July 29, 2025 • 15 mins
🎙️ Episode 90: Variable and Interactive Effects of Sex, APOE ε4 and TREM2 on Tau Deposition
🧬 In this episode of PaperCast Base by Base, we explore how genetic factors—including sex differences, Apolipoprotein E ε4 allele dosage, and rare TREM2 risk variants—shape the accumulation and spread of tau pathology in Alzheimer’s disease using multimodal imaging and causal path analysis.
🔍 Study Highlights:
This multi-cohort investigation combined PET imaging and genetic data from over 1,300 participants across ADNI, A4, and HABS‑HD cohorts to model how amyloid-beta, entorhinal cortex tau, and genetics interact. Causal path modeling revealed that females and APOE ε4 homozygotes exhibit higher entorhinal tau for a given level of amyloid-beta. Rare TREM2 variant carriers displayed enhanced propagation of tau from entorhinal regions into the neocortex. Interactive effects between APOE ε4 and TREM2 further amplified neocortical tau burden.
🧠Conclusion:
This study illuminates the roles of sex, APOE, and microglial genetics in tau pathology progression and underscores the need for personalized therapeutic timing targeting amyloid and tau in Alzheimer’s disease.
đź“– Reference:
Giorgio J, Jonson C, Wang Y, Yokoyama JS, Wang J, Jagust WJ, et al. Variable and interactive effects of sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions. Nature Communications. 2025;16:5812. doi:10.1038/s41467-025-60370-8
đź“ś License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
Mark as Played
Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:14):
Welcome to base by BASE, the AERcast that brings genomics to you
wherever you are. Imagine 2 individuals.
OK, both are showing those earlysigns of amyloid beta.
You know, that key protein link to Alzheimer's.
But for one person, the disease seems to just take off Tau
tangles, spreading really rapidly through their brain.
Or for the other, it's more likea slow, gentle creep.
(00:36):
What hidden factors could possibly explain such a critical
difference in how Alzheimer's progresses?
Yeah, it's a question that has really puzzled researchers and
clinicians for a long time. Why does the pathology vary so
much between people? Maybe more importantly, how
could understanding these differences, really getting a
handle on them, change how we approach treatment,
fundamentally change it? Right.
(00:57):
And today we're diving into a fascinating new study that
shines a light on exactly this. It starts to reveal how our
basic biology, specifically things like our sex and certain
genetic variations, can dramatically influence how
Alzheimer's actually takes hold and spreads inside the brain.
But before we unpack all these insights, we do want to give
some special recognition. Today we celebrate the work of
(01:18):
Joseph Giorgio and William J Jagest, and of course, their
dedicated colleagues. They've really advanced their
understanding of how sex and specific genetic factors can
interact and how that influencesTau deposition in Alzheimer's
disease. OK, so to set the stage a bit,
let's quickly recap the the standard model for how
Alzheimer's is thought progress.It's often called the canonical
(01:39):
cascade. So the basic idea is that the
first thing that happens, the trigger is the build up of
amyloid beta protein. Ah.
This accumulation then sort of accelerates the build up of
another protein, Tau. This starts typically in a key
memory area, the intorinal cortex, the EC.
From there, Tau spreads out intoother brain regions, especially
the neocortex. And it's this wider spread of
(02:01):
Tau that really leads to the cognitive decline we see in
Alzheimer's. OK.
That makes sense as a general pathway.
Right now, while some rare dominant genetic forms of
Alzheimer's follow this path pretty predictably, the common
form, sporadic late onset AD, isway more complex.
It's influenced by, well, a whole mix of genetic factors,
lifestyle factors. It makes the progression much
(02:23):
less straightforward, you know? And that complexity is exactly
what this study gets into. So when we talk about these
individual variations, are therespecific genetic factors that
really stand out as being particularly important in
shaping how this unfolds? Absolutely.
I mean the strongest genetic risk factor we know for sporadic
late onset AD is the APOE A4 allele.
If you have just one copy, your risk can be like over three
(02:46):
times higher than someone with the more common a free allele.
But if you have two copies for an API E4 homozygote, that risk
can shoot up to over 13 times higher.
It's a huge effect. 13 times, yeah.
And what the study really underscores is that API E 4
isn't just about amyloid beta buildup.
It seems to have these additional effects, maybe direct
effects on Tau itself, influencing how it gets
(03:08):
phosphorylated or how it spreads, so it's involved
downstream too. OK, so APOE 4 is a big one.
Are there other genetic players involved here?
Yes, definitely. Another important one is the
TREM 2 gene. You can think of TREM 2 as a
protein found on the surface of the brain's immune cells, the
microglia. It's kind of like a sensor for
them. It's really critical for how
these microglia respond to Alzheimer's pathology, like
(03:29):
clearing up debris. Certain rare changes or
polymorphisms in Trem 2 can makeit less functional.
So the immune response is weakened essentially.
Sort of of, yeah. Or at least altered variants
like R47, which for example are linked to a significantly
increased AD risk, maybe around 2.7 times higher.
And the thinking is that this less functional trem 2 might
(03:50):
actually promote Tau seeding andspreading, perhaps by messing
with the inflammatory response. And then there's the role of
sex, which you mentioned. That seems like a really
consistent finding in Alzheimer's Research, doesn't
it? It really is.
Females generally have a higher incidence of dementia later in
life, and postmortem studies consistently show more Tau
tangles in women's brains and invivo imaging, so brain scans on
(04:12):
living people backs this up. Women tend to show higher levels
of Tau and faster accumulation rates, even when they have
similar levels of amyloid beta compared to men.
So for the same out of amyloid, women might have more Tau.
Exactly. And this raises a really crucial
question that this paper tackleshead on.
Are these sex differences mainlyabout the initial buildup of Tau
in that entorhinal cortex region, or is it more about how
(04:34):
Tau spreads later on? And importantly, could these
differences be linked somehow tothe immune response, maybe
involving trem too? Understanding all these variable
effects feels incredibly important right now, especially
with the new anti amyloid drugs going online.
We've seen lecanemab and donamabshowing promise and slowing
cognitive decline by clearing amyloid, but the results weren't
(04:56):
the same for everyone. There were reports of varying
treatment effects in women depending on the specific trial
outcomes. And here's a really key point
for those APOE for homozygotes, the ones with two copies of the
risk gene, neither drug showed significant effects on the main
primary outcome measure. So this study could really help
us start to quantify why we might be seeing these different
(05:18):
responses to treatment. Definitely.
OK, let's talk about how they did this.
The researchers used a really smart, robust approach.
They combined data from three big well known students.
There was 80 and I the Alzheimer's Disease Neuroimaging
Initiative A4, which is the antiamyloid treatment in
asymptomatic Alzheimer's study and HABSHD, the health and aging
(05:40):
brain study health disparities. Pulling these together gave them
a large sample size, over 1300 people in total, which they
split into a discovery group andthen a separate replication
group to check their finding. And these weren't just
questionnaires, right? They had detailed biological
data. Oh yes, all participants had
advanced brain imaging PEAT scans to measure both their
amyloid beta levels and their Tau levels throughout the brain.
(06:03):
And critically, they also had whole genome sequencing data
giving them detailed informationabout each person's genetic
makeup, including APOE and TREM 2 status.
OK, so great data. What what about the analysis you
mentioned it was innovative. Yeah, they use my thing called
causal path modeling. It's a sophisticated statistical
method using structural equationmodels, or SEM.
Basically, it lets you test hypotheses about how different
(06:25):
factors influence each other along a proposed pathway.
So their model assumed that cascade.
We talked about a deposition happens first, which leads to a
related Tau in the EC, which then leads to Tau spreading into
the neocortex. Steps in a process.
Exactly. And then they tested how things
like FX, the number of APOE 4 allele someone had zero, one or
(06:47):
two, and whether they carried a trim 2 risk variant influenced
each step of that pathology. And importantly, they tried to
separate out effects that are just mediated by amyloid levels
versus effects that might be happening in addition to
amyloid, like direct effects on Tau accumulation or spread even
after accounting for APP. And for instance, they did some
clever things like grouping AB levels to look at interactions
(07:08):
with EC while still using the continuous AB measure as a main
factor. It let them probe these
relationships really carefully. OK, so a powerful approach to
tease apart these complex interactions.
What did they actually find? What were the key results?
All right, let's dive into the findings first looking at what
influences amyloid beta levels themselves.
As you'd probably expect, age and having APE 4 alleles had
(07:31):
significant effects. More AP4 alleles meant higher 8
levels. That's the dose dependent
effect. Interestingly, in their main
discovery sample they didn't find a significant effect of sex
or Trem 2 status directly on apelevels, though one of the
replication cohorts, HABSHD, didshow females having higher APE.
So maybe a slight nuance there. OK so APOE 4 and age are the big
(07:55):
drivers for A itself, but what about Tau?
Especially that early stage in the indoinal cortex.
Right, this is where it gets really interesting.
When they looked at Tau in the EC, that primary accumulation
spot. Here's the crucial insight.
Even when they accounted for theamount of amyloid beta present.
So for a given level of epic, both APOE, 4 homozygotes, those
with two copies and females had significantly more Tau in their
(08:17):
intortonal cortex. Wow.
So it's not just that they have more amyloid driving it, their
brains seem more susceptible to Tau buildup early on.
That's exactly what it suggests.And this wasn't just a fluke, it
was a strong, consistent findingthey replicated in their second
independent cohort. And there was another twist.
They found an interaction between Trem 2 and sex.
(08:38):
Specifically, female carriers ofa Trem 2 risk variant seem to
have the highest levels of EC Tau.
OK. So sex, APOE for homozygosity,
and maybe this Trem 2 interaction are really dialing
up that initial Tau pathology. What about the next step, the
spread of Tau into the rest of the brain, the neocortex?
Good question. So moving downstream to
(08:59):
neocortical Tau, which reflects that spread, they found that for
a given level of Tau already in the entorhinal cortex, APOEA for
homozygotes in individuals carrying a trem to risk variant
had significantly more Tau spread into the neocortex.
So not only do they maybe get more Tau starting out, but it
also spreads more easily in those groups.
Precisely, it suggests Tau movesmore readily or propagates more
(09:21):
efficiently downstream in peoplewith those genetic factors.
They also confirmed a significant interaction between
APOE sewer and Trim 2. Here, if you had both a Trim 2
risk variant and at least one APOE 4 allele, you showed
significantly more neocortical Tau spread, a kind of double
hit. But interestingly, once they
accounted for all these upstreamfactors, the A levels, the EC
(09:44):
Tau levels, the genetics, they didn't find a significant direct
effect of sex on the rate of neocortical Tau spread itself.
So sex seems more influential onthe initial Tau accumulation in
the EC given the amyloid levels,but less so on the subsequent
rate of spread. That seems to be what the data
points to courts in this analysis, yes.
This really paints a picture of highly variable genetic effects
(10:04):
playing out differently along that cascade.
It's not just one disease progressing the same way in
everyone. Absolutely.
I mean, these findings give us really compelling evidence for
substantial heterogeneity, real differences in how Tau pathology
unfolds depending on your sex, your APO, APO 4 status, and your
trem 2 status. This is a huge step towards, you
know, truly understanding personalized Alzheimer's
(10:27):
progression. So what are the big implications
then, especially when we think about treatment?
OK, let's unpack that for APOE 4homozygotes.
The data shows strong effects onboth early EC Tau accumulation
and the later neocortical spread, even beyond the effects
mediated by amyloid. This strongly suggests the APOE
4 protein itself is doing something profound to influence
(10:49):
Tau pathology directly, and the clinical implication here is
pretty significant. It suggests that people with two
copies of APO 4 might need to betreated earlier with anti
amyloid therapy. Is it lower amyloid levels than
other groups? Potentially yes, because their
biology seems to make them more vulnerable.
They're out drives higher Tau more efficiently and their Tau
spreads more aggressively. This insight could really help
(11:10):
explain why those anti amyloid trials showed weaker or even
absent benefits for APOE 4 homozygotes.
Maybe the intervention was too late for them or needed to be
tailored differently. Right.
It's about trying to get ahead of that accelerated pathology
curve for that specific group. What about the TRIM 2 findings?
The TRIM 2 results suggest that variations in how this
(11:30):
microglial protein functions play a direct role in how Tau
spreads from the EC to the neocortex.
The likely mechanism involves aberrant microglial activity.
If TRIM 2 isn't fully functional, it might disrupt
normal inflammatory signaling and somehow actually promote the
transmission of Tau between brain cells, and that
interaction between APOE 4 and TREM 2 is also key.
(11:52):
Having both risk factors seems to compound the effect on
neocortical Tau, suggesting maybe their combined impact on
microglia or other pathways is particularly detrimental.
And revisiting the sex differences, what's the take
away there? For the sex differences, the
clearest signal is that females appear more susceptible to that
early Tau deposition in the entorhinal cortex for any given
level of amyloid. So clinically this might mean
(12:15):
females could require anti amyloid treatment at lower Abara
thresholds than males to get similar benefits in reducing
that initial Tau pathology. Or perhaps future trial designs
might need to consider screeningfor both amyloid and Tau,
especially in women, to make sure their Tau pathology isn't
already more advanced than expected based on amyloid alone.
(12:36):
This could potentially shed light on why outcomes might have
differ for women between, say, the lecanemab and donanemab
trials, as donemab did include taupeet screening.
That makes a lot of sense. This is really groundbreaking
work, revealing such specific, nuanced roles for these factors.
But as always in science, it's important to consider the
limitations, right? To think critically about what
this study tells us and what maybe it doesn't yet.
(12:58):
Absolutely, that's crucial. First off, this is a
cross-sectional study. It's like taking a snapshot in
time across many people. It's powerful for finding
associations, but it can't fullycapture the longitudinal
dynamics how these things changewithin one person over years.
We infer the progression, but wedon't directly observe it start
to finish in the same individuals here.
(13:19):
OK. So trajectory is inferred, not
directly measured over time. Exactly, and while the
interpretations about the anti amyloid trials are really
compelling and fit the data well, they are still
interpretations based on these findings.
They'll need more direct validation, perhaps in
prospective studies or analysis of trial data itself.
Also, technically they grouped several different rare trim 2
(13:41):
risk variants together. This assumes they all have
similar biological effects, which might not be perfectly
true and could slightly underestimate the impact of
specific variants. The researchers acknowledged
this, noting it would likely bias results towards finding no
effect. So the fact they did find
significant effects is still strong, but it's a nuance.
Right. And any sample size issues?
(14:02):
Well, the overall sample was large, which is a major
strength, but the number of APOE4 homozygos, while sufficient to
find effects, is naturally smaller than the other groups.
However, the fact that they replicated the key ATOE 4
findings in two completely independent cohorts gives us
much greater confidence in thoseresults.
Replication is key. OK, so limitations acknowledged,
but the core findings seem robust, especially with the
(14:24):
replication. I think so.
Overall, this deep dive really reinforces that Alzheimer's
progression isn't this single monolithic path.
It's truly a complex interplay. Our specific genetic makeup,
like APOE, interim 2 status, andeven our biological sex can
dramatically shape when and how Tau pathology builds up and
spreads. And that fundamentally changes
(14:45):
our individual risk profile and quite possibly how we might
respond to different treatments.So going back to those two
individuals we imagined at the start, the one with rapid
progression, the other slower, this study gives us real
biological reasons why those different paths might exist.
It pinpoints specific roles for sex and genes at different
stages. Which leads to the big question,
(15:06):
what does this all mean for the future of personalized medicine
in Alzheimer's disease, Especially as the field pushes
towards intervening earlier before a significant cognitive
decline really sets in? This episode was based on an
Open Access article under the CCBY 4 Point O license.
You can find a direct link to the paper and the license in our
episode description. If you enjoyed this analysis,
(15:27):
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in your favorite podcast app andleave us a five star rating.
It only takes a few seconds but makes a huge difference in
helping others discover the show.
Thanks for listening and join usnext time as we explore more
science base by base.
Welcome to base by BASE, the AERcast that brings genomics to you
wherever you are. Imagine 2 individuals.
OK, both are showing those earlysigns of amyloid beta.
You know, that key protein link to Alzheimer's.
But for one person, the disease seems to just take off Tau
tangles, spreading really rapidly through their brain.
Or for the other, it's more likea slow, gentle creep.
(00:36):
What hidden factors could possibly explain such a critical
difference in how Alzheimer's progresses?
Yeah, it's a question that has really puzzled researchers and
clinicians for a long time. Why does the pathology vary so
much between people? Maybe more importantly, how
could understanding these differences, really getting a
handle on them, change how we approach treatment,
fundamentally change it? Right.
(00:57):
And today we're diving into a fascinating new study that
shines a light on exactly this. It starts to reveal how our
basic biology, specifically things like our sex and certain
genetic variations, can dramatically influence how
Alzheimer's actually takes hold and spreads inside the brain.
But before we unpack all these insights, we do want to give
some special recognition. Today we celebrate the work of
(01:18):
Joseph Giorgio and William J Jagest, and of course, their
dedicated colleagues. They've really advanced their
understanding of how sex and specific genetic factors can
interact and how that influencesTau deposition in Alzheimer's
disease. OK, so to set the stage a bit,
let's quickly recap the the standard model for how
Alzheimer's is thought progress.It's often called the canonical
(01:39):
cascade. So the basic idea is that the
first thing that happens, the trigger is the build up of
amyloid beta protein. Ah.
This accumulation then sort of accelerates the build up of
another protein, Tau. This starts typically in a key
memory area, the intorinal cortex, the EC.
From there, Tau spreads out intoother brain regions, especially
the neocortex. And it's this wider spread of
(02:01):
Tau that really leads to the cognitive decline we see in
Alzheimer's. OK.
That makes sense as a general pathway.
Right now, while some rare dominant genetic forms of
Alzheimer's follow this path pretty predictably, the common
form, sporadic late onset AD, isway more complex.
It's influenced by, well, a whole mix of genetic factors,
lifestyle factors. It makes the progression much
(02:23):
less straightforward, you know? And that complexity is exactly
what this study gets into. So when we talk about these
individual variations, are therespecific genetic factors that
really stand out as being particularly important in
shaping how this unfolds? Absolutely.
I mean the strongest genetic risk factor we know for sporadic
late onset AD is the APOE A4 allele.
If you have just one copy, your risk can be like over three
(02:46):
times higher than someone with the more common a free allele.
But if you have two copies for an API E4 homozygote, that risk
can shoot up to over 13 times higher.
It's a huge effect. 13 times, yeah.
And what the study really underscores is that API E 4
isn't just about amyloid beta buildup.
It seems to have these additional effects, maybe direct
effects on Tau itself, influencing how it gets
(03:08):
phosphorylated or how it spreads, so it's involved
downstream too. OK, so APOE 4 is a big one.
Are there other genetic players involved here?
Yes, definitely. Another important one is the
TREM 2 gene. You can think of TREM 2 as a
protein found on the surface of the brain's immune cells, the
microglia. It's kind of like a sensor for
them. It's really critical for how
these microglia respond to Alzheimer's pathology, like
(03:29):
clearing up debris. Certain rare changes or
polymorphisms in Trem 2 can makeit less functional.
So the immune response is weakened essentially.
Sort of of, yeah. Or at least altered variants
like R47, which for example are linked to a significantly
increased AD risk, maybe around 2.7 times higher.
And the thinking is that this less functional trem 2 might
(03:50):
actually promote Tau seeding andspreading, perhaps by messing
with the inflammatory response. And then there's the role of
sex, which you mentioned. That seems like a really
consistent finding in Alzheimer's Research, doesn't
it? It really is.
Females generally have a higher incidence of dementia later in
life, and postmortem studies consistently show more Tau
tangles in women's brains and invivo imaging, so brain scans on
(04:12):
living people backs this up. Women tend to show higher levels
of Tau and faster accumulation rates, even when they have
similar levels of amyloid beta compared to men.
So for the same out of amyloid, women might have more Tau.
Exactly. And this raises a really crucial
question that this paper tackleshead on.
Are these sex differences mainlyabout the initial buildup of Tau
in that entorhinal cortex region, or is it more about how
(04:34):
Tau spreads later on? And importantly, could these
differences be linked somehow tothe immune response, maybe
involving trem too? Understanding all these variable
effects feels incredibly important right now, especially
with the new anti amyloid drugs going online.
We've seen lecanemab and donamabshowing promise and slowing
cognitive decline by clearing amyloid, but the results weren't
(04:56):
the same for everyone. There were reports of varying
treatment effects in women depending on the specific trial
outcomes. And here's a really key point
for those APOE for homozygotes, the ones with two copies of the
risk gene, neither drug showed significant effects on the main
primary outcome measure. So this study could really help
us start to quantify why we might be seeing these different
(05:18):
responses to treatment. Definitely.
OK, let's talk about how they did this.
The researchers used a really smart, robust approach.
They combined data from three big well known students.
There was 80 and I the Alzheimer's Disease Neuroimaging
Initiative A4, which is the antiamyloid treatment in
asymptomatic Alzheimer's study and HABSHD, the health and aging
(05:40):
brain study health disparities. Pulling these together gave them
a large sample size, over 1300 people in total, which they
split into a discovery group andthen a separate replication
group to check their finding. And these weren't just
questionnaires, right? They had detailed biological
data. Oh yes, all participants had
advanced brain imaging PEAT scans to measure both their
amyloid beta levels and their Tau levels throughout the brain.
(06:03):
And critically, they also had whole genome sequencing data
giving them detailed informationabout each person's genetic
makeup, including APOE and TREM 2 status.
OK, so great data. What what about the analysis you
mentioned it was innovative. Yeah, they use my thing called
causal path modeling. It's a sophisticated statistical
method using structural equationmodels, or SEM.
Basically, it lets you test hypotheses about how different
(06:25):
factors influence each other along a proposed pathway.
So their model assumed that cascade.
We talked about a deposition happens first, which leads to a
related Tau in the EC, which then leads to Tau spreading into
the neocortex. Steps in a process.
Exactly. And then they tested how things
like FX, the number of APOE 4 allele someone had zero, one or
(06:47):
two, and whether they carried a trim 2 risk variant influenced
each step of that pathology. And importantly, they tried to
separate out effects that are just mediated by amyloid levels
versus effects that might be happening in addition to
amyloid, like direct effects on Tau accumulation or spread even
after accounting for APP. And for instance, they did some
clever things like grouping AB levels to look at interactions
(07:08):
with EC while still using the continuous AB measure as a main
factor. It let them probe these
relationships really carefully. OK, so a powerful approach to
tease apart these complex interactions.
What did they actually find? What were the key results?
All right, let's dive into the findings first looking at what
influences amyloid beta levels themselves.
As you'd probably expect, age and having APE 4 alleles had
(07:31):
significant effects. More AP4 alleles meant higher 8
levels. That's the dose dependent
effect. Interestingly, in their main
discovery sample they didn't find a significant effect of sex
or Trem 2 status directly on apelevels, though one of the
replication cohorts, HABSHD, didshow females having higher APE.
So maybe a slight nuance there. OK so APOE 4 and age are the big
(07:55):
drivers for A itself, but what about Tau?
Especially that early stage in the indoinal cortex.
Right, this is where it gets really interesting.
When they looked at Tau in the EC, that primary accumulation
spot. Here's the crucial insight.
Even when they accounted for theamount of amyloid beta present.
So for a given level of epic, both APOE, 4 homozygotes, those
with two copies and females had significantly more Tau in their
(08:17):
intortonal cortex. Wow.
So it's not just that they have more amyloid driving it, their
brains seem more susceptible to Tau buildup early on.
That's exactly what it suggests.And this wasn't just a fluke, it
was a strong, consistent findingthey replicated in their second
independent cohort. And there was another twist.
They found an interaction between Trem 2 and sex.
(08:38):
Specifically, female carriers ofa Trem 2 risk variant seem to
have the highest levels of EC Tau.
OK. So sex, APOE for homozygosity,
and maybe this Trem 2 interaction are really dialing
up that initial Tau pathology. What about the next step, the
spread of Tau into the rest of the brain, the neocortex?
Good question. So moving downstream to
(08:59):
neocortical Tau, which reflects that spread, they found that for
a given level of Tau already in the entorhinal cortex, APOEA for
homozygotes in individuals carrying a trem to risk variant
had significantly more Tau spread into the neocortex.
So not only do they maybe get more Tau starting out, but it
also spreads more easily in those groups.
Precisely, it suggests Tau movesmore readily or propagates more
(09:21):
efficiently downstream in peoplewith those genetic factors.
They also confirmed a significant interaction between
APOE sewer and Trim 2. Here, if you had both a Trim 2
risk variant and at least one APOE 4 allele, you showed
significantly more neocortical Tau spread, a kind of double
hit. But interestingly, once they
accounted for all these upstreamfactors, the A levels, the EC
(09:44):
Tau levels, the genetics, they didn't find a significant direct
effect of sex on the rate of neocortical Tau spread itself.
So sex seems more influential onthe initial Tau accumulation in
the EC given the amyloid levels,but less so on the subsequent
rate of spread. That seems to be what the data
points to courts in this analysis, yes.
This really paints a picture of highly variable genetic effects
(10:04):
playing out differently along that cascade.
It's not just one disease progressing the same way in
everyone. Absolutely.
I mean, these findings give us really compelling evidence for
substantial heterogeneity, real differences in how Tau pathology
unfolds depending on your sex, your APO, APO 4 status, and your
trem 2 status. This is a huge step towards, you
know, truly understanding personalized Alzheimer's
(10:27):
progression. So what are the big implications
then, especially when we think about treatment?
OK, let's unpack that for APOE 4homozygotes.
The data shows strong effects onboth early EC Tau accumulation
and the later neocortical spread, even beyond the effects
mediated by amyloid. This strongly suggests the APOE
4 protein itself is doing something profound to influence
(10:49):
Tau pathology directly, and the clinical implication here is
pretty significant. It suggests that people with two
copies of APO 4 might need to betreated earlier with anti
amyloid therapy. Is it lower amyloid levels than
other groups? Potentially yes, because their
biology seems to make them more vulnerable.
They're out drives higher Tau more efficiently and their Tau
spreads more aggressively. This insight could really help
(11:10):
explain why those anti amyloid trials showed weaker or even
absent benefits for APOE 4 homozygotes.
Maybe the intervention was too late for them or needed to be
tailored differently. Right.
It's about trying to get ahead of that accelerated pathology
curve for that specific group. What about the TRIM 2 findings?
The TRIM 2 results suggest that variations in how this
(11:30):
microglial protein functions play a direct role in how Tau
spreads from the EC to the neocortex.
The likely mechanism involves aberrant microglial activity.
If TRIM 2 isn't fully functional, it might disrupt
normal inflammatory signaling and somehow actually promote the
transmission of Tau between brain cells, and that
interaction between APOE 4 and TREM 2 is also key.
(11:52):
Having both risk factors seems to compound the effect on
neocortical Tau, suggesting maybe their combined impact on
microglia or other pathways is particularly detrimental.
And revisiting the sex differences, what's the take
away there? For the sex differences, the
clearest signal is that females appear more susceptible to that
early Tau deposition in the entorhinal cortex for any given
level of amyloid. So clinically this might mean
(12:15):
females could require anti amyloid treatment at lower Abara
thresholds than males to get similar benefits in reducing
that initial Tau pathology. Or perhaps future trial designs
might need to consider screeningfor both amyloid and Tau,
especially in women, to make sure their Tau pathology isn't
already more advanced than expected based on amyloid alone.
(12:36):
This could potentially shed light on why outcomes might have
differ for women between, say, the lecanemab and donanemab
trials, as donemab did include taupeet screening.
That makes a lot of sense. This is really groundbreaking
work, revealing such specific, nuanced roles for these factors.
But as always in science, it's important to consider the
limitations, right? To think critically about what
this study tells us and what maybe it doesn't yet.
(12:58):
Absolutely, that's crucial. First off, this is a
cross-sectional study. It's like taking a snapshot in
time across many people. It's powerful for finding
associations, but it can't fullycapture the longitudinal
dynamics how these things changewithin one person over years.
We infer the progression, but wedon't directly observe it start
to finish in the same individuals here.
(13:19):
OK. So trajectory is inferred, not
directly measured over time. Exactly, and while the
interpretations about the anti amyloid trials are really
compelling and fit the data well, they are still
interpretations based on these findings.
They'll need more direct validation, perhaps in
prospective studies or analysis of trial data itself.
Also, technically they grouped several different rare trim 2
(13:41):
risk variants together. This assumes they all have
similar biological effects, which might not be perfectly
true and could slightly underestimate the impact of
specific variants. The researchers acknowledged
this, noting it would likely bias results towards finding no
effect. So the fact they did find
significant effects is still strong, but it's a nuance.
Right. And any sample size issues?
(14:02):
Well, the overall sample was large, which is a major
strength, but the number of APOE4 homozygos, while sufficient to
find effects, is naturally smaller than the other groups.
However, the fact that they replicated the key ATOE 4
findings in two completely independent cohorts gives us
much greater confidence in thoseresults.
Replication is key. OK, so limitations acknowledged,
but the core findings seem robust, especially with the
(14:24):
replication. I think so.
Overall, this deep dive really reinforces that Alzheimer's
progression isn't this single monolithic path.
It's truly a complex interplay. Our specific genetic makeup,
like APOE, interim 2 status, andeven our biological sex can
dramatically shape when and how Tau pathology builds up and
spreads. And that fundamentally changes
(14:45):
our individual risk profile and quite possibly how we might
respond to different treatments.So going back to those two
individuals we imagined at the start, the one with rapid
progression, the other slower, this study gives us real
biological reasons why those different paths might exist.
It pinpoints specific roles for sex and genes at different
stages. Which leads to the big question,
(15:06):
what does this all mean for the future of personalized medicine
in Alzheimer's disease, Especially as the field pushes
towards intervening earlier before a significant cognitive
decline really sets in? This episode was based on an
Open Access article under the CCBY 4 Point O license.
You can find a direct link to the paper and the license in our
episode description. If you enjoyed this analysis,
(15:27):
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Thanks for listening and join usnext time as we explore more
science base by base.
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