues.

The problem arises when we suddenly challenge that paradigm with brand-new environmental cues.

When I say environment, not just things that we're exposed to in our environment like pollution, but even the food that we eat and our lifestyle.

These are all extrinsic cues that are information that are targeting our DNA in terms of its expression.

Do all of the concepts still hold true? Have you changed any of your concepts around, you know, metabolic health, carbohydrate intake in the brain?

Yeah.

I, I'm not saying that's what we should be doing for one and all right now, but I am, uh, certainly open to drugs that are incredibly effective in terms of changing metabolism, and that's really the ballpark in which we find ourselves, that there may be some, uh, y- you know, studies that demonstrate effectiveness.

The first real interventional trial using drugs, GLP-1 drugs, orally, semaglutide, uh, to target Alzheimer's really did not reach the endpoints that they wanted, although interestingly, C-reactive protein, a marker of inflammation, uh, in the intervention group was reduced by some 30%.

There's, there's some noise there in the background I think we have to pay attention to.

That said, we have seen, uh, incredible results with, uh, injectable GLP-1 agonist drugs in the treatment of, uh, Parkinson's disease.

One study in the New England Journal of Medicine actually, uh, showed that in the group receiving a GLP-1 agonist drug versus placebo, the, the placebo group over the, uh, period of the study declined as one would expect over the couple of years, whereas the, um, interventional group actually stabilized or slightly improved.

We've never seen that, uh, in Parkinson's.

And who knows, maybe socialization, you and I, well, we can't do it here, but among groups of people, we exchange bacteria all the time.

Yeah

...

the importance of synaptic destruction, and really creates an environment that is not favorable for the neurons and leads to actually breakdown of the blood-brain barrier.

You know, again, so for our, the scientific community who's gonna be watching this, we fully understand that there are an infinite number of transitional states between the M2 and M1, but that's the pretty much the standard that is used for, for purposes of discussion.

Now- Our M2 brain defender microglial cells are very sensitive to a variety of inputs or in changes in their environment that will then shift them away from being on our side to being really working against us.

For example, they have receptors on their surfaces that are responsive to what are called cytokines.

Cytokines are the messengers, if you will, or the mediators of inflammation, and they can come from anywhere in the body.

And what are the most well-researched lifestyle strategies that people should start today in order to improve their microglia function?

So exercise

is a foundational approach to improving your metabolism, getting back to targeting your microglial cells, your brain's immune cells, and redirecting your brain's destiny.

It's that simple.

So You know, the question is, well, okay, how often should I exercise and what in the heck should I be doing? And there's always the discussion of, well, which is better for me? Is it aerobics? Is it resistance training to build muscle? And I say, you know, obviously those are both important, but I always add number three, and that is flexibility.

And let's say four is balance, but flexibility is really important because if you're not flexible and you exercise, you have Increase your risk of hurting yourself, at which point you stop exercising, and that's not a good thing.

One study that was published back in 2025 was a meta-analysis, meaning it looks at various other studies of 35 different other studies that encompassed around 5,735 participants when you looked at all the studies.

And the conclusion, and they looked at evaluations of what happens to cognitive function in people who do aerobics, how about resistance training, how about both, and the conclusion was clear.

What do you listen to?

But can you explain that simply, what that means and what that means? This

is a huge dichotomy and long awaited and very much welcomed.

I mean, since the late 1980s, the messaging has been that the brain accumulates this sticky protein, misfolded protein called beta amyloid, and that is the end all cause of Alzheimer's.

Guess what? That is, it's not a medical term, but I'm going to use it anyway, bogus.

It isn't reality.

Alzheimer's is not caused by by beta amyloid.

We were all, including me as a neurologist, made to believe this myth.

What do you want to share on what you think are the most promising? Yeah.

... really signifies the importance of what you're gonna start to talk about, which is the power that we have and s- the way that we can defend our brain.

Yes.

And let, let's be clear.

They, they're not Alzheimer's drugs.

They're amyloid drugs.

They're, they work by getting rid of amyloid in the brain, but their effect on Alzheimer's is almost n- nil.

Uh, so, you know, a- and it's interesting 'cause originally when the, uh, drug makers petitioned the FDA for drug approval, uh, they were denied approval because the drugs didn't improve or slow the decline even, uh, in Alzheimer's drugs, so they were denied.

But why is it that people cannot supplement their way out of an inflammatory, high glycemic diet?

So is it the same thing in the brain where the microglial-

It, it's not a classic autoimmune condition.

I mean, in that, in, in, in those conditions that you mentioned, uh, which are, you know, by and large disease- diseases of women, which Alzheimer's is as well, two-thirds of Alzheimer's patients are women, uh, it is a very directed type of immune response against various tissues on the body, in the body, and depending upon which tissues receive the brunt of that immune response, we get the manifestations of the various disease processes that you mentioned, the ankylosing spondylitis, the rheumatoid arthritis, systemic lupus erythematosus.

This is more of a kind of a global activation of an immune response in the brain.

We can actually now do a particular type of brain scan called TSPO.

TSPO is a marker of activated microglial cells.

And when you look at TSPO imaging, you realize that this microglial activation is something that transcends all the barriers as it relates to neurodegenerative conditions.

Um, what else?

So I'd love to start there and then build kind of a broad foundation for all the things we're gonna talk about today.

Well, the reason I'm so excited, here, here's what, here's the book.

Here's the cover.

The reason I'm so excited, and, and the website, by the way, is, oddly enough, braindefenders.com. Who knew? Is because when we look, when I look at everything I've done for 40 years in neurology and in medicine, everything converges on how it affects the immune system, whether it's what I wro- wrote about in Grain Brain with respect to carbohydrates, Brain Maker with respect to the gut microbiome.

A- all of the issues that I've been describing for so many years were interesting in and of themselves, but they all come together and unify mechanistically in terms of how they play out by affecting the brain's immune system, what we call the microglial cells.

The microglial cells are sensitive to a high ultra-processed food diet, higher levels of carbohydrates, inflammation, changes in the gut bacteria.

All converge on the brain's immune system and either create a scenario where the brain is gonna really be preserved and functional and resistant to decline, as we see with Alzheimer's, or based upon our metabolic health and our inappropriate dietary choices and, as mentioned, our sedentarity, lack of good or restorative sleep, the immune system will shift and become destructive.

But I would love for you to walk us through, like within someone's daily life, within their environment, within things that are within their immediate control, what are some of the biggest levers from this understanding of the immune side of brain health that we can focus on first?