November 29, 2025 • 15 mins
This episode explores how the brain’s glymphatic system clears metabolic waste, why that drainage slows with age and APOE4 risk, and how patterned TMS may offer a breakthrough path to restoring flow and memory. Emerging evidence shows that glymphatic function is not fixed—it’s plastic—and can be selectively improved in older adults with mild cognitive impairment. We translate early but promising findings into a roadmap for future prevention.
We begin by outlining glymphatic flow as a glia-driven clearance network, then examine why APOE4 carriers show lower baseline DTI-ALPS—a proxy for reduced fluid transport. You’ll learn how researchers used a theta-burst TMS protocol with sham controls to test whether stimulation could enhance clearance. The results: selective ALPS increases and measurable memory gains, especially in APOE4 carriers.
We discuss the proposed mechanisms linking TMS to improved flow, including effects on sleep architecture, inhibitory interneurons, astrocytic channels, and meningeal lymphatic vessels. We also cover the limitations of DTI-ALPS, the absence of direct biomarkers, and what larger, multimodal trials must address next.
The episode closes with a look at personalized brain tune-ups—how noninvasive stimulation, tailored to genetic risk, may shape the future of dementia prevention.
High-volume keywords used: glymphatic system, APOE4, TMS therapy, mild cognitive impairment, brain clearance, aging brain, memory improvement, neurodegeneration
Listener Takeaways
- How glymphatic flow works and why it declines with age and APOE4
- The theta-burst TMS protocol that increased ALPS and improved memory
- Possible mechanisms linking TMS to better clearance and sleep
- Key limitations of current imaging and biomarker tools
- The emerging path to personalized, noninvasive brain prevention
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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_01 (00:00):
Welcome back to the deep dive, where we crack open
cutting edge research so you canjump straight to the knowledge.
SPEAKER_00 (00:06):
Today we are talking about something that really does
sound like it's straight out ofscience fiction.
SPEAKER_01 (00:11):
Aaron Powell It absolutely does.
We're talking about literallycleaning your brain and uh doing
it non-invasively with magneticstimulation.
SPEAKER_00 (00:19):
Yeah, it's pretty wild.
SPEAKER_01 (00:20):
So the brain is, I mean, it's the body's hungriest
organ.
It's an engine running on highoctane, you know, 24-7.
SPEAKER_00 (00:27):
Aaron Powell And like any engine, it produces
exhaust, a lot of it.
SPEAKER_01 (00:31):
Aaron Ross Powell Exactly.
It generates this massive amountof metabolic waste, especially
toxic byproducts likebeta-amyloid or a beta.
SPEAKER_00 (00:38):
Aaron Ross Powell And for decades, scientists had
this fundamental puzzle on theirhands.
SPEAKER_01 (00:43):
Aaron Powell How does the central nervous system,
which is walled off by theblood-brain barrier, how does it
clear out all this trash?
It doesn't have the normallymphatic system like the rest
of the body.
SPEAKER_00 (00:51):
Aaron Powell Right.
That was the big biologicalcontradiction.
And it wasn't really untilaround 2012 that the lymphatic
system was first characterized.
SPEAKER_01 (00:58):
Aaron Powell And that discovery gave us the
pathway.
It was the anatomical answer.
So the question is no longer ifthe brain cleans itself, but how
well does it do it as we age?
SPEAKER_00 (01:08):
Aaron Ross Powell And more importantly, could we
do anything about it when thatsystem starts to fail?
SPEAKER_01 (01:12):
Aaron Powell Okay, let's unpack this.
We are diving into a study thatshows, really for the first time
in older adults with mildcognitive impairment, that we
can use transcranial magneticstimulation or TMS to physically
boost this brain cleaningprocess.
SPEAKER_00 (01:27):
Aaron Powell And the findings are so incredibly
specific.
The real story here, the anchorfor this whole deep dive, is
that this stimulation it doesn'tjust work in general.
Its effectiveness is profoundly,I mean radically different
depending on one single thing.
SPEAKER_01 (01:42):
Aaron Powell And that's the person's genetics.
SPEAKER_00 (01:44):
Aaron Powell That's it.
We're zeroing in on the APOE A4gene.
You probably know it as thestrongest genetic risk factor
for sporadic Alzheimer'sdisease.
Right.
The data suggests that thisspecific group, the one most
genetically vulnerable, is theexact group that benefits the
most from this non-invasivecleaning boost.
SPEAKER_01 (02:00):
Aaron Powell Which is that's just fascinating
because it points to a future ofreally personalized preventative
treatment.
But okay, we need to start atthe beginning.
Before we talk about boostingthe system, we need to get a
clear picture of what theglymphatic system actually is
and you know how on earthresearchers measured it inside a
(02:21):
living person.
SPEAKER_00 (02:22):
That's the critical first step.
So the lymphatic system, it'sbest to think of it less as a
vessel and more as a reallysophisticated fluid exchange
network.
SPEAKER_01 (02:31):
Okay.
SPEAKER_00 (02:32):
It's gria-dependent, which just means it relies on
the brain's support cells.
The way it works is uh you havecerebrospinal fluid, or CSF,
that flows really rapidly intothese things called perivascular
spaces.
SPEAKER_01 (02:44):
Like little channels running alongside the arteries.
SPEAKER_00 (02:46):
Exactly, fluid-filled channels.
And once the CSF is in there, itstarts to exchange with the
fluid that's actuallysurrounding the neurons, the
interstitial fluid.
SPEAKER_01 (02:53):
And that's what carries the waste out.
SPEAKER_00 (02:55):
Yes.
And this whole process ispowerfully driven by these
specialized support cells calledastrocytes.
SPEAKER_01 (03:01):
So the astrocytes, the brain's support team, are
basically wrapping their feetaround the blood vessels and
squeezing the pump.
SPEAKER_00 (03:07):
That's a great way to think about it.
They are the control mechanism.
Their little end feet are justpacked with this critical
hardware, specifically aquaporn4 water channels, AQP4.
SPEAKER_01 (03:19):
And those channels are the key.
SPEAKER_00 (03:20):
Absolutely fundamental.
They push the fluid transportalong, and then once the
waste-filled fluid gets to theskull base, it drains out
through the meningeal lymphaticvessels.
SPEAKER_01 (03:30):
So what happens when this, I mean, this incredibly
intricate plumbing system startsto fail?
SPEAKER_00 (03:36):
Well, that's when you get the lymphatic crisis.
With age, and especially withdiseases like Alzheimer's, the
efficiency just plummets.
SPEAKER_01 (03:43):
And the clearance slows down.
SPEAKER_00 (03:44):
That deficient clearance lets toxic proteins
like a beta start to accumulate.
And the scary part is that thisbuildup is already happening,
maybe 15 years before a personshows any clinical signs of
memory loss.
SPEAKER_01 (03:55):
Wow.
So the key would be to intervenein that window when it's just
starting to slow down.
But the system isn't always on,right?
It changes throughout the day.
SPEAKER_00 (04:03):
Aaron Powell It does.
It has this powerful diurnalpattern.
It really maxes out during deepslow wave sleep, SWS.
SPEAKER_01 (04:10):
Okay.
SPEAKER_00 (04:11):
And that confirms the system has a high degree of
plasticity.
It's really responsive to ourphysiological state, which is
exactly why the researchersthought, you know, maybe we can
influence it with something likeTMS.
SPEAKER_01 (04:23):
Aaron Powell, which brings us to the measurement
problem.
If this is all happeningmicroscopically deep in the
brain, how do you even track itwithout doing something really
invasive?
SPEAKER_00 (04:32):
Aaron Powell I mean, for a long time, the gold
standard was incrediblyinvasive.
It involved a lumbar puncture,injecting a contrast agent
directly into the spine, andthen tracking it with an MRI.
SPEAKER_01 (04:41):
Aaron Powell Right.
Not something you can do for a10-day study.
SPEAKER_00 (04:43):
Not at all.
So they use this non-invasivecontrast-free MRI technique.
It's called diffusion tensorimaging analysis along the
perivascular space.
SPEAKER_01 (04:52):
Aaron Powell Thankfully shortened to DTI
ALPS.
SPEAKER_00 (04:56):
Yes, thankfully.
DTI ALPS basically measures thedirection and the speed of water
movement in the deep whitematter.
SPEAKER_01 (05:03):
Okay, so if I'm getting this right, DTI LPS is a
proxy.
You're not measuring the actualwaste, like a beta, leaving the
brain.
You're measuring the water.
It's like checking the pressureand the flow rate in the
plumbing to see if it's working.
SPEAKER_00 (05:14):
Aaron Powell That's a perfect analogy.
A higher DTI ALPS index suggestsfaster fluid movement, so you
know better lymphatic flow.
It's not the whole picture, butwe know a lower ALPS index
correlates with more a beta andworse cognitive scores.
It's a really useful snapshot ofthe pipes.
SPEAKER_01 (05:33):
Aaron Powell Excellent.
So we know what they aremeasuring.
Let's get to the interventionitself.
They use TMS, specifically thisreally potent patterned form
called theta burst stimulationor TBS.
SPEAKER_00 (05:44):
Right.
TBS delivers these rapidrepeating bursts of magnetic
pulses.
Its big advantage is that youcan get similar therapeutic
results to conventional TMS, butin a much shorter treatment
time.
SPEAKER_01 (05:55):
And this wasn't just a shot in the dark.
There was already strongpreclinical data.
SPEAKER_00 (05:59):
Oh yeah, very robust.
In mouse models of Alzheimer's,RTMS had already been shown to
physically boost fluidtransport, clear out of beta,
and even restore those criticalAQP4 channels.
SPEAKER_01 (06:09):
So this study took that promising mechanism and
brought it into humans.
They got 36 older adults, allwith mild cognitive impairment.
SPEAKER_00 (06:16):
And the protocol was really meticulous.
It was designed to separate theeffect of the real treatment
from a placebo.
SPEAKER_01 (06:23):
Right.
SPEAKER_00 (06:23):
So each person went through three separate 10-day
blocks, all randomized with awashout period in between:
continuous TBS, intermittentTBS, and a sham, or placebo TBS.
SPEAKER_01 (06:34):
Aaron Powell And they measured DTI, ALPS, and
face name associative memory,the FNEME score, before and
after each block.
SPEAKER_00 (06:42):
Exactly.
SPEAKER_01 (06:42):
This brings us back to that genetic X factor, APOE,
HO4.
We know it's a huge player inAlzheimer's risk.
What did the study find in thepeople carrying this gene?
SPEAKER_00 (06:53):
Aaron Powell What's so fascinating here is, well,
it's the massive baselinedeficit.
SPEAKER_01 (06:57):
Okay.
SPEAKER_00 (06:57):
The study identified 13 people carrying that APOED4
gene and 23 who weren't.
Right.
And even before any of theactive stimulation, the APO fee
carriers, they already showed asignificantly lower DTI ALPS
index.
SPEAKER_01 (07:09):
So their system was already slower to begin with.
SPEAKER_00 (07:11):
Exactly.
The drain was just visiblyslower in that genetically high
risk group.
It's this beautiful confirmationin living humans with MCI that
this known genetic risk actuallyshows up as reduced lymphatic
flow.
SPEAKER_01 (07:23):
Which gives a structural reason for their
heightened risk.
So the main event.
Did turning on the magnetsactually speed up the drain?
And did it help their memory?
SPEAKER_00 (07:32):
It did, but with extreme selectivity.
So when they looked at theresults and they combined the
two active TBS protocols sincethey were pretty similar, they
saw a significant increase inDTI-ALPS.
But this boost was profoundlymoderated by their genetic
status.
SPEAKER_01 (07:48):
So it was the APOE4 carriers who benefited?
SPEAKER_00 (07:52):
Yes.
They showed a large, significantpre-to-post increase in their
bilateral DTI-ALPS.
The non-carriers, on the otherhand, they showed almost no
significant change at all.
SPEAKER_01 (08:03):
Wow.
So the interventions selectivelyworked on the group that was
starting from a lower baselineand had the highest genetic
risk.
SPEAKER_00 (08:09):
Precisely.
SPEAKER_01 (08:09):
Wait, how big was this effect?
I know in these kinds of humanstudies, a strong effect is, you
know, hard to come by.
SPEAKER_00 (08:14):
It was unusually large.
The interaction between time andAPOE A4 status had an effect
size, a Cohen's D of 1.71.
SPEAKER_01 (08:21):
1.71?
SPEAKER_00 (08:22):
Yeah.
I mean, for context, inneuropsychiatry research,
anything over 0.8 is considereda large effect.
A 1.71 is just it's enormous.
It suggests this near perfectsplit where one group responds
dramatically and the otherbarely at all.
SPEAKER_01 (08:38):
That is a huge data point.
It's not just statistical noise,it's a specific target being hit
in a specific population.
But was this just a physicalmeasure?
Did the increased flow actuallyimprove brain function?
SPEAKER_00 (08:50):
It absolutely did.
And this is the key.
Within the APOE A4 carriersonly, a greater increase in that
DTI A L P S index correlatedreally strongly with larger
improvements in their memoryscores.
SPEAKER_01 (09:02):
You're kidding.
SPEAKER_00 (09:03):
Now the correlation was quite robust between 0.42
and 0.46.
SPEAKER_01 (09:06):
That closes the loop perfectly.
So the TBS helps the populationmost in need, and that physical
cleaning is directly tied to ameasurable cognitive
improvement.
SPEAKER_00 (09:15):
It provides this incredible novel evidence that
glymphatic plasticity exists inhumans.
And then we can actually engageit to improve cognition,
specifically in these vulnerablegroups.
SPEAKER_01 (09:23):
Here's where it gets really interesting.
How does this even work?
How does zapping the brain withmagnetism cause this physical
effect?
And why is it so incrediblysensitive to that one gene?
SPEAKER_00 (09:35):
The researchers laid out four really compelling
interconnected mechanisms.
The first one, and maybe themost straightforward, is sleep
augmentation.
SPEAKER_01 (09:43):
Okay.
SPEAKER_00 (09:44):
Since we know glymphatic function is maximized
during that deep slow wavesleep, TBS might simply be
working by increasing SWSactivity.
And we've seen that before inother studies with older adults.
SPEAKER_01 (09:55):
And that makes perfect sense because previous
work shows the age-related lossof that deep sleep is way faster
and ho carriers.
They have the most to gain.
SPEAKER_00 (10:04):
Exactly.
Their system is alreadystruggling because that natural
sleep boost is diminished.
And that leads to the secondidea, which focuses on neural
control.
SPEAKER_01 (10:13):
Right.
SPEAKER_00 (10:13):
The synchronized neural activity you need for
deep sleep and for goodclearance.
It's facilitated by inhibitorycells called gabergic
interneurons.
SPEAKER_01 (10:21):
This is where that great quote comes from, right?
Neurons that fire together,shower together.
SPEAKER_00 (10:26):
That's the one.
So you need that synchronizedfiring to open up the spaces and
get the fluid moving.
SPEAKER_01 (10:31):
And the inner neurons control that.
SPEAKER_00 (10:33):
Yes.
And these inner neurons areparticularly sensitive to TBS.
And critically, they're alsoknown to be dysfunctional,
specifically in APOE E4carriers.
SPEAKER_01 (10:42):
So TBS might be fixing the broken conductor of
the brain's symphony.
SPEAKER_00 (10:47):
That's a great way to put it.
It might be restoring thefunction of these vulnerable
inhibitory cells, which thenboosts the synchronized sleep
activity needed for clearance.
SPEAKER_01 (10:56):
Okay, so that handles the electrical side, but
what about the physicalstructures, the pump itself?
SPEAKER_00 (11:00):
Aaron Powell That brings us to the third
mechanism, astrocyticremodeling.
Remember, the astrocytes managethe pump with those AQP4 water
channels.
Right.
Well, the APOEO4 gene actuallypromotes the creation of a toxic
type of astrocyte called the A1phenotype.
And when astrocytes turn intothis A1 type, you get AQP4
(11:20):
mislocalization.
SPEAKER_01 (11:21):
Meaning the essential water channels move
away from where they're supposedto be, right by the vessels.
SPEAKER_00 (11:26):
It's exactly right.
AT4 fundamentally messes up thephysical structure of the pump.
But in animal models, TBS hasbeen shown to encourage a shift
away from that toxic A1 typetoward the protective A2 type.
SPEAKER_01 (11:38):
So it puts the plumbing back in the right
place.
SPEAKER_00 (11:40):
It seems to restore that AQP4 polarization.
It's a really potent cellularexplanation for both the low
baseline incurriors and theirhuge response to the
stimulation.
SPEAKER_01 (11:51):
Okay, we fixed the synchrony and the pump, but if
the final drain is backed up, itdoesn't matter.
What about the pathways thatlead out of the brain?
SPEAKER_00 (11:58):
That's the fourth mechanism, the vascular
pathways.
TMS has been shown to upregulatesomething called VGAFC.
SPEAKER_01 (12:04):
And why is that important?
SPEAKER_00 (12:06):
Because VEGSC dilates the meningeal lymphatic
vessels, the MLVs.
That's the final exit ramp forall the waste.
And since we know those MLVs arealso progressively dysfunctional
in AP4 carriers, TBS might beopening up the final drainage
pipes that are so oftenconstricted in this population.
SPEAKER_01 (12:22):
That is just an incredibly complete biological
story.
It goes from water channels tosleep cycles to the final drain
pipes.
It makes that huge effect sizeseem less random and much more
targeted.
SPEAKER_00 (12:33):
It really does.
SPEAKER_01 (12:34):
But as with any preliminary human study like
this, we have to be critical.
We have to look at thelimitations.
SPEAKER_00 (12:40):
We must maintain scientific rigor, absolutely.
First, we have to remember themain methodological limitation.
DTI ALPS is a proxy.
SPEAKER_01 (12:49):
Right.
SPEAKER_00 (12:50):
It's constrained to deep white matter.
It doesn't directly measurewhole brain clearance.
And it's not measuring big toxicmolecules like a beta.
We are inferring clearance fromfluid flow.
SPEAKER_01 (13:01):
And what other data was missing?
What would make these resultstruly unassailable?
SPEAKER_00 (13:06):
Well, there were three critical missing pieces.
One, no direct sleep data, noEEG to measure SWS architecture.
So we're hypothesizing that TBSis boosting deep sleep, but we
can't empirically confirm thatlink.
SPEAKER_01 (13:18):
Okay, that's a big one.
SPEAKER_00 (13:19):
Two, they didn't have direct Alzheimer's
biomarkers.
So no A beta or astrocyticmarkers like GFA measured in the
blood or CSF.
Without that, we can't directlyconnect the DTIALPS increase to
a physical reduction in diseasepathology.
SPEAKER_01 (13:33):
We have a proxy linked to a memory score, not a
direct confirmation of toxinremoval.
SPEAKER_00 (13:38):
Exactly.
And third, you know, the samplesize was modest, just 36 people.
And they were prettyhomogeneous, mostly female,
right-handed, highly educated.
That limits how much we cangeneralize from this.
SPEAKER_01 (13:50):
So future work is pretty clearly defined.
SPEAKER_00 (13:52):
Very clearly.
This study needs to bereplicated in much larger, more
diverse populations.
And those follow-up studiesabsolutely have to include
biofluid measures and morecomprehensive cognitive testing
to really validate the DTI ALPSproxy and confirm these
mechanisms.
SPEAKER_01 (14:08):
So what does this all mean?
SPEAKER_00 (14:10):
I think this deep dive gives us really compelling
evidence that non-invasiveneuromodulation TBS can
physically target the brain'swaste clearance system.
And crucially, the people whoshowed the biggest, most
functional benefit were thosewith the highest genetic risk.
SPEAKER_01 (14:24):
The APOE4 carriers.
SPEAKER_00 (14:25):
The ones who already had that measurable baseline
deficit.
This is just novel evidence thatthe lymphatic system has
plasticity in humans, right?
Where we need therapeutic toolsthe most.
SPEAKER_01 (14:34):
It feels like we've moved beyond just treating the
symptoms of cognitive decline.
We're now finding evidence thatwe might be able to physically
tune the brain's own cleaningcycle to improve cognition.
SPEAKER_00 (14:45):
It suggests the damage from the APOEE fees foods
might not be some immutabledestiny.
It could be a structural deficitthat we can temporarily boost or
even repair using targetedenergy.
SPEAKER_01 (14:56):
So if we can non-invasively manipulate the
brain's cleaning cycle withelectrical stimulation based on
someone's genetic risk and theirmeasured metabolic deficits,
does this suggest a future wheretargeted, personalized brain
stimulation becomes a corepreventative measure, like a
metabolic tune up for your brainto fight off aid related
cognitive decline?
SPEAKER_00 (15:16):
That is definitely something for you to mull over
until our next deep dive.
Welcome back to the deep dive, where we crack open
cutting edge research so you canjump straight to the knowledge.
SPEAKER_00 (00:06):
Today we are talking about something that really does
sound like it's straight out ofscience fiction.
SPEAKER_01 (00:11):
Aaron Powell It absolutely does.
We're talking about literallycleaning your brain and uh doing
it non-invasively with magneticstimulation.
SPEAKER_00 (00:19):
Yeah, it's pretty wild.
SPEAKER_01 (00:20):
So the brain is, I mean, it's the body's hungriest
organ.
It's an engine running on highoctane, you know, 24-7.
SPEAKER_00 (00:27):
Aaron Powell And like any engine, it produces
exhaust, a lot of it.
SPEAKER_01 (00:31):
Aaron Ross Powell Exactly.
It generates this massive amountof metabolic waste, especially
toxic byproducts likebeta-amyloid or a beta.
SPEAKER_00 (00:38):
Aaron Ross Powell And for decades, scientists had
this fundamental puzzle on theirhands.
SPEAKER_01 (00:43):
Aaron Powell How does the central nervous system,
which is walled off by theblood-brain barrier, how does it
clear out all this trash?
It doesn't have the normallymphatic system like the rest
of the body.
SPEAKER_00 (00:51):
Aaron Powell Right.
That was the big biologicalcontradiction.
And it wasn't really untilaround 2012 that the lymphatic
system was first characterized.
SPEAKER_01 (00:58):
Aaron Powell And that discovery gave us the
pathway.
It was the anatomical answer.
So the question is no longer ifthe brain cleans itself, but how
well does it do it as we age?
SPEAKER_00 (01:08):
Aaron Ross Powell And more importantly, could we
do anything about it when thatsystem starts to fail?
SPEAKER_01 (01:12):
Aaron Powell Okay, let's unpack this.
We are diving into a study thatshows, really for the first time
in older adults with mildcognitive impairment, that we
can use transcranial magneticstimulation or TMS to physically
boost this brain cleaningprocess.
SPEAKER_00 (01:27):
Aaron Powell And the findings are so incredibly
specific.
The real story here, the anchorfor this whole deep dive, is
that this stimulation it doesn'tjust work in general.
Its effectiveness is profoundly,I mean radically different
depending on one single thing.
SPEAKER_01 (01:42):
Aaron Powell And that's the person's genetics.
SPEAKER_00 (01:44):
Aaron Powell That's it.
We're zeroing in on the APOE A4gene.
You probably know it as thestrongest genetic risk factor
for sporadic Alzheimer'sdisease.
Right.
The data suggests that thisspecific group, the one most
genetically vulnerable, is theexact group that benefits the
most from this non-invasivecleaning boost.
SPEAKER_01 (02:00):
Aaron Powell Which is that's just fascinating
because it points to a future ofreally personalized preventative
treatment.
But okay, we need to start atthe beginning.
Before we talk about boostingthe system, we need to get a
clear picture of what theglymphatic system actually is
and you know how on earthresearchers measured it inside a
(02:21):
living person.
SPEAKER_00 (02:22):
That's the critical first step.
So the lymphatic system, it'sbest to think of it less as a
vessel and more as a reallysophisticated fluid exchange
network.
SPEAKER_01 (02:31):
Okay.
SPEAKER_00 (02:32):
It's gria-dependent, which just means it relies on
the brain's support cells.
The way it works is uh you havecerebrospinal fluid, or CSF,
that flows really rapidly intothese things called perivascular
spaces.
SPEAKER_01 (02:44):
Like little channels running alongside the arteries.
SPEAKER_00 (02:46):
Exactly, fluid-filled channels.
And once the CSF is in there, itstarts to exchange with the
fluid that's actuallysurrounding the neurons, the
interstitial fluid.
SPEAKER_01 (02:53):
And that's what carries the waste out.
SPEAKER_00 (02:55):
Yes.
And this whole process ispowerfully driven by these
specialized support cells calledastrocytes.
SPEAKER_01 (03:01):
So the astrocytes, the brain's support team, are
basically wrapping their feetaround the blood vessels and
squeezing the pump.
SPEAKER_00 (03:07):
That's a great way to think about it.
They are the control mechanism.
Their little end feet are justpacked with this critical
hardware, specifically aquaporn4 water channels, AQP4.
SPEAKER_01 (03:19):
And those channels are the key.
SPEAKER_00 (03:20):
Absolutely fundamental.
They push the fluid transportalong, and then once the
waste-filled fluid gets to theskull base, it drains out
through the meningeal lymphaticvessels.
SPEAKER_01 (03:30):
So what happens when this, I mean, this incredibly
intricate plumbing system startsto fail?
SPEAKER_00 (03:36):
Well, that's when you get the lymphatic crisis.
With age, and especially withdiseases like Alzheimer's, the
efficiency just plummets.
SPEAKER_01 (03:43):
And the clearance slows down.
SPEAKER_00 (03:44):
That deficient clearance lets toxic proteins
like a beta start to accumulate.
And the scary part is that thisbuildup is already happening,
maybe 15 years before a personshows any clinical signs of
memory loss.
SPEAKER_01 (03:55):
Wow.
So the key would be to intervenein that window when it's just
starting to slow down.
But the system isn't always on,right?
It changes throughout the day.
SPEAKER_00 (04:03):
Aaron Powell It does.
It has this powerful diurnalpattern.
It really maxes out during deepslow wave sleep, SWS.
SPEAKER_01 (04:10):
Okay.
SPEAKER_00 (04:11):
And that confirms the system has a high degree of
plasticity.
It's really responsive to ourphysiological state, which is
exactly why the researchersthought, you know, maybe we can
influence it with something likeTMS.
SPEAKER_01 (04:23):
Aaron Powell, which brings us to the measurement
problem.
If this is all happeningmicroscopically deep in the
brain, how do you even track itwithout doing something really
invasive?
SPEAKER_00 (04:32):
Aaron Powell I mean, for a long time, the gold
standard was incrediblyinvasive.
It involved a lumbar puncture,injecting a contrast agent
directly into the spine, andthen tracking it with an MRI.
SPEAKER_01 (04:41):
Aaron Powell Right.
Not something you can do for a10-day study.
SPEAKER_00 (04:43):
Not at all.
So they use this non-invasivecontrast-free MRI technique.
It's called diffusion tensorimaging analysis along the
perivascular space.
SPEAKER_01 (04:52):
Aaron Powell Thankfully shortened to DTI
ALPS.
SPEAKER_00 (04:56):
Yes, thankfully.
DTI ALPS basically measures thedirection and the speed of water
movement in the deep whitematter.
SPEAKER_01 (05:03):
Okay, so if I'm getting this right, DTI LPS is a
proxy.
You're not measuring the actualwaste, like a beta, leaving the
brain.
You're measuring the water.
It's like checking the pressureand the flow rate in the
plumbing to see if it's working.
SPEAKER_00 (05:14):
Aaron Powell That's a perfect analogy.
A higher DTI ALPS index suggestsfaster fluid movement, so you
know better lymphatic flow.
It's not the whole picture, butwe know a lower ALPS index
correlates with more a beta andworse cognitive scores.
It's a really useful snapshot ofthe pipes.
SPEAKER_01 (05:33):
Aaron Powell Excellent.
So we know what they aremeasuring.
Let's get to the interventionitself.
They use TMS, specifically thisreally potent patterned form
called theta burst stimulationor TBS.
SPEAKER_00 (05:44):
Right.
TBS delivers these rapidrepeating bursts of magnetic
pulses.
Its big advantage is that youcan get similar therapeutic
results to conventional TMS, butin a much shorter treatment
time.
SPEAKER_01 (05:55):
And this wasn't just a shot in the dark.
There was already strongpreclinical data.
SPEAKER_00 (05:59):
Oh yeah, very robust.
In mouse models of Alzheimer's,RTMS had already been shown to
physically boost fluidtransport, clear out of beta,
and even restore those criticalAQP4 channels.
SPEAKER_01 (06:09):
So this study took that promising mechanism and
brought it into humans.
They got 36 older adults, allwith mild cognitive impairment.
SPEAKER_00 (06:16):
And the protocol was really meticulous.
It was designed to separate theeffect of the real treatment
from a placebo.
SPEAKER_01 (06:23):
Right.
SPEAKER_00 (06:23):
So each person went through three separate 10-day
blocks, all randomized with awashout period in between:
continuous TBS, intermittentTBS, and a sham, or placebo TBS.
SPEAKER_01 (06:34):
Aaron Powell And they measured DTI, ALPS, and
face name associative memory,the FNEME score, before and
after each block.
SPEAKER_00 (06:42):
Exactly.
SPEAKER_01 (06:42):
This brings us back to that genetic X factor, APOE,
HO4.
We know it's a huge player inAlzheimer's risk.
What did the study find in thepeople carrying this gene?
SPEAKER_00 (06:53):
Aaron Powell What's so fascinating here is, well,
it's the massive baselinedeficit.
SPEAKER_01 (06:57):
Okay.
SPEAKER_00 (06:57):
The study identified 13 people carrying that APOED4
gene and 23 who weren't.
Right.
And even before any of theactive stimulation, the APO fee
carriers, they already showed asignificantly lower DTI ALPS
index.
SPEAKER_01 (07:09):
So their system was already slower to begin with.
SPEAKER_00 (07:11):
Exactly.
The drain was just visiblyslower in that genetically high
risk group.
It's this beautiful confirmationin living humans with MCI that
this known genetic risk actuallyshows up as reduced lymphatic
flow.
SPEAKER_01 (07:23):
Which gives a structural reason for their
heightened risk.
So the main event.
Did turning on the magnetsactually speed up the drain?
And did it help their memory?
SPEAKER_00 (07:32):
It did, but with extreme selectivity.
So when they looked at theresults and they combined the
two active TBS protocols sincethey were pretty similar, they
saw a significant increase inDTI-ALPS.
But this boost was profoundlymoderated by their genetic
status.
SPEAKER_01 (07:48):
So it was the APOE4 carriers who benefited?
SPEAKER_00 (07:52):
Yes.
They showed a large, significantpre-to-post increase in their
bilateral DTI-ALPS.
The non-carriers, on the otherhand, they showed almost no
significant change at all.
SPEAKER_01 (08:03):
Wow.
So the interventions selectivelyworked on the group that was
starting from a lower baselineand had the highest genetic
risk.
SPEAKER_00 (08:09):
Precisely.
SPEAKER_01 (08:09):
Wait, how big was this effect?
I know in these kinds of humanstudies, a strong effect is, you
know, hard to come by.
SPEAKER_00 (08:14):
It was unusually large.
The interaction between time andAPOE A4 status had an effect
size, a Cohen's D of 1.71.
SPEAKER_01 (08:21):
1.71?
SPEAKER_00 (08:22):
Yeah.
I mean, for context, inneuropsychiatry research,
anything over 0.8 is considereda large effect.
A 1.71 is just it's enormous.
It suggests this near perfectsplit where one group responds
dramatically and the otherbarely at all.
SPEAKER_01 (08:38):
That is a huge data point.
It's not just statistical noise,it's a specific target being hit
in a specific population.
But was this just a physicalmeasure?
Did the increased flow actuallyimprove brain function?
SPEAKER_00 (08:50):
It absolutely did.
And this is the key.
Within the APOE A4 carriersonly, a greater increase in that
DTI A L P S index correlatedreally strongly with larger
improvements in their memoryscores.
SPEAKER_01 (09:02):
You're kidding.
SPEAKER_00 (09:03):
Now the correlation was quite robust between 0.42
and 0.46.
SPEAKER_01 (09:06):
That closes the loop perfectly.
So the TBS helps the populationmost in need, and that physical
cleaning is directly tied to ameasurable cognitive
improvement.
SPEAKER_00 (09:15):
It provides this incredible novel evidence that
glymphatic plasticity exists inhumans.
And then we can actually engageit to improve cognition,
specifically in these vulnerablegroups.
SPEAKER_01 (09:23):
Here's where it gets really interesting.
How does this even work?
How does zapping the brain withmagnetism cause this physical
effect?
And why is it so incrediblysensitive to that one gene?
SPEAKER_00 (09:35):
The researchers laid out four really compelling
interconnected mechanisms.
The first one, and maybe themost straightforward, is sleep
augmentation.
SPEAKER_01 (09:43):
Okay.
SPEAKER_00 (09:44):
Since we know glymphatic function is maximized
during that deep slow wavesleep, TBS might simply be
working by increasing SWSactivity.
And we've seen that before inother studies with older adults.
SPEAKER_01 (09:55):
And that makes perfect sense because previous
work shows the age-related lossof that deep sleep is way faster
and ho carriers.
They have the most to gain.
SPEAKER_00 (10:04):
Exactly.
Their system is alreadystruggling because that natural
sleep boost is diminished.
And that leads to the secondidea, which focuses on neural
control.
SPEAKER_01 (10:13):
Right.
SPEAKER_00 (10:13):
The synchronized neural activity you need for
deep sleep and for goodclearance.
It's facilitated by inhibitorycells called gabergic
interneurons.
SPEAKER_01 (10:21):
This is where that great quote comes from, right?
Neurons that fire together,shower together.
SPEAKER_00 (10:26):
That's the one.
So you need that synchronizedfiring to open up the spaces and
get the fluid moving.
SPEAKER_01 (10:31):
And the inner neurons control that.
SPEAKER_00 (10:33):
Yes.
And these inner neurons areparticularly sensitive to TBS.
And critically, they're alsoknown to be dysfunctional,
specifically in APOE E4carriers.
SPEAKER_01 (10:42):
So TBS might be fixing the broken conductor of
the brain's symphony.
SPEAKER_00 (10:47):
That's a great way to put it.
It might be restoring thefunction of these vulnerable
inhibitory cells, which thenboosts the synchronized sleep
activity needed for clearance.
SPEAKER_01 (10:56):
Okay, so that handles the electrical side, but
what about the physicalstructures, the pump itself?
SPEAKER_00 (11:00):
Aaron Powell That brings us to the third
mechanism, astrocyticremodeling.
Remember, the astrocytes managethe pump with those AQP4 water
channels.
Right.
Well, the APOEO4 gene actuallypromotes the creation of a toxic
type of astrocyte called the A1phenotype.
And when astrocytes turn intothis A1 type, you get AQP4
(11:20):
mislocalization.
SPEAKER_01 (11:21):
Meaning the essential water channels move
away from where they're supposedto be, right by the vessels.
SPEAKER_00 (11:26):
It's exactly right.
AT4 fundamentally messes up thephysical structure of the pump.
But in animal models, TBS hasbeen shown to encourage a shift
away from that toxic A1 typetoward the protective A2 type.
SPEAKER_01 (11:38):
So it puts the plumbing back in the right
place.
SPEAKER_00 (11:40):
It seems to restore that AQP4 polarization.
It's a really potent cellularexplanation for both the low
baseline incurriors and theirhuge response to the
stimulation.
SPEAKER_01 (11:51):
Okay, we fixed the synchrony and the pump, but if
the final drain is backed up, itdoesn't matter.
What about the pathways thatlead out of the brain?
SPEAKER_00 (11:58):
That's the fourth mechanism, the vascular
pathways.
TMS has been shown to upregulatesomething called VGAFC.
SPEAKER_01 (12:04):
And why is that important?
SPEAKER_00 (12:06):
Because VEGSC dilates the meningeal lymphatic
vessels, the MLVs.
That's the final exit ramp forall the waste.
And since we know those MLVs arealso progressively dysfunctional
in AP4 carriers, TBS might beopening up the final drainage
pipes that are so oftenconstricted in this population.
SPEAKER_01 (12:22):
That is just an incredibly complete biological
story.
It goes from water channels tosleep cycles to the final drain
pipes.
It makes that huge effect sizeseem less random and much more
targeted.
SPEAKER_00 (12:33):
It really does.
SPEAKER_01 (12:34):
But as with any preliminary human study like
this, we have to be critical.
We have to look at thelimitations.
SPEAKER_00 (12:40):
We must maintain scientific rigor, absolutely.
First, we have to remember themain methodological limitation.
DTI ALPS is a proxy.
SPEAKER_01 (12:49):
Right.
SPEAKER_00 (12:50):
It's constrained to deep white matter.
It doesn't directly measurewhole brain clearance.
And it's not measuring big toxicmolecules like a beta.
We are inferring clearance fromfluid flow.
SPEAKER_01 (13:01):
And what other data was missing?
What would make these resultstruly unassailable?
SPEAKER_00 (13:06):
Well, there were three critical missing pieces.
One, no direct sleep data, noEEG to measure SWS architecture.
So we're hypothesizing that TBSis boosting deep sleep, but we
can't empirically confirm thatlink.
SPEAKER_01 (13:18):
Okay, that's a big one.
SPEAKER_00 (13:19):
Two, they didn't have direct Alzheimer's
biomarkers.
So no A beta or astrocyticmarkers like GFA measured in the
blood or CSF.
Without that, we can't directlyconnect the DTIALPS increase to
a physical reduction in diseasepathology.
SPEAKER_01 (13:33):
We have a proxy linked to a memory score, not a
direct confirmation of toxinremoval.
SPEAKER_00 (13:38):
Exactly.
And third, you know, the samplesize was modest, just 36 people.
And they were prettyhomogeneous, mostly female,
right-handed, highly educated.
That limits how much we cangeneralize from this.
SPEAKER_01 (13:50):
So future work is pretty clearly defined.
SPEAKER_00 (13:52):
Very clearly.
This study needs to bereplicated in much larger, more
diverse populations.
And those follow-up studiesabsolutely have to include
biofluid measures and morecomprehensive cognitive testing
to really validate the DTI ALPSproxy and confirm these
mechanisms.
SPEAKER_01 (14:08):
So what does this all mean?
SPEAKER_00 (14:10):
I think this deep dive gives us really compelling
evidence that non-invasiveneuromodulation TBS can
physically target the brain'swaste clearance system.
And crucially, the people whoshowed the biggest, most
functional benefit were thosewith the highest genetic risk.
SPEAKER_01 (14:24):
The APOE4 carriers.
SPEAKER_00 (14:25):
The ones who already had that measurable baseline
deficit.
This is just novel evidence thatthe lymphatic system has
plasticity in humans, right?
Where we need therapeutic toolsthe most.
SPEAKER_01 (14:34):
It feels like we've moved beyond just treating the
symptoms of cognitive decline.
We're now finding evidence thatwe might be able to physically
tune the brain's own cleaningcycle to improve cognition.
SPEAKER_00 (14:45):
It suggests the damage from the APOEE fees foods
might not be some immutabledestiny.
It could be a structural deficitthat we can temporarily boost or
even repair using targetedenergy.
SPEAKER_01 (14:56):
So if we can non-invasively manipulate the
brain's cleaning cycle withelectrical stimulation based on
someone's genetic risk and theirmeasured metabolic deficits,
does this suggest a future wheretargeted, personalized brain
stimulation becomes a corepreventative measure, like a
metabolic tune up for your brainto fight off aid related
cognitive decline?
SPEAKER_00 (15:16):
That is definitely something for you to mull over
until our next deep dive.
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