How to Slow Cognitive Decline | Dr. Peter Attia & Dr. Andrew Huberman
00:00:00.000 | What is the story with neurodegenerative disease, Alzheimer's in particular?
00:00:07.440 | How can we offset it?
00:00:09.400 | And perhaps as importantly, how can we all slow our own cognitive decline irrespective
00:00:17.520 | of whether or not we get what is called Alzheimer's dementia?
00:00:21.440 | So Alzheimer's disease is both the most prevalent form of dementia and the most prevalent neurodegenerative
00:00:29.960 | disease.
00:00:31.560 | So it occupies that unique spot.
00:00:35.120 | We're talking about roughly 6 million people in the United States have Alzheimer's disease.
00:00:40.440 | That's one in, let's see, I mean, about 2% of the total population.
00:00:48.880 | Okay.
00:00:49.960 | But that doesn't include those with mild cognitive impairment or pre-dementia or other forms
00:00:55.220 | of dementia.
00:00:56.220 | And of course, the right metric is not what percent of the population, which of course
00:01:00.080 | includes children, things like that.
00:01:02.080 | It's, you know, so...
00:01:03.080 | That's a function of age.
00:01:04.080 | Yeah.
00:01:05.080 | But is age the major risk factor for getting Alzheimer's?
00:01:07.760 | We stay with glaucoma, a disease I'm much more familiar with because my lab worked on
00:01:11.880 | it for many years.
00:01:12.920 | The biggest risk factor for getting glaucoma is age.
00:01:15.720 | Yeah.
00:01:16.720 | The greatest risk factor for cardiovascular disease is age.
00:01:19.800 | The greatest risk factor for cancer is age.
00:01:23.240 | We tend to not spend a lot of time talking about that because it's not a modifiable risk.
00:01:28.880 | So you know, we tend to focus on modifiable risk factors.
00:01:35.100 | So what else can we tell you just to give you kind of lay of the land?
00:01:38.840 | So the second most prevalent neurodegenerative disease would probably be Lewy body dementia
00:01:45.360 | followed by Parkinson's disease, although the rate of growth of Parkinson's disease
00:01:49.940 | is the highest.
00:01:50.940 | So I think we'd probably be most, you know, those three diseases we want to really be
00:01:54.780 | paying a lot of attention to.
00:01:55.900 | As you know, there are a lot of other neurodegenerative diseases.
00:01:58.860 | Every one of these things is devastating.
00:02:00.380 | Like multiple sclerosis.
00:02:01.380 | Yeah, multiple sclerosis, ALS, Huntington's disease.
00:02:05.380 | These are awful, awful diseases.
00:02:09.520 | There are also other kinds of dementia.
00:02:11.700 | Vascular dementia is not Alzheimer's dementia, but it produces comparable symptoms.
00:02:18.760 | Each of these things, by the way, are slightly different.
00:02:20.260 | Lewy body is a dementia.
00:02:22.100 | It's a dementing disease, but it also has a movement component.
00:02:25.700 | So it sort of sits on a spectrum that's sort of, you know, loosely halfway between Alzheimer's
00:02:31.220 | disease and Parkinson's disease.
00:02:35.020 | We talked obviously about age being the number one risk factor.
00:02:37.660 | Kind of not that interesting because you can't do anything about it.
00:02:39.700 | So the real goal is, as we age, what are we doing to reduce risk?
00:02:44.220 | Well, let's start with an important gene.
00:02:48.500 | The gene that everybody's heard of, certainly came up a lot on the Limitless special where
00:02:54.500 | Chris Hemsworth was, you know, made the decision to reveal something that none of us expected
00:02:59.420 | when we started that whole series, which was that he ended up being homozygous for the
00:03:05.020 | ApoE4 isoform.
00:03:07.940 | So maybe folks understand, we have two copies of every gene.
00:03:12.820 | So for gene X, you have copy that you got from your mom and copy that you got from your
00:03:16.900 | dad and the ApoE gene is kind of a unique gene in that it really, it has three different
00:03:23.540 | isoforms that are all considered normal.
00:03:25.780 | None of them are mutations.
00:03:28.220 | So you have the E2 isoform, the E3 isoform and the E4 isoform.
00:03:33.980 | The E4 isoform is the OG isoform.
00:03:37.460 | That's the one that we have historically had as far back as we can go.
00:03:42.340 | We actually think the E4 isoform offered a lot of advantages back in the day.
00:03:48.420 | It's a bit of a pro-inflammatory isoform and it certainly offered protection against infections,
00:03:55.260 | especially parasitic infections in the CNS, which would have been a really important thing
00:03:59.420 | to select for 200,000 years ago.
00:04:02.340 | How do parasites get into the CNS?
00:04:03.820 | I mean, you have a blood-brain barrier, you got a thick skull.
00:04:06.500 | I mean, not you.
00:04:07.500 | Trauma.
00:04:08.500 | I'm not calling, I'm not telling you you have a thick skull, but, but I mean, it just seems
00:04:11.540 | like parasites and other tissues would be an issue.
00:04:14.340 | Because what we're talking about here is brain disease.
00:04:15.740 | Yeah.
00:04:16.740 | Yeah.
00:04:17.740 | Anyway.
00:04:18.740 | I don't want to take us off course.
00:04:19.740 | But it also could have protected them.
00:04:20.740 | It probably offered some protection outside of the brain as well.
00:04:23.400 | Anyway, the, the E3 isoform I think showed up, I think 50,000 years ago.
00:04:33.540 | And the E2 isoform showed up very recently, about 10,000 years ago.
00:04:38.980 | Now today we realize that there's a clear stratification of risk when it comes to Alzheimer's
00:04:46.900 | disease that tracks with those isoforms.
00:04:50.140 | So because you have two copies, you basically have six combinations of how you can combine
00:04:54.860 | those genes.
00:04:55.860 | You could be 2/2, 2/3, 2/4, 3/3, 3/4, 4/4.
00:05:00.380 | The prevalence of them is basically as follows.
00:05:03.780 | 3/3 is now the most common, 3 is the most common.
00:05:06.760 | So double 3 is 55-ish percent of the population.
00:05:12.220 | The next most common is the 3/4, which is about 25% of the population.
00:05:16.940 | And then after that, most things are kind of a rounding error.
00:05:19.680 | So 2/3s and 2/4s would be the next most common, 4/4s are very rare, and 2/2s are the rarest
00:05:28.900 | of them all.
00:05:29.900 | 2/2s are less than 1%.
00:05:32.040 | 4/4s are about 1-2%.
00:05:37.800 | Very important point here is that the E4 genes are not deterministic.
00:05:43.120 | So they're highly associated with the risk, but they're not deterministic.
00:05:47.160 | There are at least three deterministic genes in Alzheimer's disease.
00:05:53.200 | One is called PSCN1, another one is called PSCN2, and another one is called APP.
00:05:59.360 | Those genes collectively make up about 1% of cases of people with Alzheimer's disease.
00:06:05.040 | So they're fortunately very rare genes, but sadly they are deterministic, meaning if you
00:06:10.240 | have those genes, you do get Alzheimer's disease.
00:06:12.960 | And what's perhaps most devastating about those genes is how early the onset is of the
00:06:18.480 | disease.
00:06:19.480 | These are people that are usually getting Alzheimer's disease in their 50s.
00:06:23.520 | So we do have a patient in our practice, actually she's spoken about this very openly, who's
00:06:29.040 | mom had one of these genes.
00:06:32.040 | And she got Alzheimer's disease in her early 50s.
00:06:36.520 | I think she might have made it into her 60s before she died.
00:06:40.560 | But absolutely devastating consequences here.
00:06:44.280 | Why do people with Alzheimer's die?
00:06:45.720 | Because I know about the hippocampal degeneration, hippocampus of course being an area of the
00:06:49.360 | brain important for learning and memory.
00:06:51.860 | But is there brainstem degeneration?
00:06:53.480 | Do they lose breathing centers or cardiovascular control?
00:06:56.760 | Usually what happens is it's sort of failure to thrive, aspiration, things like that.
00:07:01.320 | So it's usually they just stop eating.
00:07:04.920 | Or they can't control secretions, they aspirate, they get a pneumonia.
00:07:08.600 | Or they really lose the ability to even sense pain in their body.
00:07:14.240 | And therefore they'll get an ulcer and they don't realize it and it'll become cellulitic
00:07:18.080 | and they'll develop a horrible infection in response to it.
00:07:21.080 | I see.
00:07:22.080 | So it's a body vulnerability.
00:07:23.080 | The reason I ask is every once in a while a news report will come out based on a legitimate
00:07:28.280 | case study where they'll do a scan on some person and discover that they're missing literally
00:07:34.520 | half their cerebral cortex, like huge chunks of brain and they're functioning relatively
00:07:38.480 | normally.
00:07:39.480 | And so here we're talking about a neurodegenerative disease of relatively, it's widespread, but
00:07:43.440 | there are a few hotspots of course in the brain that degenerate more profoundly than
00:07:46.840 | others and the people dying.
00:07:48.400 | So that makes sense.
00:07:49.400 | So it extends to lack of peripheral awareness or control and then some acute injury or infection.
00:07:55.280 | Got it.
00:07:57.160 | You mentioned earlier some of the controversy, right?
00:07:59.280 | So what are we talking about here?
00:08:00.800 | Well it's, and I do write about this at length in the chapter on Alzheimer's disease because
00:08:07.240 | I think this is a very important point, right?
00:08:09.360 | Which is the index case for Alzheimer's disease, there's always an index case, right?
00:08:16.280 | The quote unquote patient zero.
00:08:18.240 | The index case was a woman who, you know, a hundred years later we realized had an APP
00:08:26.240 | mutation.
00:08:27.240 | These are APP or PSEN1, but she had one of these deterministic genes that led to a very
00:08:32.260 | early onset of disease, which by the way, without which we may not have come up with
00:08:37.000 | the diagnosis because had she just got Alzheimer's disease in her 70s, it would have just been
00:08:42.100 | referred to as senility, which is, you know, was not interesting enough to pay attention
00:08:47.080 | to.
00:08:49.900 | But I think it probably set the field on the path towards an overemphasis on amyloid beta.
00:08:59.280 | And it's not really clear how important amyloid is, which is not to say it's not important.
00:09:07.600 | It is important and there's no ambiguity that amyloid is responsible for the changes that
00:09:16.680 | we see in the brain, but it's not crystal clear because there are lots of autopsies
00:09:22.400 | that are done on people that are completely healthy and have died with no cognitive impairment
00:09:27.960 | and they're chock full of amyloid.
00:09:30.480 | So what we don't fully understand is exactly what does removing amyloid do.
00:09:38.960 | The other thing that complicates the story is there has been no shortage of drugs that
00:09:43.080 | target amyloid that have seemed unsuccessful.
00:09:47.000 | And just to clarify, when you say amyloid, you mean people have died with their brains
00:09:52.460 | examined in autopsy and see that there are tons of so-called amyloid plaques?
00:09:56.000 | Correct.
00:09:57.000 | Amyloid is different than arterial plaques, of course, but within the brain.
00:10:00.520 | So the two hallmarks of Alzheimer's histopathologically would be plaques and tangles.
00:10:07.200 | And even that now is, of course, coming under question.
00:10:11.280 | But that's what we teach every neuroscience graduate student.
00:10:15.080 | It's what we teach every undergraduate.
00:10:16.080 | It's also what we teach every medical student, and not just at Stanford, but everywhere.
00:10:21.540 | So I have heard that the link between APP and whether or not one develops genes for
00:10:26.340 | it related to APP and whether or not it's cleaved at one site or another, which is what
00:10:31.140 | you were describing, and risk for Alzheimer's...
00:10:33.100 | Yeah.
00:10:34.100 | So it's basically a cleavage.
00:10:35.100 | It's a cleavage question.
00:10:36.100 | Right.
00:10:37.100 | So people with the APP mutation, I think, have one extra cleavage site.
00:10:41.940 | They result in one extra cleavage of amyloid and then it misfolds.
00:10:45.540 | And the misfolding is what the plaque is that's being created.
00:10:49.060 | That also then predisposes them to the neurofibrillary tangles.
00:10:53.080 | And again...
00:10:55.740 | But all this is under question now, right?
00:10:57.300 | Well...
00:10:58.300 | I mean, this is what I was told.
00:10:59.300 | And when I look, it sounds like there were some papers early in the chain of discovery
00:11:04.380 | and the research in Alzheimer's that were either wrong because they were intentionally
00:11:11.580 | falsified.
00:11:12.580 | There was an intentionally falsified paper on one particular amyloid variant.
00:11:17.980 | And that clearly set the field back a decade because a lot of people went down that rabbit
00:11:22.260 | hole based on deliberately falsified data.
00:11:26.660 | What happened to that guy?
00:11:27.660 | I'm going to assume...
00:11:28.660 | I don't know why I assume it was a guy.
00:11:29.660 | But what happened to that guy?
00:11:30.660 | Yeah.
00:11:31.660 | That's a good question.
00:11:32.660 | I think I wrote one piece about it when it happened.
00:11:35.780 | I actually reached out to the person who broke the story because I wanted to have them on
00:11:39.500 | my podcast.
00:11:41.180 | And I forget why he didn't do it.
00:11:43.500 | I forget why he wouldn't commit to it or something like that.
00:11:46.100 | But I thought it was a little odd because I thought this would be a great way to talk
00:11:49.380 | about this.
00:11:51.100 | I do not know what came of that scandal.
00:11:54.420 | In other words, I haven't paid attention to it for probably nine months.
00:11:57.500 | So I don't know.
00:11:58.500 | You know, obviously the paper has probably been recalled, but I don't know what disciplinary
00:12:02.800 | action was taken.
00:12:06.660 | The field is...
00:12:10.140 | I don't know.
00:12:11.140 | I don't want to speak like I'm in the field because I'm not.
00:12:13.120 | So I want to be careful what I say.
00:12:15.740 | But I think the field is probably in a bit of a crisis because there have been so many
00:12:24.740 | bets placed on anti-amyloid therapies and amyloid biomarkers and amyloid everything.
00:12:32.620 | And we just haven't seen efficacy, right?
00:12:35.440 | So contrast that with cardiovascular disease where, you know, you have this ApoB biomarker,
00:12:42.660 | you understand the pathophysiology of how it works, you have drugs that target it.
00:12:48.700 | So you have a biomarker, so you give somebody a drug that lowers ApoB, you can measure ApoB.
00:12:53.540 | That's a really important and obvious thing to be able to do.
00:12:56.460 | And then you have clinical outcomes, which is, oh, when you take a bunch of people in
00:13:00.080 | primary prevention, it takes this long before you see an effect.
00:13:03.580 | In secondary prevention, it only takes this long to see an effect, right?
00:13:07.140 | Different risk stratifications, all these different things.
00:13:09.100 | We don't have any of that for Alzheimer's disease.
00:13:12.220 | So we do use...
00:13:13.220 | There are now serum amyloid biomarkers that we use and we do track these in our highest
00:13:17.940 | risk patients, but only because we believe, and I don't know if we're right, by the way,
00:13:23.860 | that lower is better.
00:13:25.940 | And therefore, if we make these changes to you and your serum amyloid levels come down,
00:13:31.860 | that that tells us something about what's happening in your brain that's favorable.
00:13:35.420 | But I mean, I would hate to represent that we are practicing nearly the level of precision
00:13:41.180 | medicine there that we are in cardiovascular medicine.
00:13:46.300 | When it comes to Alzheimer's disease, maybe take a step back.
00:13:49.900 | When it comes to brain health, I think there are a handful of things that seem unequivocally
00:13:55.540 | true.
00:13:57.180 | And there's a lot of stuff that is signal to noise ratio that's really low.
00:14:03.120 | So the unequivocally true things for brain health are sleep matters.
00:14:10.940 | Another unequivocally true thing for brain health is that lower LDL cholesterol and ApoB
00:14:17.140 | is better than higher.
00:14:20.100 | Another thing that is unequivocally true is not having type 2 diabetes matters.
00:14:25.900 | So having really...
00:14:26.900 | Being insulin...
00:14:27.900 | Yeah.
00:14:28.900 | By...
00:14:29.900 | By insulin sensitive or not insulin sensitive.
00:14:30.900 | Being insulin sensitive matters.
00:14:32.580 | Sleeping adequately matters.
00:14:35.180 | Having lower lipids matters.
00:14:38.060 | Those three things are clear.
00:14:40.380 | And the fourth one that is unequivocally clear is exercise matters.
00:14:45.500 | More exercise...
00:14:46.500 | A specific form of exercise.
00:14:47.500 | Very...
00:14:48.500 | I mean, so I tried to answer this question on a recent AMA that I did because the answer
00:14:53.720 | is more is always better.
00:14:55.900 | But if you...
00:14:57.260 | If I tried to have one of our analysts look at it through the lens of if you could only
00:15:01.600 | exercise three hours a week, what would be the highest use case?
00:15:06.060 | And our interpretation of the literature was if you could only spend three hours a
00:15:10.780 | week exercising, you'd be best off doing one hour of low intensity cardio, one hour of
00:15:17.460 | strength and one hour of interval training.
00:15:20.860 | [Music]