00;00;06;06 – 00;00;33;09
Podcast introduction:
Welcome to Beyond Lab Walls, a podcast from the Salk Institute. Join hosts Isabella Davis and Nicole Mlynaryk on a journey behind the scenes of the renowned research institute in San Diego, California. We’re taking you inside the lab to hear the latest discoveries and cutting-edge neuroscience, plant biology, cancer, aging, and more. Explore the fascinating world of science while listening to the stories of the brilliant minds behind it. Here at Salk, we’re unlocking the secrets of life itself and sharing them beyond lab walls.
00;00;54;25 – 00;01;16;29
Nicole:
Hi, all. I’m your co-host, Nicole, and we’re going to shake things up a little today on this episode of Beyond Lab Walls. We’re going to tell a story that is near and dear to our community. So many of us have been affected in some way by the challenges of Alzheimer’s disease and other forms of dementia. Many have also felt frustrated by the pace of progress in finding a cure.
00;01;17;01 – 00;01;44;13
But things are changing in Alzheimer’s research. 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 2025 our “Year of Alzheimer’s.” We’ll be highlighting all the new ways that Salk scientists are thinking about Alzheimer’s, and how their efforts are bringing us closer to a more modern and personalized landscape of Alzheimer’s diagnosis, treatment, and prevention.
00;01;44;16 – 00;02;26;22
Nicole:
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 experience caring for her mother through the disease. And for many of our scientists who are working tirelessly to help families like hers. So without further ado, here’s getting to the root of Alzheimer’s.
00;02;26;25 – 00;02;35;09
Nicole:
Annie Alessio was about to start her junior year at the University of San Diego when her mother, Carol, was diagnosed with early onset Alzheimer’s disease.
00;02;35;12 – 00;02;37;17
Annie Alessio:
I, oh, my gosh, I remember it like it was yesterday when she walked through the door. I remember we were at our house and I can remember exactly what she was wearing, this blue pantsuit. She walked in and she told us what had happened and she said, ‘I’m going to beat this.’ But I have no doubt that for like the next 14 years, she fhought like hell. If there was somebody at that time that could have beat it, oh, she would have been the one.
00;03;00;15 – 00;03;26;04
Nicole:
Carol Alessio had always been an independent and strong-willed woman. In her youth, the spunky Midwestern girl often dreamed of a bigger and better life outside of her small town. 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.
00;03;26;06 – 00;03;43;10
Nicole:
It was on a trip back home in the summer of 2000 that Carol was suddenly injured in a fall. In the aftermath of the accident, family members began to recall a few other peculiar incidents from recent years and ultimately encouraged her to undergo some tests. The doctors soon discovered abnormalities in her brain scans, and the diagnosis came shortly thereafter.
00;03;43;12 – 00;03;44;13
Annie Alessio:
Alzheimer’s wasn’t 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.
00;03;51;08 – 00;04;12;21
Nicole:
“We knew it had to do with memory loss,” she says, “but we didn’t know about the behavioral issues or the hallucinations. There weren’t websites or pamphlets explaining these things to us, so we didn’t know what to expect. And all of our lives just kind of stopped.”
00;04;12;23 – 00;04;42;12
Nicole:
Annie moved back home to take care of her mother. In the years before, she was transferred to a nearby care facility for the next 14 years, the family tried every medication and rehabilitation strategy her doctor suggested. But Carol’s mental and physical health continued to decline. This perpetual struggle would be completely discouraging for most people, but Annie decided to channel her frustration into volunteer work as a board member of the San Diego Alzheimer’s Association. She met with local doctors, led multiple fundraisers, and helped raise awareness of the disease.
00;04;42;14 – 00;05;18;17
Nicole:
August 2024 marked the 10th anniversary of Carol’s passing, and Annie hopes to honor her mother’s legacy with continued advocacy.
“I want to fight even harder on her behalf,” she says, “because I know that’s what she would do.”
00;05;18;20 – 00;05;54;17
Nicole:
Annie’s enthusiasm comes at a good time. As the landscape of Alzheimer’s research is currently experiencing a seismic shift, after decades of rather disappointing progress, scientists and clinicians are now reexamining the disease with new tools and a fresh perspective.
A main source of stagnation in Alzheimer’s research has been the overemphasis on amyloid plaques and tangles. These abnormal clumps of proteins in the brain were first observed by Alois Alzheimer himself in 1906, and thus became the defining biomarkers of the disease.
00;05;54;20 – 00;06;17;27
Nicole:
For decades, these proteins were the focus of nearly all Alzheimer’s research, drug development, and clinical trials. Many cases of the rare early onset form of Alzheimer’s, like Carol’s, can be directly linked to gene mutations associated with amyloid and tau proteins. This was another early piece of evidence that got scientists and clinicians thinking these pathways must be the source of the pathology.
00;06;17;29 – 00;06;32;06
Nicole:
But over the years, it’s become clear that only a small subset of Alzheimer’s patients actually have these particular gene mutations, and that not everyone who has these mutations goes on to develop the disease. So there must be other factors at play.
00;06;32;08 – 00;06;47;05
Rusty Gage:
The field has really suffered by having this monolithic amyloid tau, which really inhibited people from looking at other things. If it wasn’t related to that, then it wasn’t going to be very important.
00;06;47;07 – 00;06;59;17
Nicole:
Says Salk professor Rusty Gage, who holds the Adler Chair for research on age-related neurodegenerative disease.
00;06;59;19 – 00;07;02;12
Rusty Gage:
It had such a hold on the field that researchers had little opportunity to study other ideas. That has changed dramatically and is changing.
00;07;02;15 – 00;07;32;20
Nicole:
The current sense is that these plaques and tangles represent specific genetic subtypes of Alzheimer’s, or otherwise indicate a later stage of the disease that is likely much more difficult to treat. Scientists are now shifting their efforts to identify other sources of the disease different genes, proteins and pathways that, if treated early enough, could have much more success in improving patient outcomes.
00;07;32;23 – 00;07;57;26
Nicole:
To get to the root of Alzheimer’s, Salk scientists are looking at the disease from all angles and incorporating the latest insights from healthy aging science through the Unlocking Healthy Aging Initiative. The institute is expanding its efforts to understand aging on a more fundamental biological level. One major goal of these projects is to identify the cellular and molecular processes that contribute to aging in the brain.
00;07;57;28 – 00;08;23;15
Nicole:
Aging is the biggest risk factor for neurodegenerative disease. So much so that many assume one just inevitably comes with the other. And yet everyone’s aging experience is different. And not everyone develops Alzheimer’s. So what makes the difference between mental fitness and frailty? What goes on in our brains as we age? And why does it sometimes lead to Alzheimer’s?
00;08;23;17 – 00;08;50;08
Nicole:
“For many diseases like cancer, the risk of developing the disease increases fairly steadily as we age,” says Gerald Shadel, professor and Audrey Geisel Chair in Biomedical Science at Salk, “but there’s a different trajectory for the risk of Alzheimer’s, and that it’s nearly flat for 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 phenomena that can happen around that point and trigger a quicker progression of Alzheimer’s.”
00;08;50;11 – 00;09;15;24
Nicole:
Shadel is the director of the San Diego Nathan Chalk Center, funded by the National Institute on Aging. The center was launched in 2020 to understand how intrinsic and environmental factors contribute to human aging.
00;09;15;26 – 00;09;27;14
Nicole:
Its goal is to learn how these different factors affect each person’s aging trajectory, so that personalized interventions can be developed to extend their health span, or the number of healthy years in their life.
00;09;27;20 – 00;09;50;24
Gerald Shadel:
We all age and we know as we age, we slow down and we become weak, physically lose our senses. We lose a little bit of cognitive ability blue. And we have a higher risk for diseases. Right. But I think what the breakthrough idea for healthy was, people used to think it wasn’t malleable. You couldn’t change it.
00;09;50;26 – 00;10;24;17
Gerald Shadel:
But many experiments in model organisms in mice and now even in humans, show if you understand the pathways that are driving aging, if you know the 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 ability to know that we could actually do that, not with the goal of making everybody live like 15 years longer, but to just not go through the same rate of decline and the same risk for disease.
00;10;24;19 – 00;10;51;29
Nicole:
When Salk scientists discuss their aging research, they often refer to the idea of an aging dashboard on each person’s dashboard. They imagine various gauges reporting the health status of different cells, tissues, organs, and even specific molecular pathways in their body. For some people, aging might look like a steady decline across all gauges, while others might have 1 or 2 areas in which aging is taking a bigger toll.
00;10;52;01 – 00;11;18;29
Nicole:
In a future in which these sorts of measurements could be collected at every doctor’s visit, artificial intelligence could analyze each person’s dashboard and predict their risk of developing and aging related diseases like Alzheimer’s. The key is being able to not just treat the symptoms of the disease as they emerge, but proactively target the biggest sources of aging in that person to delay or even prevent the onset of disease altogether.
00;11;19;02 – 00;12;11;27
Nicole:
In the case of Alzheimer’s, scientists are finding that there are probably multiple potential starting points for the disease, rather than one singular cause. This means the solution may come down to identifying which biological process or processes is being most affected by aging in each patient, and targeting them as early as possible. If we could slow the major pathways contributing to someone’s neurological, aging, societal, even just silly them 5 or 10 years, that could make the difference between whether their final years are spent succumbing to Alzheimer’s, or if they can have that time with their loved ones and eventually pass in a less devastating manner.
00;12;12;00 – 00;12;40;12
Nicole:
So what are these major brain aging pathways, and how can we slow them down to prevent disease? Gage, Sheetal and their colleagues are hard at work figuring this out. In 2018, the team was awarded $19.2 million by the American Heart Association and Allen Initiative to launch a series of studies analyzing the interactions between proteins, genes, epigenetics, inflammation, and metabolism, and Alzheimer’s in the aging brain.
00;12;40;15 – 00;12;50;27
Rusty Gage:
This is a team effort that started six years ago, and I picked up people that had expertise in different parts of it.
00;12;50;29 – 00;12;52;26
Nicole:
Says Gage, who leads the initiative.
00;12;52;27 – 00;13;04;23
Rusty Gage:
So it’s an amazing group of people from different disciplines working together. There are no walls keeping us apart, and what’s fun is we all learn from each other.
00;13;04;26 – 00;13;37;27
Nicole:
Gage and his team are pioneers of a modern research tool for modeling human brain aging in the lab. In this approach, the researchers collect skin samples from older adults, plate them on petri dishes, and then use molecular tools to convert the skin cells directly into neurons or brain cells. Recently, they advanced the technology to create 3D models called brain organoids, which include additional brain cell types like microglia and astrocytes to more accurately resemble human brain tissue.
00;13;37;29 – 00;14;10;07
Nicole:
Their key breakthrough is finding a way to have these brain cells retain the molecular signatures of the patient’s age, making them incredibly valuable for studying age related diseases. Using these models, Gage’s lab can compare the biology of brain cells from Alzheimer’s patients and age matched healthy adults. In 2022, they published a study showing that many neurons derived from Alzheimer’s patients exhibit an age related deterioration process called senescence.
00;14;10;10 – 00;14;44;14
Nicole:
As the cells age, they become unable to produce enough energy to perform all their usual functions, eventually losing even the physical characteristics of neurons. In most cases, this much deterioration would cause cells to die, but senescent cells actually stay alive in this low energy, zombie like state and start to secrete inflammatory molecules. These leaky signals ultimately damage the surrounding tissue, exacerbating the problem and leading to cognitive decline.
00;14;44;16 – 00;15;07;04
Nicole:
To understand what triggers these cells to enter senescence, Gage has drawn on Shadel’s experience in mitochondrial biology, colloquially referred to as the powerhouse of the cell. Mitochondria convert energy from the food we eat into chemical energy that our cells, tissues, and organs use to function.
00;15;07;06 – 00;15;44;19
Nicole:
Human neurons require a lot of energy. So mitochondrial health is critical for normal brain function. However, aging can damage mitochondria in many ways and if left untreated, can lead to an energetic crisis. Inflammation and neurodegeneration. Gage Cheadle and other Salk scientists are now studying the various aging processes that weaken mitochondria in the brain. They’re already seeing promising results from targeting these molecular pathways, with existing drugs offering hope for more effective treatments in the future.
00;15;44;21 – 00;16;16;03
Nicole:
In another line of research at Salk, scientists are looking at the ways that non-neuronal brain cells, called glia can also contribute to Alzheimer’s. Interestingly, when scientists compare the gene expression profiles of brain cells from Alzheimer’s patients to those of healthy older adults, glial cells actually appear to be more affected by the disease than neurons. Salk Associate Professor Nicola Allen is an expert on a subtype of glial cells called astrocytes, named for their star-like shape.
00;16;16;05 – 00;16;42;08
Nicole:
Her lab is now uncovering the role that astrocytes play in Alzheimer’s disease. Allen and her team have discovered that astrocytes are crucial for shaping communication across the brain. They mainly do this by guiding the formation and removal of synapses, where neurons meet and share electrochemical signals. Gene expression levels suggest that in Alzheimer’s patients, astrocytes are less able to create or strengthen synapses, while their ability to remove synapses increases.
00;16;42;16 – 00;17;11;24
Nicole:
This leads to a destabilized and overly pruned synaptic network that ultimately disrupts brain communication. Allen is now characterizing a class of proteins the astrocytes use to encourage the formation of new synaptic connections. Current experiments are testing whether re-expressing these proteins in the Alzheimer’s brain can restore synaptic function and delay disease progression.
00;17;11;26 – 00;17;28;10
Nicole:
Their initial results in mice are promising, increasing the amount of these proteins and astrocytes restored the number of synapses and memory related brain areas, and improved animals’ performance in memory and spatial cognition tasks.
00;17;28;12 – 00;17;41;00
Nicole:
The study represents one of many cellular and molecular pathways that Allen’s team is exploring for the treatment of Alzheimer’s. Other lines of work in the lab are studying the relationship between astrocytes and neuroinflammation.
00;17;41;03 – 00;17;55;26
Nicola Allen:
Everyone isn’t doing the same thing anymore, and it is quite broad now. And I think to me that’s the exciting part that people will take different approaches. Some will work, some won’t work. But we’re going to learn a lot.
00;17;55;29 – 00;18;13;23
Nicole:
Another Salk scientist studying inflammation is Professor Susan Kaech, who co-directs Salk’s new Neuroimmunology Initiative with Allen. Kaech’s research is centered on the immune system and cancer. But at Salk, she also lends her expertise to the study of aging and Alzheimer’s.
00;18;13;26 – 00;18;30;12
Susan Kaech:
So 90% of what we know about aging in humans is from sampling blood. And the major change that occurs in our blood as we age is we accumulate more memory T cells.
00;18;30;15 – 00;18;57;04
Nicole:
When the body experiences an infection, the immune system produces an army of cells to 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 recognize and attack it even faster next time. But memory T cells are designed to respond not only to that one specific pathogen, but also to others that are similar to it.
00;18;57;07 – 00;19;25;24
Nicole:
This broad response is a smart strategy for fighting infection earlier in our lives. But as we accumulate more memory T cells with every infection, the net result is a large population of over responsive immune cells across the body. Immunologists think this could be contributing to the chronically higher levels of inflammation seen in older adults.
00;19;25;26 – 00;19;31;26
Nicole:
“Long Covid showed people the lasting effects of that infection,” says Kaech, “but a lot of infections have long-lasting effects, and we still don’t know what they actually do to our tissues.”
00;19;31;28 – 00;19;42;03
Susan Kaech:
There’s probably a lot more immune involvement and maybe even direct immune involvement in the form of other immunity in a lot of these neurodegenerative diseases.
00;19;42;07 – 00;19;56;11
Nicole:
Kaech first got involved in Alzheimer’s research at Salk to help study microglia, a type of immune cell found in the brain. But the more she spoke with her colleagues about their experiments, the more another question began to consume her.
00;19;56;13 – 00;20;06;20
Susan Kaech:
I was like, man, you know, all these people are studying the brain. They’re studying behavior. They’re not studying animals in which they haven’t experienced the immune system.
00;20;06;23 – 00;20;10;23
Nicole:
Referring to the sterile environment that laboratory mice are traditionally housed in.
00;20;10;28 – 00;20;30;21
Susan Kaech:
No one’s really taking into account these additional accumulating immune cells or coming into tissues, and how that could maybe be playing a factor that was really kind of the impetus with like, well, let’s try to create a more physiological model of aging where we are actually exposing the immune system.
00;20;30;24 – 00;20;53;00
Nicole:
Kaech is now pioneering a new experimental set up to introduce common infectious pathogens into the animal’s living environment in order to study the effects of infection on aging and brain health. Researchers across the institute are eager to learn from her findings. But amidst all the excitement, Kaech notes, one of the reasons these kinds of experiments aren’t done more often.
00;20;53;03 – 00;21;11;26
Susan Kaech:
Well because these are extremely expensive. So first of all, it’s always expensive to do an aging experiment, but now confound it with infecting mice and housing these mice in biohazardous conditions, because that’s what we have to do. So it’s like double the price.
00;21;11;28 – 00;21;42;11
Nicole:
It’s obstacles like these that Salk’s Unlocking Healthy Aging Initiative is looking to overcome by generating funding support to make this critical and cutting-edge research possible. The Institute also provides a unique environment that brings immunologists like Keck to the same rooms as neuroscientists like Allen and Gage, which inspires these ideas in the first place. Kaech’s work sets up a new paradigm for studying the biology of aging and Alzheimer’s against the natural backdrop of infection. And she’s not stopping there.
00;21;42;14 – 00;22;11;06
Nicole:
“Now that we’re establishing these controlled ways to introduce environmental factors into our experiments, we can systematically build on that, to add things like exercise or Western diets, incrementally creating conditions that more accurately model our real world,” she says. “Trying to study the effects of these environmental and lifestyle factors was previously considered too difficult or uncontrolled to be hard science, but now we have tools to do this in a systematic, scientific, and quantitative way.”
00;22;28;11 – 00;22;49;13
Nicole:
With all this scientific innovation emerging across the institute, Salk researchers are feeling hopeful about the future of Alzheimer’s treatments. But it may look a little different than we expected.
00;22;49;13 – 00;22;51;29
Pamela Mahr:
“Our studies are suggesting that there are different drivers of the disease in different people,” says Salk Research Professor Pamela Mahr. “It’s likely that there’s not going to be one drug that treats everybody. We’re going to need different drugs for different people. There may be different individuals with different drivers of the disease. So in some cases inflammation might be a major driver, but in others it could be mitochondrial dysfunction. Or it could be some other metabolic changes that lead to the dysfunction of nerve cells. So I think that developing a variety of different compounds that perhaps is going to be needed to effectively treat the disease.”
00;23;24;18 – 00;23;58;08
Nicole:
Mahr was one of the first to take aging into account in Alzheimer’s drug discovery. She was able to identify a class of compounds known as gero-neuro-protectors that slowed brain aging in mice and protected their cognitive function. Mahr’s work has led to the development of several new drugs currently in clinical trials to treat Alzheimer’s. Her sense is that Alzheimer’s patients can likely be sorted into several groups based on biomarkers in their blood, and that different classes of drugs could be prescribed based on which group one falls into.
00;23;58;11 – 00;24;22;10
Nicole:
“The good thing is, most of these aging pathways don’t have to be completely corrected or restored to make a difference,” says Gage. When aging affects a specific molecular pathway in a person, he says, it’s not that this pathway has dropped to 0% functionality and has to be recovered back to 100%. It may be that by a certain age, that process is already hovering around 50% in most people.
00;24;22;12 – 00;24;48;21
Nicole:
But if things go lower than, say, 30%, that’s when Alzheimer’s may start to kick in. This means that if a medication or lifestyle change could target that specific pathway in a person and get it back up and running around even 40%, that might be enough to prevent the onset of the disease. It’s helpful that many of these fundamental aging pathways affect many aspects of our health at once, says shadow.
00;24;48;23 – 00;25;04;26
Nicole:
So just by delaying aging, you’ll likely delay many different things that could go wrong in the brain. While there is much work left to be done, this new perspective on Alzheimer’s research is finally paving the way to understanding its various root causes and how each can be best treated.
00;25;04;28 – 00;25;50;29
Rusty Gage:
I think I’m more hopeful now for real therapeutics dealing with the cell molecular biology of the disease than ever before, absolutely. We will see disease modifying medication for Alzheimer’s disease or for, let’s say, dementia, in the near future, and it won’t be just a decrease in the rate of decline, it will be halting and improving cognitive performance.
00;25;51;02 – 00;25;58;01
Nicole:
In reflecting on her family’s experience with Alzheimer’s. Annie Alessio feels a certain kinship with its researchers.
00;25;58;03 – 00;26;32;11
Annie Alessio:
We’ll never not be grateful for, you know, all of the research that is continually being done. Again, I don’t know how it looks from a scientist perspective, but that if things seem bleak or things seem stagnant or things seem frustrating, that, you know, I don’t want to be like, there’s people counting on you, but there’s a lot of people that are happy to support and to fund what they can do, because there is everybody on the other side, like me, who is hoping and praying that there is a breakthrough that is going to cure somebody one day.
00;26;32;11 – 00;26;51;05
Annie Alessio:
But their efforts don’t go unnoticed from our side, too. I’m hopeful, and I think in my lifetime there will be somebody that will come through it on the other side.
00;26;51;07 – 00;27;15;07
Nicole:
Thanks for listening to this special edition of Beyond Lab Walls, and special thanks to Annie and all the scientists who contributed to the story. I had such interesting and meaningful conversations with all of them while putting it together, and there really is such a cool collection of experiments and new technologies happening here. But what really stood out was just how much energy and hope everyone is feeling in this new chapter.
00;27;15;09 – 00;27;38;14
Nicole:
I can’t wait for you to hear our upcoming episodes with some of the scientists doing the work we just described. And if you want to learn more about Salk’s “Year of Alzheimer’s” and how you can support this work, please visit salk.edu. The news tab will also direct you to the digital version of Inside Salk magazine, where you can read more stories like this one, and sign up to receive a printed copy delivered right to your door.
00;27;38;16 – 00;27;44;25
Nicole:
Next issue comes out in April, folks, so get on that mailing list. And thanks for joining us at Beyond Lab Walls.