February 24, 2025 • 28 mins
Things are changing in Alzheimer's research. We've got new tools and new ideas, and we want you to know about them. To kick off Salk’s “Year of Alzheimer’s,” hear how our scientists are bringing us closer to a more modern and personalized landscape of Alzheimer's diagnosis, treatment, and prevention.
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Episode Transcript
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(00:06):
Welcome to Beyond
Lab Walls, a podcastfrom the Salk Institute.
Join hosts Isabella Davis and NicoleMelnick on a journey
behind the scenes of the renowned Researchinstitute in San Diego, California.
We're taking you inside the labto hear the latest discoveries
and cutting edge neuroscience,plant biology, cancer, aging, and more.
(00:27):
Explore the fascinating world of sciencewhile listening to the stories
of the brilliant minds behind it.
Here at Salk, we'reunlocking the secrets of life itself
and sharing them beyond lab walls.
(00:54):
Hi, all.
I'm your co-host, Nicole,and we're going to shake things up
a little todayon this episode of Beyond Lab Walls.
We're going to tell a storythat is near and dear to our community.
So many of us have been affectedin some way by the challenges
of Alzheimer's diseaseand other forms of dementia.
Many have also felt frustratedby the pace of progress in finding a cure.
(01:17):
But things are changing in Alzheimer'sresearch.
We've got new tools and new ideas,
and we want you to know about them.
To mark this new chapter,the Salk Institute
has officially named 2025Our Year of Alzheimer's.
We'll be highlightingall the new ways that Salk scientists
are thinking about Alzheimer's,and how their efforts are bringing us
(01:37):
closer to a more modernand personalized landscape
of Alzheimer's diagnosis, treatment,and prevention.
In this episode of Beyond Lab Walls,we're sharing a story from a recent issue
of Inside Salk magazine,which helps paint this picture.
You'll hear from Annie Alessio, who shares
her experiencecaring for her mother through the disease.
(01:57):
And for many of our scientists
who are working tirelesslyto help families like hers.
So without further ado, here'sgetting to the root of Alzheimer's.
(02:26):
Annie Alessio was about to
start her junior yearat the University of San Diego
when her mother, Carol, was diagnosedwith early onset Alzheimer's disease.
I oh, my gosh,
I remember it like it was yesterdaywhen she walks through the door.
I remember we were at our house
and I can remember exactlywhere she's wearing this blue suit.
She she walked inand she told us what had happened.
(02:47):
And she said, I'm going to beat this.
But I have no doubt that
for like the next 14 years,she fought like hell.
If there was somebody at that timethat could have beat it,
oh, she would have been the one.
Carol Alessio had always beenan independent and strong willed woman.
In heryouth, the spunky Midwestern girl often
dreamed of a bigger and better lifeoutside of her small town.
(03:11):
At 18 years old,she bravely moved to Southern California,
where she eventually met her husband,Mike, and immersed herself in San Diego's
business and political scenes.
It was on a trip back home in
the summer of 2000that Carol was suddenly injured in a fall.
In the aftermath of the accident,family members began
to recall a few other peculiar incidentsfrom recent years
(03:33):
and ultimately encouraged herto undergo some tests.
The doctors soon discoveredabnormalities in her brain scans,
and the diagnosis came shortly thereafter.
Alzheimer's wasn't, you know,on the forefront of anybody's mind for it
to be like, well, this is what you have,or, you know, these are the signs.
We knew it had to do with memory loss,but we didn't know
(03:54):
about the behavioral issuesor the hallucinations.
There weren't websites or pamphletsexplaining these things to us,
so we didn't know what to.
Welcome to Beyond
Lab Walls, a podcastfrom the Salk Institute.
Join hosts IsabellaDavis and Nicole Milner on a journey
(04:15):
behind the scenes of the renowned researchinstitute in San Diego, California.
We're taking you inside the labto hear the latest discoveries
and cutting edge neuroscience,plant biology, cancer, aging, and more.
Explore the fascinating world of sciencewhile listening to the stories
of the brilliant minds behind it.
Here at Salkwere unlocking the secrets of life itself
(04:38):
and sharing them beyond lab walls.
Hi, all.
I'm your co-host, Nicole,and we're going to shake things up
(05:00):
a little todayon this episode of Beyond Lab Walls.
We're going to tell a storythat is near and dear to our community.
So many of us have been affectedin some way by the challenges
of Alzheimer's diseaseand other forms of dementia.
Many have also felt frustratedby the pace of progress in finding a cure.
But things are changing in Alzheimer'sresearch.
(05:21):
We've got new tools and new ideas,
and we want you to know about them.
To mark this new chapter.
The Salk Institute has officially named2025 Our Year of Alzheimer's.
We'll be highlightingall the new ways that Salk scientists
are thinking about Alzheimer's,and how their efforts are bringing us
closer to a more modernand personalized landscape
(05:42):
of Alzheimer's diagnosis, treatment,and prevention.
In this episode of Beyond Lab Walls,we're sharing a story from a recent issue
of Inside Salk Magazine,which helps paint this picture.
You'll hear from Annie Alessio, who shares
her experiencecaring for her mother through the disease.
And for many of our scientists
who are working tirelesslyto help families like hers.
(06:04):
So without further ado, here'sgetting to the root of Alzheimer's.
(06:28):
Annie Alessio was about to
start her junior yearat the University of San Diego
when her mother, Carol, was diagnosedwith early onset Alzheimer's disease.
I oh my gosh, I remember it like it wasyesterday when she walks through the door.
I remember we were at our house
and I can remember exactlywhat she's wearing, this voluminous suit.
She she walkedand she told us what had happened.
(06:49):
And she said, I'm going to beat this.
But I have no doubt that
for like the next 14 years,she fought like hell.
If there was somebody at that timethat could have beat it,
oh, she would have been the one.
CarolAlessio had always been an independent
and strong willed woman in heryouth, the spunky Midwestern girl
often dreamed of a bigger and better lifeoutside of her small town.
(07:12):
At 18 years old,she bravely moved to Southern California,
where she eventually mether husband, Mike,
and immersed herself in San Diego'sbusiness and political scenes.
It was on a trip back home in
the summer of 2000that Carol was suddenly injured in a fall.
In the aftermath of the accident,family members began
to recall a few other peculiar incidentsfrom recent years
(07:35):
and ultimately encouraged herto undergo some tests.
The doctors soon discoveredabnormalities in her brain scans,
and the diagnosis came shortly thereafter.
Alzheimer's wasn't, you know,on the forefront of anybody's mind
for it to be like, this is what you haveor, you know, and these are the signs.
We knew and had to do with memory loss,but we didn't know
(07:55):
about the behavioral issuesor the hallucinations.
There weren't websites or pamphletsexplaining
these things to us, so we didn't know what to expect.
And all of ourlives just kind of stopped.
Anniemoved back home to take care of her mother
(08:16):
in the years before, she was transferredto a nearby care facility
for the next 14 years,the family tried every medication
and rehabilitation strategyher doctor suggested,
but Carol's mental and physical healthcontinued to decline.
This perpetual struggle would becompletely discouraging for most people,
but Annie decided to channelher frustration into volunteer work
(08:40):
as a board member of the San DiegoAlzheimer's Association.
She met with local doctors,led multiple fundraisers,
and helped raise awareness of the disease.
August 2024 marked
the 10th anniversary of Carol's passing,and Annie hopes
to honor her mother's legacywith continued advocacy.
(09:00):
I want to fight even harder on her behalf,
she says,because I know that's what she would do
for. Annie'senthusiasm comes at a good time,
(09:23):
as the landscape of Alzheimer'sresearch is currently experiencing
a seismic shift after decades of ratherdisappointing progress.
Scientists and cliniciansare now reexamining the disease
with new tools and a fresh perspective.
A main source of stagnation in Alzheimer'sresearch
has been the overemphasison amyloid plaques and tangles.
(09:45):
These abnormal clumps of proteinsin the brain, or first observed by Alois
Alzheimer himself in 1906 and thus became
the defining biomarkers of the disease.
For decades, these proteinswere the focus of nearly all
Alzheimer's research, drug development,and clinical trials.
Many cases of the rare early onsetform of Alzheimer's, like Carol's,
(10:07):
can be directly linked to gene mutationsassociated with amyloid and tau proteins.
This was another early piece of evidencethat got scientists and clinicians
thinking these pathwaysmust be the source of the pathology.
But over the years, it's become clearthat only a small subset of Alzheimer's
patients actually have these particulargene mutations, and that not everyone
(10:27):
who has these mutationsgoes on to develop the disease.
So there must be other factors at play.
The old had really sufferedby having this monolithic
amyloidtau, which is really inhibiting people
from looking at other thingskind of directly related to that.
Then it wasn't going to be very important.
(10:48):
Says Salk professor Rusty Gage,who holds the Adler chair
for research on agerelated neurodegenerative disease.
It had such a hold on the fieldthat researchers had little opportunity
to study other ideas.
That has changed dramatically,and it is changing.
The current sense is that these plaquesand tangles represent specific genetic
subtypes of Alzheimer's, or otherwiseindicate a later stage of the disease
(11:12):
that is likely much more difficultto treat.
Scientists are now shifting their effortsto identify other sources of the disease.
Different genes, proteins and pathwaysthat, if treated
early enough, could have much more successin improving patient outcomes.
(11:34):
To get to the root of Alzheimer's,
Salk scientists are looking at the diseasefrom all angles
and incorporating the latest insightsfrom healthy aging science
through the unlocking HealthyAging initiative.
The institute is expanding its efforts
to understand aging on a more fundamentalbiological level.
One major goal of these projectsis to identify the cellular
(11:55):
and molecular processesthat contribute to aging in the brain.
Aging is the biggest risk factorfor neurodegenerative disease,
so much so that many assume onejust inevitably comes with the other.
And yet,everyone's aging experience is different.
And not everyone develops Alzheimer's.
So what makes the differencebetween mental fitness and frailty?
(12:19):
What goes on in our brains as we age?
And why does itsometimes lead to Alzheimer's?
For many diseases like cancer,
the risk of developing the disease
increases fairly steadily as we age, saysGerald Cheadle,
professor and Audrey Geisel Chairin biomedical science at Salt.
But there's a different trajectoryfor the risk of Alzheimer's,
(12:40):
and that it's nearly flatfor most of our lives.
And then it takes off around age 70.
In my mind,that means there's a distinct set of aging
related phenomenathat can happen around that point
and triggera quicker progression of Alzheimer's.
Cheadle is the director of the San DiegoNathan
Chalk Center,funded by the National Institute on Aging.
(13:02):
The center was launched in 2020to understand how intrinsic
and environmental factorscontribute to human aging.
Its goal is to learn
how these different factorsaffect each person's aging trajectory,
so that personalized interventionscan be developed to extend
their health span, or the numberof healthy years in their life.
We all age and we know as we age,
(13:24):
we slow down and we become weak,physically lose our senses.
We lose a little bitof cognitive ability blue.
And we have a higher riskfor diseases, right.
But I think what the breakthroughidea for Healthspan
was, peopleused to think it wasn't malleable.
You couldn't change.You couldn't change it.
But many, many experimentsin model organisms, in mice
(13:48):
and now even in humans,some if you understand the pathways
that are driving aging, if you knowthis biochemical or genetic pathways, now
you have targets to actually change them
and actually change the rate of aging.
And so the breakthrough was our abilityto know that we could actually do that,
not with the goal of making everybody livelike 50 years longer, but to just not go
(14:13):
through the same rate of declineand the same risk for disease.
When Salk scientistsdiscuss their aging research,
they often refer to the idea of an agingdashboard on each person's dashboard.
They imagine various gaugesreporting the health status of different
cells, tissues, organs, and even specificmolecular pathways in their body.
(14:34):
For some people,
aging might look like a steadydecline across all gauges,
while others might have 1 or 2 areasin which aging is taking a bigger toll.
In a futurein which these sorts of measurements
could be collected at every doctor'svisit.
Artificial intelligence could analyzeeach person's dashboard and predict
their risk of developing and aging relateddiseases like Alzheimer's.
(14:58):
The key is being able to not just treatthe symptoms of the disease
as they emerge, but proactively targetthe biggest sources of aging
in that person to delay or even prevent
the onset of disease altogether.
In the case of Alzheimer's, scientists arefinding that there are probably multiple
potential starting points for the disease,rather than one singular cause.
(15:20):
This means the solutionmay come down to identifying
which biological processor processes is being most affected
by aging in each patient,and targeting them as early as possible.
If we could slow the major pathwayscontributing
to someone'sneurological, aging, societal,
even just silly them 5 or 10 years,that could make the difference between
(15:42):
whether their final yearsare spent succumbing to Alzheimer's,
or if they can have that timewith their loved ones and eventually pass
in a less devastating manner.
(16:05):
So what are thesemajor brain aging pathways,
and how can we slow them down to preventdisease?
Gage, Sheetal and their colleaguesare hard at work figuring this out.
In 2018, the team was awarded$19.2 million by the American Heart
Association Allen Initiativeto launch a series of studies analyzing
the interactions between proteins,genes, epigenetics,
(16:28):
inflammation and metabolism,and Alzheimer's in the aging brain.
And so
this is a team effort.
Six years ago, and I picked up
people that were had expertisein different parts of it.
Says Gage, who leads the initiative.
So it's an amazing group of people fromdifferent disciplines working together.
(16:51):
There are no walls to this part, andwe're fun as we all learn from each other.
Gage and his team are
pioneers of a modern research toolfor modeling human brain aging.
In the lab.
In this approach, the researcherscollect skin samples from older adults,
plate them on petri dishes,and then use molecular tools
(17:12):
to convert the skin cellsdirectly into neurons or brain cells.
Recently, they advanced the technologyto create 3D models called brain
organoids, which include additional braincell types like microglia and astrocytes
to more accurately resemblehuman brain tissue.
Their key breakthrough is finding a wayto have these brain cells
(17:34):
retain the molecular signaturesof the patient's age,
making them incredibly valuablefor studying age related diseases.
Using these models, Gage's labcan compare the biology of brain cells
from Alzheimer's patients and age matchedhealthy adults.
In 2022, they published a study showingthat many neurons derived from Alzheimer's
(17:56):
patients exhibit an age relateddeterioration process called senescence.
As the cells age, they become
unable to produce enough energyto perform all their usual functions,
eventually losing eventhe physical characteristics of neurons.
In most cases, this much deteriorationwould cause cells to die,
(18:18):
but senescent cells actually stay alive
in this low energy zombie like state
and start to secreteinflammatory molecules.
These leaky signals ultimately damagethe surrounding tissue,
exacerbating the problemand leading to cognitive
decline.
To understand what triggersthese cells to enter senescence,
(18:41):
gates has drawn on Sheedy's experiencein mitochondrial biology,
colloquially referred to as the powerhouseof the cell.
Mitochondria convert energy from the foodwe eat into chemical energy
that our cells, tissues,and organs use to function.
Human neurons require a lot of energy.
(19:03):
So mitochondrial health is criticalfor normal brain function.
However, aging can damage mitochondriain many ways
and if left untreated,can lead to an energetic crisis.
Inflammation and neurodegeneration.
Gage Cheadle and other Salk scientistsare now studying
the various aging processesthat weaken mitochondria in the brain.
(19:26):
They're already seeing promising resultsfrom targeting these molecular pathways,
with existing drugs offeringhope for more effective treatments
in the future.
In another
line of research at social, scientistsare looking at the ways that non
neuronal brain cells, calledglia can also contribute to Alzheimer's.
(19:46):
Interestingly, when scientists comparethe gene expression profiles
of brain cells from Alzheimer's patientsto those of healthy older adults,
glial cells actually appear to be moreaffected by the disease than neurons.
SoC Associate ProfessorNicola Allen is an expert on a subtype
of glial cells called astrocytes,named for their star like shape.
(20:09):
Her lab is now uncovering the role thatastrocytes play in Alzheimer's disease.
Allen and her team have discovered
that astrocytes are crucial for shapingcommunication across the brain.
They mainly do thisby guiding the formation
and removal of synapses,where neurons meet
and share electrochemical signals.
Gene expression levelssuggest that in Alzheimer's patients,
(20:32):
astrocytes are less able to createor strengthen synapses.
While their ability to remove synapsesincreases,
this leads to a destabilizedand overly pruned synaptic network
that ultimately disruptsbrain communication.
Allen is now characterizinga class of proteins that astrocytes
use to encourage the formationof new synaptic connections.
(20:55):
Current experiments are testingwhether re expressing these proteins
in the Alzheimer's brain
can restore synaptic functionand delay disease progression.
Their initial resultsin mice are promising,
increasing the amount of these proteinsand astrocytes,
restore the number of synapses and memoryrelated brain areas,
and improved animal's performancein memory and spatial cognition.
(21:18):
Tasks.
The study
represents one of many cellularand molecular pathways
that Allen's team is exploringfor the treatment of Alzheimer's.
Other lines of work in the lab
are studying the relationshipbetween astrocytes and neuroinflammation.
Everyone isn't doing the same thinganymore.
And it is quite broad now.
And I think to me
(21:38):
that's the exciting part that peoplewill take different approaches.
Some will work, some won't work.
But we're going to learn a lot.
Another Salk
scientists studyinginflammation is Professor Susan Keck,
who co-directs Salk's new NeuroImmunology Initiative with Alan
Keck.
(21:58):
Researcherscentered on the immune system and cancer.
But at Sok, she also lends her expertiseto the study of aging and Alzheimer's.
So 90% of what we know about aging in
humans is from sampling blood, says Keck.
And the major changethat occurs in our blood
(22:18):
as we ageis we accumulate more memory T cells.
When the body
experiences an infection,the immune system produces
an army of cellsto find and kill the pathogen.
It also produces memory T cells,
whose job it is to remember the pathogen,
so that the immune system can recognizeand attack it even faster.
(22:40):
Next time.
But memory T cells are designed to respondnot only to that one
specific pathogen,but also to others that are similar to it.
This broad response is a smart strategyfor fighting infection
earlier in our lives.
But as we accumulate more memory T cellswith every infection, the net result is
(23:00):
a large population of overall responsiveimmune cells across the body.
Immunologiststhink this could be contributing
to the chronically higher levelsof inflammation seen in older adults.
Long Covid showed people the
lasting effects of that infection,says Keck.
But a lot of infectionshave long lasting effects,
(23:21):
and we still don't knowwhat they actually do to our tissues.
There'sprobably a lot more immune involvement
and maybe even direct immune involvementin the form of other immunity
in a lot of these neurodegenerativediseases.
Keck first got involved in Alzheimer'sresearch at Salk to help study microglia,
a type of immune cell found in the brain.
(23:43):
But the more she spoke with her colleaguesabout their experiments,
the more another question beganto consume her.
I was like, man,
you know, all these people are studyingthe brain, their same behavior.
They're not studying animals
in which they haven't experiencedthe immune system.
Referring to the sterile environmentthat laboratory mice
are traditionally housed in.
(24:04):
No one's really taking into accountthese additional accumulating immune cells
or coming into tissues, and how that couldmaybe be playing a factor
that was really kind of the impetuswith like,
well, let's try to createa more physiological model of aging
where we are actuallyexposing the immune system.
Tech is now
(24:24):
pioneering a new experimentalset up to introduce
common infectious pathogensinto the animal's living environment
in order to study the effects of infectionon aging and brain health.
Researchers across the instituteare eager to learn from her findings.
But amidst all the excitement, Keck notes,one of the reasons
these kinds of experimentsaren't done more often.
(24:46):
Because these are extremely expensive.
So first of all, it's always expensiveto do an aging experiment,
but now confound it with infecting miceand housing
these mice in biohazard conditions,because that's what we have to do.
So it's like double the price. So.
So that'sthat's one thing from a practical reality.
It's obstacles like these that solvesunlocking
(25:07):
Healthy Aging Initiativeis looking to overcome by generating
funding support to make this criticaland cutting edge research possible.
The Institute also providesa unique environment
that brings immunologists like Keckto the same rooms as neuroscientists
like Allen and Gage, which inspires theseideas in the first place.
Keck work
(25:28):
sets up a new paradigm for studyingthe biology of aging and Alzheimer's.
Against the natural backdrop of infection.
And she's not stopping there.
Now that we're establishingthese controlled ways
to introduce environmental factorsinto our experiments,
we can systematically buildon that to add things like exercise
or Western diets,incrementally creating conditions
(25:50):
that more accurately model our real world,she says.
Trying to study the effectsof these environmental and lifestyle
factors was previously consideredtoo difficult or uncontrolled
to be hard science,but now we have tools to do this
in a systematic, scientificand quantitative way.
(26:21):
With all this
scientific innovation emerging acrossthe institute, Salk researchers
are feeling hopeful about the futureof Alzheimer's treatments.
But it may look a littledifferent than we expected.
Our studies
are suggesting thatthere are different drivers of the disease
in different people, says Salk researchprofessor Pamela ma.
It's likely that there's not going to beone drug that treats everybody.
(26:45):
We're going to need different drugsfor different people.
There may be different individuals,different drivers of the disease.
So in some cases inflammationmight be a major driver, but in others
it could be mitochondrial dysfunctionor it could be some other
metabolic changes that leadto the dysfunction of nerve cells.
(27:08):
So I think that developing a varietyof different compounds
that perhaps is going to be neededto effectively treat the disease.
Ma was one of the first to take aging
into account in Alzheimer'sdrug discovery.
She was able to identify a class ofcompounds known as gyro neuro protectors,
that slowed brain aging in miceand protected their cognitive function.
(27:32):
Ma's work has led to the developmentof several new drugs,
currently in clinical trialsto treat Alzheimer's.
Her senses that Alzheimer's patientscan likely be sorted
into several groups based on biomarkersin their blood, and that different
classes of drugs could be prescribedbased on which group one falls into.
The good thing is, most of theseaging pathways don't have to be
(27:54):
completely corrected or restoredto make a difference, says Gage.
When aging affects a specific molecularpathway in a person, he says, it's
not that this pathway has dropped to0% functionality and has to be.
Welcome to Beyond
Lab Walls, a podcastfrom the Salk Institute.
Join hosts Isabella Davis and NicoleMelnick on a journey
behind the scenes of the renowned Researchinstitute in San Diego, California.
We're taking you inside the labto hear the latest discoveries
and cutting edge neuroscience,plant biology, cancer, aging, and more.
(00:27):
Explore the fascinating world of sciencewhile listening to the stories
of the brilliant minds behind it.
Here at Salk, we'reunlocking the secrets of life itself
and sharing them beyond lab walls.
(00:54):
Hi, all.
I'm your co-host, Nicole,and we're going to shake things up
a little todayon this episode of Beyond Lab Walls.
We're going to tell a storythat is near and dear to our community.
So many of us have been affectedin some way by the challenges
of Alzheimer's diseaseand other forms of dementia.
Many have also felt frustratedby the pace of progress in finding a cure.
(01:17):
But things are changing in Alzheimer'sresearch.
We've got new tools and new ideas,
and we want you to know about them.
To mark this new chapter,the Salk Institute
has officially named 2025Our Year of Alzheimer's.
We'll be highlightingall the new ways that Salk scientists
are thinking about Alzheimer's,and how their efforts are bringing us
(01:37):
closer to a more modernand personalized landscape
of Alzheimer's diagnosis, treatment,and prevention.
In this episode of Beyond Lab Walls,we're sharing a story from a recent issue
of Inside Salk magazine,which helps paint this picture.
You'll hear from Annie Alessio, who shares
her experiencecaring for her mother through the disease.
(01:57):
And for many of our scientists
who are working tirelesslyto help families like hers.
So without further ado, here'sgetting to the root of Alzheimer's.
(02:26):
Annie Alessio was about to
start her junior yearat the University of San Diego
when her mother, Carol, was diagnosedwith early onset Alzheimer's disease.
I oh, my gosh,
I remember it like it was yesterdaywhen she walks through the door.
I remember we were at our house
and I can remember exactlywhere she's wearing this blue suit.
She she walked inand she told us what had happened.
(02:47):
And she said, I'm going to beat this.
But I have no doubt that
for like the next 14 years,she fought like hell.
If there was somebody at that timethat could have beat it,
oh, she would have been the one.
Carol Alessio had always beenan independent and strong willed woman.
In heryouth, the spunky Midwestern girl often
dreamed of a bigger and better lifeoutside of her small town.
(03:11):
At 18 years old,she bravely moved to Southern California,
where she eventually met her husband,Mike, and immersed herself in San Diego's
business and political scenes.
It was on a trip back home in
the summer of 2000that Carol was suddenly injured in a fall.
In the aftermath of the accident,family members began
to recall a few other peculiar incidentsfrom recent years
(03:33):
and ultimately encouraged herto undergo some tests.
The doctors soon discoveredabnormalities in her brain scans,
and the diagnosis came shortly thereafter.
Alzheimer's wasn't, you know,on the forefront of anybody's mind for it
to be like, well, this is what you have,or, you know, these are the signs.
We knew it had to do with memory loss,but we didn't know
(03:54):
about the behavioral issuesor the hallucinations.
There weren't websites or pamphletsexplaining these things to us,
so we didn't know what to.
Welcome to Beyond
Lab Walls, a podcastfrom the Salk Institute.
Join hosts IsabellaDavis and Nicole Milner on a journey
(04:15):
behind the scenes of the renowned researchinstitute in San Diego, California.
We're taking you inside the labto hear the latest discoveries
and cutting edge neuroscience,plant biology, cancer, aging, and more.
Explore the fascinating world of sciencewhile listening to the stories
of the brilliant minds behind it.
Here at Salkwere unlocking the secrets of life itself
(04:38):
and sharing them beyond lab walls.
Hi, all.
I'm your co-host, Nicole,and we're going to shake things up
(05:00):
a little todayon this episode of Beyond Lab Walls.
We're going to tell a storythat is near and dear to our community.
So many of us have been affectedin some way by the challenges
of Alzheimer's diseaseand other forms of dementia.
Many have also felt frustratedby the pace of progress in finding a cure.
But things are changing in Alzheimer'sresearch.
(05:21):
We've got new tools and new ideas,
and we want you to know about them.
To mark this new chapter.
The Salk Institute has officially named2025 Our Year of Alzheimer's.
We'll be highlightingall the new ways that Salk scientists
are thinking about Alzheimer's,and how their efforts are bringing us
closer to a more modernand personalized landscape
(05:42):
of Alzheimer's diagnosis, treatment,and prevention.
In this episode of Beyond Lab Walls,we're sharing a story from a recent issue
of Inside Salk Magazine,which helps paint this picture.
You'll hear from Annie Alessio, who shares
her experiencecaring for her mother through the disease.
And for many of our scientists
who are working tirelesslyto help families like hers.
(06:04):
So without further ado, here'sgetting to the root of Alzheimer's.
(06:28):
Annie Alessio was about to
start her junior yearat the University of San Diego
when her mother, Carol, was diagnosedwith early onset Alzheimer's disease.
I oh my gosh, I remember it like it wasyesterday when she walks through the door.
I remember we were at our house
and I can remember exactlywhat she's wearing, this voluminous suit.
She she walkedand she told us what had happened.
(06:49):
And she said, I'm going to beat this.
But I have no doubt that
for like the next 14 years,she fought like hell.
If there was somebody at that timethat could have beat it,
oh, she would have been the one.
CarolAlessio had always been an independent
and strong willed woman in heryouth, the spunky Midwestern girl
often dreamed of a bigger and better lifeoutside of her small town.
(07:12):
At 18 years old,she bravely moved to Southern California,
where she eventually mether husband, Mike,
and immersed herself in San Diego'sbusiness and political scenes.
It was on a trip back home in
the summer of 2000that Carol was suddenly injured in a fall.
In the aftermath of the accident,family members began
to recall a few other peculiar incidentsfrom recent years
(07:35):
and ultimately encouraged herto undergo some tests.
The doctors soon discoveredabnormalities in her brain scans,
and the diagnosis came shortly thereafter.
Alzheimer's wasn't, you know,on the forefront of anybody's mind
for it to be like, this is what you haveor, you know, and these are the signs.
We knew and had to do with memory loss,but we didn't know
(07:55):
about the behavioral issuesor the hallucinations.
There weren't websites or pamphletsexplaining
these things to us, so we didn't know what to expect.
And all of ourlives just kind of stopped.
Anniemoved back home to take care of her mother
(08:16):
in the years before, she was transferredto a nearby care facility
for the next 14 years,the family tried every medication
and rehabilitation strategyher doctor suggested,
but Carol's mental and physical healthcontinued to decline.
This perpetual struggle would becompletely discouraging for most people,
but Annie decided to channelher frustration into volunteer work
(08:40):
as a board member of the San DiegoAlzheimer's Association.
She met with local doctors,led multiple fundraisers,
and helped raise awareness of the disease.
August 2024 marked
the 10th anniversary of Carol's passing,and Annie hopes
to honor her mother's legacywith continued advocacy.
(09:00):
I want to fight even harder on her behalf,
she says,because I know that's what she would do
for. Annie'senthusiasm comes at a good time,
(09:23):
as the landscape of Alzheimer'sresearch is currently experiencing
a seismic shift after decades of ratherdisappointing progress.
Scientists and cliniciansare now reexamining the disease
with new tools and a fresh perspective.
A main source of stagnation in Alzheimer'sresearch
has been the overemphasison amyloid plaques and tangles.
(09:45):
These abnormal clumps of proteinsin the brain, or first observed by Alois
Alzheimer himself in 1906 and thus became
the defining biomarkers of the disease.
For decades, these proteinswere the focus of nearly all
Alzheimer's research, drug development,and clinical trials.
Many cases of the rare early onsetform of Alzheimer's, like Carol's,
(10:07):
can be directly linked to gene mutationsassociated with amyloid and tau proteins.
This was another early piece of evidencethat got scientists and clinicians
thinking these pathwaysmust be the source of the pathology.
But over the years, it's become clearthat only a small subset of Alzheimer's
patients actually have these particulargene mutations, and that not everyone
(10:27):
who has these mutationsgoes on to develop the disease.
So there must be other factors at play.
The old had really sufferedby having this monolithic
amyloidtau, which is really inhibiting people
from looking at other thingskind of directly related to that.
Then it wasn't going to be very important.
(10:48):
Says Salk professor Rusty Gage,who holds the Adler chair
for research on agerelated neurodegenerative disease.
It had such a hold on the fieldthat researchers had little opportunity
to study other ideas.
That has changed dramatically,and it is changing.
The current sense is that these plaquesand tangles represent specific genetic
subtypes of Alzheimer's, or otherwiseindicate a later stage of the disease
(11:12):
that is likely much more difficultto treat.
Scientists are now shifting their effortsto identify other sources of the disease.
Different genes, proteins and pathwaysthat, if treated
early enough, could have much more successin improving patient outcomes.
(11:34):
To get to the root of Alzheimer's,
Salk scientists are looking at the diseasefrom all angles
and incorporating the latest insightsfrom healthy aging science
through the unlocking HealthyAging initiative.
The institute is expanding its efforts
to understand aging on a more fundamentalbiological level.
One major goal of these projectsis to identify the cellular
(11:55):
and molecular processesthat contribute to aging in the brain.
Aging is the biggest risk factorfor neurodegenerative disease,
so much so that many assume onejust inevitably comes with the other.
And yet,everyone's aging experience is different.
And not everyone develops Alzheimer's.
So what makes the differencebetween mental fitness and frailty?
(12:19):
What goes on in our brains as we age?
And why does itsometimes lead to Alzheimer's?
For many diseases like cancer,
the risk of developing the disease
increases fairly steadily as we age, saysGerald Cheadle,
professor and Audrey Geisel Chairin biomedical science at Salt.
But there's a different trajectoryfor the risk of Alzheimer's,
(12:40):
and that it's nearly flatfor most of our lives.
And then it takes off around age 70.
In my mind,that means there's a distinct set of aging
related phenomenathat can happen around that point
and triggera quicker progression of Alzheimer's.
Cheadle is the director of the San DiegoNathan
Chalk Center,funded by the National Institute on Aging.
(13:02):
The center was launched in 2020to understand how intrinsic
and environmental factorscontribute to human aging.
Its goal is to learn
how these different factorsaffect each person's aging trajectory,
so that personalized interventionscan be developed to extend
their health span, or the numberof healthy years in their life.
We all age and we know as we age,
(13:24):
we slow down and we become weak,physically lose our senses.
We lose a little bitof cognitive ability blue.
And we have a higher riskfor diseases, right.
But I think what the breakthroughidea for Healthspan
was, peopleused to think it wasn't malleable.
You couldn't change.You couldn't change it.
But many, many experimentsin model organisms, in mice
(13:48):
and now even in humans,some if you understand the pathways
that are driving aging, if you knowthis biochemical or genetic pathways, now
you have targets to actually change them
and actually change the rate of aging.
And so the breakthrough was our abilityto know that we could actually do that,
not with the goal of making everybody livelike 50 years longer, but to just not go
(14:13):
through the same rate of declineand the same risk for disease.
When Salk scientistsdiscuss their aging research,
they often refer to the idea of an agingdashboard on each person's dashboard.
They imagine various gaugesreporting the health status of different
cells, tissues, organs, and even specificmolecular pathways in their body.
(14:34):
For some people,
aging might look like a steadydecline across all gauges,
while others might have 1 or 2 areasin which aging is taking a bigger toll.
In a futurein which these sorts of measurements
could be collected at every doctor'svisit.
Artificial intelligence could analyzeeach person's dashboard and predict
their risk of developing and aging relateddiseases like Alzheimer's.
(14:58):
The key is being able to not just treatthe symptoms of the disease
as they emerge, but proactively targetthe biggest sources of aging
in that person to delay or even prevent
the onset of disease altogether.
In the case of Alzheimer's, scientists arefinding that there are probably multiple
potential starting points for the disease,rather than one singular cause.
(15:20):
This means the solutionmay come down to identifying
which biological processor processes is being most affected
by aging in each patient,and targeting them as early as possible.
If we could slow the major pathwayscontributing
to someone'sneurological, aging, societal,
even just silly them 5 or 10 years,that could make the difference between
(15:42):
whether their final yearsare spent succumbing to Alzheimer's,
or if they can have that timewith their loved ones and eventually pass
in a less devastating manner.
(16:05):
So what are thesemajor brain aging pathways,
and how can we slow them down to preventdisease?
Gage, Sheetal and their colleaguesare hard at work figuring this out.
In 2018, the team was awarded$19.2 million by the American Heart
Association Allen Initiativeto launch a series of studies analyzing
the interactions between proteins,genes, epigenetics,
(16:28):
inflammation and metabolism,and Alzheimer's in the aging brain.
And so
this is a team effort.
Six years ago, and I picked up
people that were had expertisein different parts of it.
Says Gage, who leads the initiative.
So it's an amazing group of people fromdifferent disciplines working together.
(16:51):
There are no walls to this part, andwe're fun as we all learn from each other.
Gage and his team are
pioneers of a modern research toolfor modeling human brain aging.
In the lab.
In this approach, the researcherscollect skin samples from older adults,
plate them on petri dishes,and then use molecular tools
(17:12):
to convert the skin cellsdirectly into neurons or brain cells.
Recently, they advanced the technologyto create 3D models called brain
organoids, which include additional braincell types like microglia and astrocytes
to more accurately resemblehuman brain tissue.
Their key breakthrough is finding a wayto have these brain cells
(17:34):
retain the molecular signaturesof the patient's age,
making them incredibly valuablefor studying age related diseases.
Using these models, Gage's labcan compare the biology of brain cells
from Alzheimer's patients and age matchedhealthy adults.
In 2022, they published a study showingthat many neurons derived from Alzheimer's
(17:56):
patients exhibit an age relateddeterioration process called senescence.
As the cells age, they become
unable to produce enough energyto perform all their usual functions,
eventually losing eventhe physical characteristics of neurons.
In most cases, this much deteriorationwould cause cells to die,
(18:18):
but senescent cells actually stay alive
in this low energy zombie like state
and start to secreteinflammatory molecules.
These leaky signals ultimately damagethe surrounding tissue,
exacerbating the problemand leading to cognitive
decline.
To understand what triggersthese cells to enter senescence,
(18:41):
gates has drawn on Sheedy's experiencein mitochondrial biology,
colloquially referred to as the powerhouseof the cell.
Mitochondria convert energy from the foodwe eat into chemical energy
that our cells, tissues,and organs use to function.
Human neurons require a lot of energy.
(19:03):
So mitochondrial health is criticalfor normal brain function.
However, aging can damage mitochondriain many ways
and if left untreated,can lead to an energetic crisis.
Inflammation and neurodegeneration.
Gage Cheadle and other Salk scientistsare now studying
the various aging processesthat weaken mitochondria in the brain.
(19:26):
They're already seeing promising resultsfrom targeting these molecular pathways,
with existing drugs offeringhope for more effective treatments
in the future.
In another
line of research at social, scientistsare looking at the ways that non
neuronal brain cells, calledglia can also contribute to Alzheimer's.
(19:46):
Interestingly, when scientists comparethe gene expression profiles
of brain cells from Alzheimer's patientsto those of healthy older adults,
glial cells actually appear to be moreaffected by the disease than neurons.
SoC Associate ProfessorNicola Allen is an expert on a subtype
of glial cells called astrocytes,named for their star like shape.
(20:09):
Her lab is now uncovering the role thatastrocytes play in Alzheimer's disease.
Allen and her team have discovered
that astrocytes are crucial for shapingcommunication across the brain.
They mainly do thisby guiding the formation
and removal of synapses,where neurons meet
and share electrochemical signals.
Gene expression levelssuggest that in Alzheimer's patients,
(20:32):
astrocytes are less able to createor strengthen synapses.
While their ability to remove synapsesincreases,
this leads to a destabilizedand overly pruned synaptic network
that ultimately disruptsbrain communication.
Allen is now characterizinga class of proteins that astrocytes
use to encourage the formationof new synaptic connections.
(20:55):
Current experiments are testingwhether re expressing these proteins
in the Alzheimer's brain
can restore synaptic functionand delay disease progression.
Their initial resultsin mice are promising,
increasing the amount of these proteinsand astrocytes,
restore the number of synapses and memoryrelated brain areas,
and improved animal's performancein memory and spatial cognition.
(21:18):
Tasks.
The study
represents one of many cellularand molecular pathways
that Allen's team is exploringfor the treatment of Alzheimer's.
Other lines of work in the lab
are studying the relationshipbetween astrocytes and neuroinflammation.
Everyone isn't doing the same thinganymore.
And it is quite broad now.
And I think to me
(21:38):
that's the exciting part that peoplewill take different approaches.
Some will work, some won't work.
But we're going to learn a lot.
Another Salk
scientists studyinginflammation is Professor Susan Keck,
who co-directs Salk's new NeuroImmunology Initiative with Alan
Keck.
(21:58):
Researcherscentered on the immune system and cancer.
But at Sok, she also lends her expertiseto the study of aging and Alzheimer's.
So 90% of what we know about aging in
humans is from sampling blood, says Keck.
And the major changethat occurs in our blood
(22:18):
as we ageis we accumulate more memory T cells.
When the body
experiences an infection,the immune system produces
an army of cellsto find and kill the pathogen.
It also produces memory T cells,
whose job it is to remember the pathogen,
so that the immune system can recognizeand attack it even faster.
(22:40):
Next time.
But memory T cells are designed to respondnot only to that one
specific pathogen,but also to others that are similar to it.
This broad response is a smart strategyfor fighting infection
earlier in our lives.
But as we accumulate more memory T cellswith every infection, the net result is
(23:00):
a large population of overall responsiveimmune cells across the body.
Immunologiststhink this could be contributing
to the chronically higher levelsof inflammation seen in older adults.
Long Covid showed people the
lasting effects of that infection,says Keck.
But a lot of infectionshave long lasting effects,
(23:21):
and we still don't knowwhat they actually do to our tissues.
There'sprobably a lot more immune involvement
and maybe even direct immune involvementin the form of other immunity
in a lot of these neurodegenerativediseases.
Keck first got involved in Alzheimer'sresearch at Salk to help study microglia,
a type of immune cell found in the brain.
(23:43):
But the more she spoke with her colleaguesabout their experiments,
the more another question beganto consume her.
I was like, man,
you know, all these people are studyingthe brain, their same behavior.
They're not studying animals
in which they haven't experiencedthe immune system.
Referring to the sterile environmentthat laboratory mice
are traditionally housed in.
(24:04):
No one's really taking into accountthese additional accumulating immune cells
or coming into tissues, and how that couldmaybe be playing a factor
that was really kind of the impetuswith like,
well, let's try to createa more physiological model of aging
where we are actuallyexposing the immune system.
Tech is now
(24:24):
pioneering a new experimentalset up to introduce
common infectious pathogensinto the animal's living environment
in order to study the effects of infectionon aging and brain health.
Researchers across the instituteare eager to learn from her findings.
But amidst all the excitement, Keck notes,one of the reasons
these kinds of experimentsaren't done more often.
(24:46):
Because these are extremely expensive.
So first of all, it's always expensiveto do an aging experiment,
but now confound it with infecting miceand housing
these mice in biohazard conditions,because that's what we have to do.
So it's like double the price. So.
So that'sthat's one thing from a practical reality.
It's obstacles like these that solvesunlocking
(25:07):
Healthy Aging Initiativeis looking to overcome by generating
funding support to make this criticaland cutting edge research possible.
The Institute also providesa unique environment
that brings immunologists like Keckto the same rooms as neuroscientists
like Allen and Gage, which inspires theseideas in the first place.
Keck work
(25:28):
sets up a new paradigm for studyingthe biology of aging and Alzheimer's.
Against the natural backdrop of infection.
And she's not stopping there.
Now that we're establishingthese controlled ways
to introduce environmental factorsinto our experiments,
we can systematically buildon that to add things like exercise
or Western diets,incrementally creating conditions
(25:50):
that more accurately model our real world,she says.
Trying to study the effectsof these environmental and lifestyle
factors was previously consideredtoo difficult or uncontrolled
to be hard science,but now we have tools to do this
in a systematic, scientificand quantitative way.
(26:21):
With all this
scientific innovation emerging acrossthe institute, Salk researchers
are feeling hopeful about the futureof Alzheimer's treatments.
But it may look a littledifferent than we expected.
Our studies
are suggesting thatthere are different drivers of the disease
in different people, says Salk researchprofessor Pamela ma.
It's likely that there's not going to beone drug that treats everybody.
(26:45):
We're going to need different drugsfor different people.
There may be different individuals,different drivers of the disease.
So in some cases inflammationmight be a major driver, but in others
it could be mitochondrial dysfunctionor it could be some other
metabolic changes that leadto the dysfunction of nerve cells.
(27:08):
So I think that developing a varietyof different compounds
that perhaps is going to be neededto effectively treat the disease.
Ma was one of the first to take aging
into account in Alzheimer'sdrug discovery.
She was able to identify a class ofcompounds known as gyro neuro protectors,
that slowed brain aging in miceand protected their cognitive function.
(27:32):
Ma's work has led to the developmentof several new drugs,
currently in clinical trialsto treat Alzheimer's.
Her senses that Alzheimer's patientscan likely be sorted
into several groups based on biomarkersin their blood, and that different
classes of drugs could be prescribedbased on which group one falls into.
The good thing is, most of theseaging pathways don't have to be
(27:54):
completely corrected or restoredto make a difference, says Gage.
When aging affects a specific molecularpathway in a person, he says, it's
not that this pathway has dropped to0% functionality and has to be.
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