November 28, 2025 • 14 mins
This episode reframes Alzheimer’s disease by tracing how the plaque-first narrative emerged from rare genetic mutations—and why most age-related cognitive decline is actually driven by systemic metabolic and microvascular health. We break down the evidence across neurodegenerative diseases, highlight what truly predicts risk, and outline four powerful levers that individuals can control today: sleep, lipid management, insulin sensitivity, and exercise.
We begin by mapping the spectrum of Alzheimer’s, Lewy body, Parkinson’s, and vascular dementia, explaining why these conditions often lead to death through complications like aspiration and infection. We clarify the difference between APOE isoforms as probabilistic risk versus deterministic genes such as APP, PSEN1, and PSEN2, which drive rare early-onset disease. We revisit the rise—and unraveling—of the amyloid hypothesis, including failed trials and the controversy that reshaped the field.
Then we turn to what the data supports: cardiology’s APOB as a model biomarker, the role of microvascular injury in the brain, insulin resistance as a driver of neuroinflammation, and the metabolic underpinnings of long-term cognitive decline. We present the four proven pillars of brain protection and outline a practical three-hour weekly plan built around strength training, intervals, and BDNF-boosting movement.
High-volume keywords used: Alzheimer’s prevention, brain health, metabolic health, microvascular disease, insulin resistance, APOE, exercise, dementia risk
Listener Takeaways
- Why most cognitive decline is metabolic and microvascular—not amyloid-first
- The difference between APOE risk and deterministic Alzheimer’s genes
- How sleep, lipids, insulin sensitivity, and exercise protect the brain
- The role of APOB, glymphatic clearance, and insulin resistance in decline
- A practical three-hour weekly training plan to lower lifetime risk
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This podcast is created by Ai for educational and entertainment purposes only and does not constitute professional medical or health advice. Please talk to your healthcare team for medical advice.
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
SPEAKER_00 (00:00):
Welcome to the deep dive.
Our mission today is well, it'sboth highly personal and
profoundly scientific.
We're diving deep into slowingcognitive decline.
Right.
We're going to synthesize thelatest expert knowledge, not
just about fighting diseaseslike Alzheimer's, but about how
all of us can apply thesestrategies.
SPEAKER_01 (00:20):
Aaron Powell And that's the key, isn't it?
That distinction.
I mean, we're looking at amassive problem: Alzheimer's
disease, AD, it affects aboutsix million people in the U.S.
alone.
It's the most prevalent form ofdementia.
It's huge numbers.
But the real goal here isempowerment.
What can you actually do?
SPEAKER_00 (00:35):
And when we talk about Alzheimer's, the
conversation nearly always getsstuck on the one thing none of
us can change.
SPEAKER_01 (00:40):
Aaron Ross Powell Exactly.
The single greatest risk factorfor AD, for cardiovascular
disease, for most cancers, it'sage.
SPEAKER_00 (00:47):
Just getting older.
SPEAKER_01 (00:48):
Just getting older.
You can't modify time.
So to make any practicaldifference, we have to shift our
focus completely.
We have to identify and then acton the modifiable risk factors,
the things you can control asyou move through your 50s, 60s,
and beyond.
This deep dive is all about whatwe can actually control.
SPEAKER_00 (01:05):
Okay, so let's start with the lay of the land.
We know AD is number one, butwhat are the other major
diseases the research communityis fighting here?
SPEAKER_01 (01:13):
Following Alzheimer's, the next most
prevalent is Lewy body dementia,a really devastating illness.
After that, you've gotParkinson's disease.
SPEAKER_00 (01:22):
And Parkinson's is the one with the fastest growth
rate, right?
SPEAKER_01 (01:25):
It is, which is really worrisome.
While it's third most commonright now, its documented rate
of growth is the highest of themajor neurodegenerative
diseases.
It really suggests that theremight be rising environmental or
systemic issues at play.
SPEAKER_00 (01:39):
Aaron Powell And of course we have to mention other
terrible conditions like MS,ALS, Huntington's, and vascular
dementia, which can look a lotlike AD but has completely
different roots.
SPEAKER_01 (01:50):
Right.
It's rooted in blood flowissues, not the classic plaques.
And Lewy body dementia isfascinating in a sad way because
it's a kind of hybrid.
A hybrid.
It sort of sits halfway betweenAlzheimer's and Parkinson's.
You get the memory and cognitivedecline you associate with AD,
but you also get the reallysignificant movement issues, the
stiffness, the tremors that arehallmarks of Parkinson's.
SPEAKER_00 (02:11):
You know, speaking of the end stages of these
diseases, I think there's a bigmisunderstanding.
People assume the brain justshuts down.
SPEAKER_01 (02:17):
Yeah.
SPEAKER_00 (02:18):
But when experts talk about the cause of death,
it's often more complex.
It's not the brain stem justfailing.
SPEAKER_01 (02:23):
Aaron Powell It is.
The disease itself rarely causesa primary failure of, say, your
core autonomic functions likebreathing.
Clinically, it's oftencategorized as failure to
thrive.
SPEAKER_00 (02:36):
Okay.
SPEAKER_01 (02:36):
As the disease progresses, patients lose that
peripheral awareness andcontrol.
They might forget how to swalloweffectively, or they might just
lose the reflex to clearsecretions from their throat.
SPEAKER_00 (02:48):
And that sounds like a direct path to a major
complication.
SPEAKER_01 (02:51):
It is.
Aspiration pneumonia, where foodor secretions get into the
lungs, is a tragically commoncause of death.
Another one is a severe systemicinfection.
It can start as something thatseems preventable, like a
pressure ulcer.
SPEAKER_00 (03:03):
Because they can't feel it to move.
SPEAKER_01 (03:05):
Exactly.
A patient might not have thesensation of pain or discomfort
that tells them to move.
The ulcer gets infected, itleads to severe cellulitis, then
sepsis.
It's a failure of the body'sentire protective system because
those peripheral signals aregone.
SPEAKER_00 (03:21):
That really drives home why brain health has to be
seen as systemic health.
SPEAKER_01 (03:24):
Yeah.
SPEAKER_00 (03:25):
Okay, let's switch gears to the topic everyone asks
about genetics.
We have to talk about the APOEgene.
Aaron Powell Right.
SPEAKER_01 (03:30):
Acho E is the major known risk factor gene.
You get two copies, one fromeach parent, and the gene comes
in three normal versions orisoforms E2, E3, and E4.
None of them are reallymutations, they just carry
different levels of riskdepending on the combination you
have.
SPEAKER_00 (03:47):
Aaron Powell So how does that risk break down?
What are the combinations?
SPEAKER_01 (03:50):
Well the most common is the E3E3 pairing.
About 55% of the population hasthat.
SPEAKER_00 (03:55):
So that's the baseline.
SPEAKER_01 (03:56):
That's the baseline.
The next most common is E3E4,which is around 25% people.
Now, when we talk about highrisk, we're usually talking
about the E4, E4 pairing, butthat's actually quite rare, only
one to two percent of thepopulation.
SPEAKER_00 (04:09):
And there's a protective one too, right?
SPEAKER_01 (04:10):
Yes.
E2E2 is also very rare, lessthan 1%.
And it seems to be somewhatprotective against the disease.
SPEAKER_00 (04:16):
Aaron Powell Okay.
And here is the point that Ifeel needs to be shouted from
the rooftops.
Having one or even two copies ofApo E4 is highly associated with
an increased risk, but it isabsolutely not deterministic.
SPEAKER_01 (04:28):
Aaron Powell Not at all.
It just increases yourstatistical likelihood.
Doesn't guarantee you'll get thedisease.
And you know, if we look at thehistory of E4, this is where it
gets really interesting.
E4 is the OG isoform, is theoldest one, goes back maybe
200,000 years.
SPEAKER_00 (04:43):
The original.
SPEAKER_01 (04:44):
The original.
And it's pro-inflammatory, whichsounds bad in our modern world,
but evolutionarily we think itwas highly protective.
SPEAKER_00 (04:50):
Aaron Powell Protective against what?
SPEAKER_01 (04:51):
Probably against parasitic infections, especially
those that targeted the centralnervous system.
Back then, that was a muchbigger threat to your survival
than living to be 95.
SPEAKER_00 (05:00):
So it's a classic evolutionary trade-off.
A trait, a really robustinflammatory response helped you
survive long enough to havekids, even if it might cause
problems decades later in atotally different environment.
SPEAKER_01 (05:13):
A textbook example.
The E3 isoform showed up muchlater, around 50,000 years ago,
and E2 is brand new, relativelyspeaking, maybe 10,000 years
old.
You can almost see evolutiondialing down the inflammation as
humans started to live longer.
SPEAKER_00 (05:30):
So if ApoE4 isn't deterministic, there must be
genes that actually do guaranteethe disease.
SPEAKER_01 (05:35):
There are three of them PSCN1, PSCN2, and APP.
If you inherit one of these, youare virtually guaranteed to get
early onset Alzheimer's.
SPEAKER_00 (05:45):
But these are incredibly rare.
SPEAKER_01 (05:46):
Incredibly rare, yes.
Altogether, they account formaybe 1% of all AD cases.
But they're devastating.
They cause the disease to showup very early, sometimes in
people's forties or fifties.
SPEAKER_00 (05:57):
And these rare deterministic genes, they are
the flashpoint for the biggestscientific debate in this entire
field.
SPEAKER_01 (06:03):
The amyloid hypothesis.
SPEAKER_00 (06:05):
Exactly.
SPEAKER_01 (06:05):
Absolutely.
The scientific community's focusfor decades on amyloid beta
comes directly from studyingthese genes.
The original index case, thevery first patient diagnosed
with what we now callAlzheimer's, was later found to
have a mutation on that APPgene.
SPEAKER_00 (06:19):
One of the rare ones you just mentioned.
SPEAKER_01 (06:20):
Yes.
The APP gene makes somethingcalled amyloid precursor
protein.
In a healthy brain, enzymes snipthis protein into harmless,
soluble little pieces.
But the mutation creates anabnormal cleavage site.
So instead of being cut neatly,the protein gets cut in the
wrong spot, and that results inthese misfolded pieces of
amyloid beta.
SPEAKER_00 (06:40):
And these misfolded pieces are sticky.
SPEAKER_01 (06:42):
Extremely sticky.
They clumped together and formplaques.
That's one of the two historichallmarks of AD pathology.
SPEAKER_00 (06:49):
And the second is tangles.
SPEAKER_01 (06:50):
Right.
These plaques then chemicallypredispose the brain to develop
the second hallmark: neurofibrillary tangles, which (06:54):
undefined
are made of a differentmisfolded protein called tau.
The link in these early onsetcases is undeniable.
SPEAKER_00 (07:03):
So the entire foundation of Alzheimer's
research was built on thisreally clear, visible pathology
found in a tinynon-representative slice of the
population.
What happens when you try toapply that finding to the 99% of
people whose disease is lateonset and, you know, sporadic?
SPEAKER_01 (07:18):
That's where the crisis is.
That's the problem.
Because while the amyloid isresponsible for those visible
changes in the brain, itsrelationship to your actual
cognitive function is well, it'sfar from crystal clear.
SPEAKER_00 (07:32):
How so?
SPEAKER_01 (07:33):
We have lots of autopsy data from people who are
cognitively healthy, people wholived and died with their minds
completely intact, and theirbrains were absolutely chock
full of amyloid plaques.
SPEAKER_00 (07:44):
That is genuinely shocking.
If you can be healthy and stillhave the hallmark pathology, how
can we be so sure the plaquesare causing the problem?
SPEAKER_01 (07:52):
It raises profound questions.
And it's why the field has beenin such turmoil.
Huge amounts of money, decadesof research, all funneled into
anti-amyloid therapies.
The assumption was if you clearthe plaques, you fix the
problem.
SPEAKER_00 (08:04):
But it hasn't worked out that way.
SPEAKER_01 (08:06):
The efficacy has been consistently lacking in
clinical trials for the vastmajority of patients.
SPEAKER_00 (08:10):
And all of that was made worse by the scandal, the
falsified data.
SPEAKER_01 (08:13):
Unfortunately, yes.
The field was set back probablya decade because one
intentionally falsified paper ona very specific type of toxic
amyloid sent thousands ofresearchers down a rabbit hole.
It diverted just enormousresources and talent away from
other ideas like inflammation ormetabolic causes.
SPEAKER_00 (08:32):
This sounds completely different from how we
treat something likecardiovascular disease, where we
have really reliable biomarkers.
SPEAKER_01 (08:38):
Oh, the contrast is stark.
Look at cardiovascular disease.
We have high fidelity biomarkerslike APOB.
SPEAKER_00 (08:43):
Okay, let's define that for a second.
We all hear about LDL or badcholesterol.
What is APOB?
SPEAKER_01 (08:48):
So APOB or A APO protein B is the structural
protein on the surface of theselipoproteins, including LDL.
Think of it like this (08:55):
every single particle that can cause
plaques in your arteries, everypotentially athrogenic particle
have exactly one APOB moleculeon it.
SPEAKER_00 (09:05):
So counting APOB is just counting the number of
dangerous particles.
SPEAKER_01 (09:08):
Exactly.
It's a direct count.
So in cardiovascular medicine,if we give you a drug, we can
track your ApoB level and we canreliably predict your clinical
outcome.
Lower is better.
That's precision medicine.
SPEAKER_00 (09:18):
Which we don't have in Alzheimer's.
SPEAKER_01 (09:19):
We don't.
We track serum amyloid inhigh-risk patients based on the
belief.
And it is a belief that lower isbetter for the brain.
We're forced to make assumptionsthat we just don't have to make
in cardiology.
The link between the marker andthe outcome is so much less
defined.
SPEAKER_00 (09:35):
So since the genetic risks are not a guarantee for
99% of us, and the centralamyloid theory is in crisis, our
energy really has to be focusedon the modifiable factors.
What does the research say,unequivocally, is effective for
brain health?
Where's the signal, loud andclear?
SPEAKER_01 (09:53):
Aaron Powell We've synthesized the literature down
to four pillars, four areaswhere the evidence is just
overwhelmingly consistent.
These are the levers thateveryone should be pulling.
SPEAKER_00 (10:01):
Okay, pillar number one, adequate sleep.
This is just foundational.
SPEAKER_01 (10:05):
It absolutely is.
And we now understand themechanism, which is fascinating.
It's called the lymphaticsystem.
SPEAKER_00 (10:11):
The brain's waste disposal.
SPEAKER_01 (10:12):
Essentially, yes.
During deep non-REM sleep, yourbrain actually shrinks a little
bit.
And that allows cerebrospinalfluid to rush in and literally
flush out metabolic waste.
And yes, that includes thoseamyloid proteins that built up
while you were awake.
SPEAKER_00 (10:28):
So if you consistently shortchange sleep,
you're shortchanging yourbrain's daily detox.
SPEAKER_01 (10:32):
You are skipping the cleanup crew.
SPEAKER_00 (10:34):
Okay, pillar number two, maintaining healthy lipids.
We talked about APOB for hearthealth.
Why does it matter so much forthe brain?
SPEAKER_01 (10:42):
Because brain health is systemic health, high levels
of LDL and especially highparticle counts, high APOB, they
don't just damage your heart'sarteries, they damage the tiny
blood vessels everywhere.
The microvasculator, includingthe intricate network that feeds
your brain.
High APOB is directly linked tomicrovascular disease in the
brain.
If you compromise that bloodflow or you damage the
(11:04):
blood-brain barrier, you'regoing to accelerate cognitive
impairment.
Lower LDL and lower APOB aredefinitively protective for the
brain.
SPEAKER_00 (11:12):
Pillar number three, ensuring insulin sensitivity.
This connection between bloodsuch and the brain seems to be
one of the most powerful linkswe found recently.
SPEAKER_01 (11:22):
It is absolutely critical.
Some experts have even startedcalling Alzheimer's type 3
diabetes.
SPEAKER_00 (11:28):
Suggesting the brain itself becomes insulin
resistant.
SPEAKER_01 (11:31):
Exactly.
Insulin isn't just for bloodsugar, it's a powerful growth
factor in the brain.
When your brain cells, yourneurons, become resistant to
insulin signals, they'rebasically starved of fuel.
They can't repair themselves,they can't signal efficiently.
SPEAKER_00 (11:46):
So having type 2 diabetes isn't just a risk
factor, it's a direct triggerfor a damaging process in the
brain.
SPEAKER_01 (11:53):
Precisely.
Chronic high glucose leads tochronic low-level inflammation,
neuroinflammation, which justspeeds up the whole degenerative
process.
Being insulin sensitive is oneof the single greatest defenses
you have against cognitivedecline.
SPEAKER_00 (12:05):
And that brings us to the fourth pillar, the one
that always seems to mattermost.
SPEAKER_01 (12:09):
Exercise.
SPEAKER_00 (12:10):
Exercise.
SPEAKER_01 (12:10):
It's completely non-negotiable.
And more is always better, notjust for your body, but for
stimulating crucial neurotrophicfactors in your brain.
SPEAKER_00 (12:18):
Give us an example of one of those.
SPEAKER_01 (12:19):
The most famous one is BDNF, brain-derived
neurotrophic factor.
SPEAKER_00 (12:23):
Fertilizer for the brain.
SPEAKER_01 (12:25):
That's a perfect way to put it.
It's like fertilizer for yourbrain.
SPEAKER_00 (12:27):
Yeah.
SPEAKER_01 (12:28):
Exercise, especially high-intensity work and strength
training, dramatically increasesits production.
BDNF helps grow new neurons, ithelps existing neurons survive,
and it strengthens theconnections between them.
If you want a biologicallyyounger brain, you have to
stimulate BDNF.
SPEAKER_00 (12:45):
So the advice is more specific than just, you
know, go for a walk.
If someone is really short ontime, so they only have three
hours a week.
SPEAKER_01 (12:55):
Yes, there is a very efficient high yield strategy.
If you only have those threehours, the optimal approach
seems to be one hour of lowintensity cardio, which is
fantastic for cerebral bloodflow.
Okay.
One hour of strength training,which is crucial for hormonal
signaling and that BDNF release,and one hour of interval
training.
That dramatically improves thehealth of your mitochondria,
(13:17):
which we know degrades severelyin Alzheimer's.
SPEAKER_00 (13:20):
This is great actionable knowledge.
So to recap for everyonelistening, the key takeaway is,
you know, understand yourgenetic risks like APOE4, but
put the vast majority of yourenergy into the four proven
modifiable pillars.
Prioritize sleep, maintainhealthy lipids in APOB, ensure
you are insulin sensitive, andget consistent structured
(13:41):
exercise.
SPEAKER_01 (13:42):
If you take one thing from this deep dive, let
it be this.
SPEAKER_00 (13:59):
Which brings us right back to the heart of this
research dilemma.
We spent a century chasing apathology found in 1% of cases,
the amyloid plaques, while theanswers for the other 99% seem
to be rooted in fundamentalmetabolic health.
SPEAKER_01 (14:11):
And that leaves us with a really provocative
thought for you to consider.
Given the controversy, thehistorical reliance on those
rare deterministic cases, andthe failure of the anti-amyloid
drugs, how might future researchredefine what Alzheimer's
disease even is?
What happens when the fieldfully embraces the evidence that
it may primarily be a metabolicand microvascular disorder
(14:33):
rather than just a simpleprotein misfolding problem?
You should continue to explorethat profound interconnectedness
between the health of your bodyand the future of your brain.
Welcome to the deep dive.
Our mission today is well, it'sboth highly personal and
profoundly scientific.
We're diving deep into slowingcognitive decline.
Right.
We're going to synthesize thelatest expert knowledge, not
just about fighting diseaseslike Alzheimer's, but about how
all of us can apply thesestrategies.
SPEAKER_01 (00:20):
Aaron Powell And that's the key, isn't it?
That distinction.
I mean, we're looking at amassive problem: Alzheimer's
disease, AD, it affects aboutsix million people in the U.S.
alone.
It's the most prevalent form ofdementia.
It's huge numbers.
But the real goal here isempowerment.
What can you actually do?
SPEAKER_00 (00:35):
And when we talk about Alzheimer's, the
conversation nearly always getsstuck on the one thing none of
us can change.
SPEAKER_01 (00:40):
Aaron Ross Powell Exactly.
The single greatest risk factorfor AD, for cardiovascular
disease, for most cancers, it'sage.
SPEAKER_00 (00:47):
Just getting older.
SPEAKER_01 (00:48):
Just getting older.
You can't modify time.
So to make any practicaldifference, we have to shift our
focus completely.
We have to identify and then acton the modifiable risk factors,
the things you can control asyou move through your 50s, 60s,
and beyond.
This deep dive is all about whatwe can actually control.
SPEAKER_00 (01:05):
Okay, so let's start with the lay of the land.
We know AD is number one, butwhat are the other major
diseases the research communityis fighting here?
SPEAKER_01 (01:13):
Following Alzheimer's, the next most
prevalent is Lewy body dementia,a really devastating illness.
After that, you've gotParkinson's disease.
SPEAKER_00 (01:22):
And Parkinson's is the one with the fastest growth
rate, right?
SPEAKER_01 (01:25):
It is, which is really worrisome.
While it's third most commonright now, its documented rate
of growth is the highest of themajor neurodegenerative
diseases.
It really suggests that theremight be rising environmental or
systemic issues at play.
SPEAKER_00 (01:39):
Aaron Powell And of course we have to mention other
terrible conditions like MS,ALS, Huntington's, and vascular
dementia, which can look a lotlike AD but has completely
different roots.
SPEAKER_01 (01:50):
Right.
It's rooted in blood flowissues, not the classic plaques.
And Lewy body dementia isfascinating in a sad way because
it's a kind of hybrid.
A hybrid.
It sort of sits halfway betweenAlzheimer's and Parkinson's.
You get the memory and cognitivedecline you associate with AD,
but you also get the reallysignificant movement issues, the
stiffness, the tremors that arehallmarks of Parkinson's.
SPEAKER_00 (02:11):
You know, speaking of the end stages of these
diseases, I think there's a bigmisunderstanding.
People assume the brain justshuts down.
SPEAKER_01 (02:17):
Yeah.
SPEAKER_00 (02:18):
But when experts talk about the cause of death,
it's often more complex.
It's not the brain stem justfailing.
SPEAKER_01 (02:23):
Aaron Powell It is.
The disease itself rarely causesa primary failure of, say, your
core autonomic functions likebreathing.
Clinically, it's oftencategorized as failure to
thrive.
SPEAKER_00 (02:36):
Okay.
SPEAKER_01 (02:36):
As the disease progresses, patients lose that
peripheral awareness andcontrol.
They might forget how to swalloweffectively, or they might just
lose the reflex to clearsecretions from their throat.
SPEAKER_00 (02:48):
And that sounds like a direct path to a major
complication.
SPEAKER_01 (02:51):
It is.
Aspiration pneumonia, where foodor secretions get into the
lungs, is a tragically commoncause of death.
Another one is a severe systemicinfection.
It can start as something thatseems preventable, like a
pressure ulcer.
SPEAKER_00 (03:03):
Because they can't feel it to move.
SPEAKER_01 (03:05):
Exactly.
A patient might not have thesensation of pain or discomfort
that tells them to move.
The ulcer gets infected, itleads to severe cellulitis, then
sepsis.
It's a failure of the body'sentire protective system because
those peripheral signals aregone.
SPEAKER_00 (03:21):
That really drives home why brain health has to be
seen as systemic health.
SPEAKER_01 (03:24):
Yeah.
SPEAKER_00 (03:25):
Okay, let's switch gears to the topic everyone asks
about genetics.
We have to talk about the APOEgene.
Aaron Powell Right.
SPEAKER_01 (03:30):
Acho E is the major known risk factor gene.
You get two copies, one fromeach parent, and the gene comes
in three normal versions orisoforms E2, E3, and E4.
None of them are reallymutations, they just carry
different levels of riskdepending on the combination you
have.
SPEAKER_00 (03:47):
Aaron Powell So how does that risk break down?
What are the combinations?
SPEAKER_01 (03:50):
Well the most common is the E3E3 pairing.
About 55% of the population hasthat.
SPEAKER_00 (03:55):
So that's the baseline.
SPEAKER_01 (03:56):
That's the baseline.
The next most common is E3E4,which is around 25% people.
Now, when we talk about highrisk, we're usually talking
about the E4, E4 pairing, butthat's actually quite rare, only
one to two percent of thepopulation.
SPEAKER_00 (04:09):
And there's a protective one too, right?
SPEAKER_01 (04:10):
Yes.
E2E2 is also very rare, lessthan 1%.
And it seems to be somewhatprotective against the disease.
SPEAKER_00 (04:16):
Aaron Powell Okay.
And here is the point that Ifeel needs to be shouted from
the rooftops.
Having one or even two copies ofApo E4 is highly associated with
an increased risk, but it isabsolutely not deterministic.
SPEAKER_01 (04:28):
Aaron Powell Not at all.
It just increases yourstatistical likelihood.
Doesn't guarantee you'll get thedisease.
And you know, if we look at thehistory of E4, this is where it
gets really interesting.
E4 is the OG isoform, is theoldest one, goes back maybe
200,000 years.
SPEAKER_00 (04:43):
The original.
SPEAKER_01 (04:44):
The original.
And it's pro-inflammatory, whichsounds bad in our modern world,
but evolutionarily we think itwas highly protective.
SPEAKER_00 (04:50):
Aaron Powell Protective against what?
SPEAKER_01 (04:51):
Probably against parasitic infections, especially
those that targeted the centralnervous system.
Back then, that was a muchbigger threat to your survival
than living to be 95.
SPEAKER_00 (05:00):
So it's a classic evolutionary trade-off.
A trait, a really robustinflammatory response helped you
survive long enough to havekids, even if it might cause
problems decades later in atotally different environment.
SPEAKER_01 (05:13):
A textbook example.
The E3 isoform showed up muchlater, around 50,000 years ago,
and E2 is brand new, relativelyspeaking, maybe 10,000 years
old.
You can almost see evolutiondialing down the inflammation as
humans started to live longer.
SPEAKER_00 (05:30):
So if ApoE4 isn't deterministic, there must be
genes that actually do guaranteethe disease.
SPEAKER_01 (05:35):
There are three of them PSCN1, PSCN2, and APP.
If you inherit one of these, youare virtually guaranteed to get
early onset Alzheimer's.
SPEAKER_00 (05:45):
But these are incredibly rare.
SPEAKER_01 (05:46):
Incredibly rare, yes.
Altogether, they account formaybe 1% of all AD cases.
But they're devastating.
They cause the disease to showup very early, sometimes in
people's forties or fifties.
SPEAKER_00 (05:57):
And these rare deterministic genes, they are
the flashpoint for the biggestscientific debate in this entire
field.
SPEAKER_01 (06:03):
The amyloid hypothesis.
SPEAKER_00 (06:05):
Exactly.
SPEAKER_01 (06:05):
Absolutely.
The scientific community's focusfor decades on amyloid beta
comes directly from studyingthese genes.
The original index case, thevery first patient diagnosed
with what we now callAlzheimer's, was later found to
have a mutation on that APPgene.
SPEAKER_00 (06:19):
One of the rare ones you just mentioned.
SPEAKER_01 (06:20):
Yes.
The APP gene makes somethingcalled amyloid precursor
protein.
In a healthy brain, enzymes snipthis protein into harmless,
soluble little pieces.
But the mutation creates anabnormal cleavage site.
So instead of being cut neatly,the protein gets cut in the
wrong spot, and that results inthese misfolded pieces of
amyloid beta.
SPEAKER_00 (06:40):
And these misfolded pieces are sticky.
SPEAKER_01 (06:42):
Extremely sticky.
They clumped together and formplaques.
That's one of the two historichallmarks of AD pathology.
SPEAKER_00 (06:49):
And the second is tangles.
SPEAKER_01 (06:50):
Right.
These plaques then chemicallypredispose the brain to develop
the second hallmark: neurofibrillary tangles, which (06:54):
undefined
are made of a differentmisfolded protein called tau.
The link in these early onsetcases is undeniable.
SPEAKER_00 (07:03):
So the entire foundation of Alzheimer's
research was built on thisreally clear, visible pathology
found in a tinynon-representative slice of the
population.
What happens when you try toapply that finding to the 99% of
people whose disease is lateonset and, you know, sporadic?
SPEAKER_01 (07:18):
That's where the crisis is.
That's the problem.
Because while the amyloid isresponsible for those visible
changes in the brain, itsrelationship to your actual
cognitive function is well, it'sfar from crystal clear.
SPEAKER_00 (07:32):
How so?
SPEAKER_01 (07:33):
We have lots of autopsy data from people who are
cognitively healthy, people wholived and died with their minds
completely intact, and theirbrains were absolutely chock
full of amyloid plaques.
SPEAKER_00 (07:44):
That is genuinely shocking.
If you can be healthy and stillhave the hallmark pathology, how
can we be so sure the plaquesare causing the problem?
SPEAKER_01 (07:52):
It raises profound questions.
And it's why the field has beenin such turmoil.
Huge amounts of money, decadesof research, all funneled into
anti-amyloid therapies.
The assumption was if you clearthe plaques, you fix the
problem.
SPEAKER_00 (08:04):
But it hasn't worked out that way.
SPEAKER_01 (08:06):
The efficacy has been consistently lacking in
clinical trials for the vastmajority of patients.
SPEAKER_00 (08:10):
And all of that was made worse by the scandal, the
falsified data.
SPEAKER_01 (08:13):
Unfortunately, yes.
The field was set back probablya decade because one
intentionally falsified paper ona very specific type of toxic
amyloid sent thousands ofresearchers down a rabbit hole.
It diverted just enormousresources and talent away from
other ideas like inflammation ormetabolic causes.
SPEAKER_00 (08:32):
This sounds completely different from how we
treat something likecardiovascular disease, where we
have really reliable biomarkers.
SPEAKER_01 (08:38):
Oh, the contrast is stark.
Look at cardiovascular disease.
We have high fidelity biomarkerslike APOB.
SPEAKER_00 (08:43):
Okay, let's define that for a second.
We all hear about LDL or badcholesterol.
What is APOB?
SPEAKER_01 (08:48):
So APOB or A APO protein B is the structural
protein on the surface of theselipoproteins, including LDL.
Think of it like this (08:55):
every single particle that can cause
plaques in your arteries, everypotentially athrogenic particle
have exactly one APOB moleculeon it.
SPEAKER_00 (09:05):
So counting APOB is just counting the number of
dangerous particles.
SPEAKER_01 (09:08):
Exactly.
It's a direct count.
So in cardiovascular medicine,if we give you a drug, we can
track your ApoB level and we canreliably predict your clinical
outcome.
Lower is better.
That's precision medicine.
SPEAKER_00 (09:18):
Which we don't have in Alzheimer's.
SPEAKER_01 (09:19):
We don't.
We track serum amyloid inhigh-risk patients based on the
belief.
And it is a belief that lower isbetter for the brain.
We're forced to make assumptionsthat we just don't have to make
in cardiology.
The link between the marker andthe outcome is so much less
defined.
SPEAKER_00 (09:35):
So since the genetic risks are not a guarantee for
99% of us, and the centralamyloid theory is in crisis, our
energy really has to be focusedon the modifiable factors.
What does the research say,unequivocally, is effective for
brain health?
Where's the signal, loud andclear?
SPEAKER_01 (09:53):
Aaron Powell We've synthesized the literature down
to four pillars, four areaswhere the evidence is just
overwhelmingly consistent.
These are the levers thateveryone should be pulling.
SPEAKER_00 (10:01):
Okay, pillar number one, adequate sleep.
This is just foundational.
SPEAKER_01 (10:05):
It absolutely is.
And we now understand themechanism, which is fascinating.
It's called the lymphaticsystem.
SPEAKER_00 (10:11):
The brain's waste disposal.
SPEAKER_01 (10:12):
Essentially, yes.
During deep non-REM sleep, yourbrain actually shrinks a little
bit.
And that allows cerebrospinalfluid to rush in and literally
flush out metabolic waste.
And yes, that includes thoseamyloid proteins that built up
while you were awake.
SPEAKER_00 (10:28):
So if you consistently shortchange sleep,
you're shortchanging yourbrain's daily detox.
SPEAKER_01 (10:32):
You are skipping the cleanup crew.
SPEAKER_00 (10:34):
Okay, pillar number two, maintaining healthy lipids.
We talked about APOB for hearthealth.
Why does it matter so much forthe brain?
SPEAKER_01 (10:42):
Because brain health is systemic health, high levels
of LDL and especially highparticle counts, high APOB, they
don't just damage your heart'sarteries, they damage the tiny
blood vessels everywhere.
The microvasculator, includingthe intricate network that feeds
your brain.
High APOB is directly linked tomicrovascular disease in the
brain.
If you compromise that bloodflow or you damage the
(11:04):
blood-brain barrier, you'regoing to accelerate cognitive
impairment.
Lower LDL and lower APOB aredefinitively protective for the
brain.
SPEAKER_00 (11:12):
Pillar number three, ensuring insulin sensitivity.
This connection between bloodsuch and the brain seems to be
one of the most powerful linkswe found recently.
SPEAKER_01 (11:22):
It is absolutely critical.
Some experts have even startedcalling Alzheimer's type 3
diabetes.
SPEAKER_00 (11:28):
Suggesting the brain itself becomes insulin
resistant.
SPEAKER_01 (11:31):
Exactly.
Insulin isn't just for bloodsugar, it's a powerful growth
factor in the brain.
When your brain cells, yourneurons, become resistant to
insulin signals, they'rebasically starved of fuel.
They can't repair themselves,they can't signal efficiently.
SPEAKER_00 (11:46):
So having type 2 diabetes isn't just a risk
factor, it's a direct triggerfor a damaging process in the
brain.
SPEAKER_01 (11:53):
Precisely.
Chronic high glucose leads tochronic low-level inflammation,
neuroinflammation, which justspeeds up the whole degenerative
process.
Being insulin sensitive is oneof the single greatest defenses
you have against cognitivedecline.
SPEAKER_00 (12:05):
And that brings us to the fourth pillar, the one
that always seems to mattermost.
SPEAKER_01 (12:09):
Exercise.
SPEAKER_00 (12:10):
Exercise.
SPEAKER_01 (12:10):
It's completely non-negotiable.
And more is always better, notjust for your body, but for
stimulating crucial neurotrophicfactors in your brain.
SPEAKER_00 (12:18):
Give us an example of one of those.
SPEAKER_01 (12:19):
The most famous one is BDNF, brain-derived
neurotrophic factor.
SPEAKER_00 (12:23):
Fertilizer for the brain.
SPEAKER_01 (12:25):
That's a perfect way to put it.
It's like fertilizer for yourbrain.
SPEAKER_00 (12:27):
Yeah.
SPEAKER_01 (12:28):
Exercise, especially high-intensity work and strength
training, dramatically increasesits production.
BDNF helps grow new neurons, ithelps existing neurons survive,
and it strengthens theconnections between them.
If you want a biologicallyyounger brain, you have to
stimulate BDNF.
SPEAKER_00 (12:45):
So the advice is more specific than just, you
know, go for a walk.
If someone is really short ontime, so they only have three
hours a week.
SPEAKER_01 (12:55):
Yes, there is a very efficient high yield strategy.
If you only have those threehours, the optimal approach
seems to be one hour of lowintensity cardio, which is
fantastic for cerebral bloodflow.
Okay.
One hour of strength training,which is crucial for hormonal
signaling and that BDNF release,and one hour of interval
training.
That dramatically improves thehealth of your mitochondria,
(13:17):
which we know degrades severelyin Alzheimer's.
SPEAKER_00 (13:20):
This is great actionable knowledge.
So to recap for everyonelistening, the key takeaway is,
you know, understand yourgenetic risks like APOE4, but
put the vast majority of yourenergy into the four proven
modifiable pillars.
Prioritize sleep, maintainhealthy lipids in APOB, ensure
you are insulin sensitive, andget consistent structured
(13:41):
exercise.
SPEAKER_01 (13:42):
If you take one thing from this deep dive, let
it be this.
SPEAKER_00 (13:59):
Which brings us right back to the heart of this
research dilemma.
We spent a century chasing apathology found in 1% of cases,
the amyloid plaques, while theanswers for the other 99% seem
to be rooted in fundamentalmetabolic health.
SPEAKER_01 (14:11):
And that leaves us with a really provocative
thought for you to consider.
Given the controversy, thehistorical reliance on those
rare deterministic cases, andthe failure of the anti-amyloid
drugs, how might future researchredefine what Alzheimer's
disease even is?
What happens when the fieldfully embraces the evidence that
it may primarily be a metabolicand microvascular disorder
(14:33):
rather than just a simpleprotein misfolding problem?
You should continue to explorethat profound interconnectedness
between the health of your bodyand the future of your brain.
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