How can we offset it?

And perhaps as importantly, how can we all slow our own cognitive decline irrespective of whether or not we get what is called Alzheimer's dementia?

So Alzheimer's disease is both the most prevalent form of dementia and the most prevalent neurodegenerative disease.

So it occupies that unique spot.

We're talking about roughly 6 million people in the United States have Alzheimer's disease.

That's one in, let's see, I mean, about 2% of the total population.

But that doesn't include those with mild cognitive impairment or pre-dementia or other forms of dementia.

And of course, the right metric is not what percent of the population, which of course includes children, things like that.

It's, you know, so...

It's a function of age.

Yeah.

So is age the major risk factor for getting Alzheimer's? We stay with glaucoma, a disease I'm much more familiar with because my lab worked on it for many years.

The biggest risk factor for getting glaucoma is age.

Yeah.

The greatest risk factor for cardiovascular disease is age.

The greatest risk factor for cancer is age.

We tend to not spend a lot of time talking about that because it's not a modifiable risk.

So, you know, we tend to focus on modifiable risk factors.

So what else can we tell you just to give you kind of lay of the land?

So the second most prevalent neurodegenerative disease would probably be Lewy body dementia followed by Parkinson's disease, although the rate of growth of Parkinson's disease is the highest.

So I think it would probably be most, you know, those three diseases we want to really be paying a lot of attention to.

As you know, there are a lot of other neurodegenerative diseases.

Every one of these things is devastating.

Like multiple sclerosis. Multiple sclerosis, ALS, Huntington's disease.

These are awful, awful diseases.

There are also other kinds of dementia.

Vascular dementia is not Alzheimer's dementia, but it produces comparable symptoms.

Each of these things, by the way, are slightly different.

Lewy body is a dementia.

It's a dementing disease, but it also has a movement component.

So it sort of sits on a spectrum that's sort of, you know, I mean, loosely halfway between Alzheimer's disease and Parkinson's disease.

We talked obviously about age being the number one risk factor.

Kind of not that interesting because you can't do anything about it.

So the real goal is as we age, what are we doing to reduce risk?

Well, let's start with an important gene.

The gene that everybody's heard of certainly came up a lot on the Limitless special where Chris Hemsworth was, you know, made the decision to reveal something that none of us expected when we started that whole series, which was that he ended up being homozygous for the ApoE4 isoform.

So maybe folks understand we have two copies of every gene.

So for gene X, you have copy that you got from your mom and copy that you got from your dad.

And the ApoE gene is kind of a unique gene in that it really, it has three different isoforms that are all considered normal.

None of them are mutations.

So you have the E2 isoform, the E3 isoform, and the E4 isoform.

The E4 isoform is the OG isoform.

That's the one that we have historically had as far back as we can go.

We actually think the E4 isoform offered a lot of advantages back in the day.

It's a bit of a pro-inflammatory isoform and it certainly offered protection against infections, especially parasitic infections in the CNS, which would have been a really important thing to select for 200,000 years ago.

How do parasites get into the CNS?

I mean, you have a blood-brain barrier, you have a thick skull.

I mean, I'm not calling, I'm not telling you you have a thick skull, but, but I mean, it just seems like parasites and other tissues would be an issue because what we're talking about here is brain disease.

Yeah.

Yeah.

Anyway, I don't want to take us off course.

But it also could have protected them.

It probably offered some protection outside of the brain as well.

Anyway, the, the E3 isoform I think showed up, God, I think 50,000 years ago.

And the E2 isoform showed up very recently, about 10,000 years ago.

Now, today we realize that there's a clear stratification of risk when it comes to Alzheimer's disease that tracks with those isoforms.

So because you have two copies, you basically have six combinations of how you can combine those genes.

You could be 2-2, 2-3, 2-4, 3-3, 3-4, 4-4.

The prevalence of them is basically as follows. 3-3 is now the most common. 3 is the most common.

So double 3 is 55-ish percent of the population.

The next most common is the 3-4, which is about 25% of the population.

And then after that, most things are kind of a rounding error.

So 2-3s and 2-4s would be the next most common. 4-4s are very rare.

And 2-2s are the rarest of them all. 2-2s are less than 1%. 4-4s are about 1-2%.

Very important point here is that the E4 genes are not deterministic.

So they're highly associated with the risk, but they're not deterministic.

There are at least three deterministic genes in Alzheimer's disease.

One is called PSEN1, another one is called PSEN2, and another one is called APP.

Those genes collectively make up about 1% of cases of people with Alzheimer's disease.

So they're fortunately very rare genes, but sadly they are deterministic.

Meaning if you have those genes, you do get Alzheimer's disease.

And what's perhaps most devastating about those genes is how early the onset is of the disease.

These are people that are usually getting Alzheimer's disease in their 50s.

So we do have a patient in our practice.

Actually, she's spoken about this very openly, whose mom had one of these genes.

And she got Alzheimer's disease in her early 50s.

I think she might have made it into her 60s before she died.

But absolutely devastating consequences here.

Why do people with Alzheimer's die?

Because I know about the hippocampal degeneration.

Hippocampus, of course, being an area of the brain important for learning and memory.

But is there brainstem degeneration?

Do they lose breathing centers or cardiovascular control?

Usually what happens is it's sort of failure to thrive, aspiration, things like that.

So it's usually they just stop eating or they can't control secretions.

They aspirate, they get a pneumonia.

Or they really lose the ability to even sense pain in their body.

And therefore they'll get an ulcer and they don't realize it.

And it'll become cellulitic and they'll develop a horrible infection in response to it.

I see.

So it's a body vulnerability.

The reason I ask is every once in a while a news report will come out based on a legitimate case study where they'll do a scan on some person and discover that they're missing literally half their cerebral cortex.

Like huge chunks of brain and they're functioning relatively normally.

And so here we're talking about a neurodegenerative disease of relatively, it's widespread but there are a few hot spots, of course, in the brain that degenerate more profoundly than others and the people dying.

So that makes sense.

It extends to lack of peripheral awareness or control and then some acute injury or infection.

Yeah.

Got it.

You mentioned earlier some of the controversy, right?

So what are we talking about here?

Well, it's, and I do write about this at length in the chapter on Alzheimer's disease because I think this is a very important point, right?

Which is the index case for Alzheimer's disease, there's always an index case, right?

There's the quote-unquote patient zero.

The index case was a woman who 100 years later we realized had an APP mutation.

These are APP or PSEN1.

But she had one of these deterministic genes that led to a very early onset of disease, which by the way, without which we may not have come up with the diagnosis because had she just got Alzheimer's disease in her 70s, it would have just been referred to as senility, which is, you know, was not interesting enough to pay attention to.

But I think it probably set the field on the path towards an overemphasis on amyloid beta.

And it's not really clear how important amyloid is, which is not to say it's not important.

It is important.

And there's no ambiguity that amyloid is responsible for the changes that we see in the brain.

But it's not crystal clear because there are lots of autopsies that are done on people that are completely healthy and have died with no cognitive impairment and they're chock full of amyloid.

So what we don't fully understand is exactly what does removing amyloid do.

The other thing that complicates the story is there has been no shortage of drugs that target amyloid that have seemed unsuccessful.

And just to clarify, when you say amyloid, you mean people have died with their brains examined in autopsy and see that there are tons of so-called amyloid plaques?

Correct.

Different than arterial plaques, of course, but within the brain.

So the two hallmarks of Alzheimer's histopathologically would be plaques and tangles.

And even that now is, of course, coming under question.

But it's what we teach every neuroscience graduate student.

It's what we teach every undergraduate.

It's also what we teach every medical student.

And not just at Stanford, but everywhere.

So I have heard that the link between APP and whether or not one develops genes related to APP and whether or not it's cleaved at one site or another, which is what you were describing, and risk for Alzheimer's.

Yeah, so it's basically a cleavage question.

So people with the APP mutation, I think, have one extra cleavage site.

They result in one extra cleavage of amyloid, and then it misfolds.

And the misfolding is what the plaque is that's being created.

That also then predisposes them to the neurofibrillary tangles.

And again...

But all this is under question now, right?

Well...

I mean, this is what I was told.

And when I look, it sounds like there were some papers early in the chain of discovery in the research in Alzheimer's that were either wrong because they were falsified, intentionally falsified.

There was an intentionally falsified paper on one particular amyloid variant.

And that clearly set the field back a decade because a lot of people went down that rabbit hole based on deliberately falsified data.

So what happened to that guy?

I don't know why I assume it was a guy, but what happened to that guy?

Yeah, it's a good question.

I think I wrote one piece about it when it happened.

I actually reached out to the person who broke the story because I wanted to have them on my podcast.

And I forget why he didn't do it.

I forget why he wouldn't commit to it or something like that.

I thought it was a little odd because I thought this would be a great way to talk about this.

I do not know what came of that scandal.

In other words, I haven't paid attention to it for probably nine months.

So I don't know...

Obviously the paper has probably been recalled, but I don't know what disciplinary action was taken.

The field is...

I don't know.

I don't want to speak like I'm in the field because I'm not.

So I want to be careful what I say.

But I think the field is probably in a bit of a crisis because there have been so many bets placed on anti-amyloid therapies and amyloid biomarkers and amyloid everything.

And we just haven't seen efficacy.

So contrast that with cardiovascular disease where you have this ApoB biomarker.

You understand the pathophysiology of how it works.

You have drugs that target it.

So you have a biomarker.

So you give somebody a drug that lowers ApoB.

You can measure ApoB.