We all know the drill: You go to the doctor’s office, and before you ever see a physician, a nurse slides a cuff on your arm and takes your blood pressure. The result gives some insight into your risk for a heart attack or a stroke.
But what if that result could also reveal your risk for developing Alzheimer’s?
A blood pressure reading at a moment in time doesn’t tell much, says Daniel Nation, the Merle H. Bensinger Professor of Gerontology at the USC Leonard Davis School of Gerontology. But Nation’s research shows that charting how blood pressure varies may offer insights on brain health.
“We have found that your variability in your blood pressure — how much it changes, beat to beat, minute to minute, even within a single heartbeat — is a major risk factor for cognitive decline and dementia,” he says.
Think of them as “dementia detectives.” USC neuroscientists like Nation pore over clues, determined to piece together the facts that will reveal dementia’s modus operandi. Some study possible dementia triggers, such as traumatic brain injuries, vascular degeneration and air pollution. Others examine the role of the musculoskeletal system, or genetics, or fingernail-size brain centers, or the effect of sex differences in the development of Alzheimer’s. But they share a common hope: that their research will help reveal if, when and how dementia will strike.
Tracking vascular disease and injury within the brain
Vascular disease affects the brain’s blood vessels and is a common cause of dementia. But how does one lead to the other, and can we tell if someone’s at risk? These are questions Nation is trying to answer.
The brain, he explains, cannot store energy. Instead, it gets it “on the fly” from nearly 400 miles of blood vessels that ribbon through and around it, he says. That makes the brain “very vulnerable to any kind of vascular problem,” Nation says.
There are two main ways someone can develop vas- cular dementia, he says. One is from a stroke, or a series of strokes, that causes accumulated destruction to the brain’s memory centers. The second way is small vessel disease. This is when the brain’s small blood vessels start to degenerate, leading to extensive damage to the white matter that connects the different parts of the brain, Nation says. It’s often only clear as symptoms of cognitive decline begin to show. Many dementia patients have both small vessel disease and Alzheimer’s, he says. Some of Nation’s research is focused on angiogenesis, the process by which blood vessels repair and even regrow. By growing brain blood vessels in a dish, he says, his lab is hoping for findings that “may generate new ideas that are totally different types of [dementia] interventions” than we currently have.
Nation also wants to understand how and why vascular dementia develops, and to create tools to track it as it’s happening. Graphing blood pressure variability over a period as short as seven minutes offers clues into the presence of small vessel disease, he says. It’s not yet clear whether the vessel damage is due to surges in blood pressure that damage vessel walls, or the dips in pressure that repeatedly deprive the brain of blood flow, he says.
Either way, the issue “is currently not treated, be- cause all of the treatments are just based on average pressure,” he says. Were physicians to begin treating such variability, “it would have a big effect, potentially,” he says, “because we have consistently observed high blood pressure variability as a risk factor.”
Another risk factor for dementia is brain injury. Nation’s colleague Andrei Irimia is studying the risk that traumatic brain injuries, or TBIs, pose for the development of Alzheimer’s, while also exploring possible interventions that can prevent the worst effects of TBIs from happening at all.
“The processes that take place in the brain after a traumatic brain injury also age the brain,” says Irimia, associate professor of gerontology, quantitative and computational biology, biomedical engineering and neuroscience. Such processes, like brain swelling and inflammation, are also present in Alzheimer’s disease, he says.
“The question is whether TBI could lead to changes in brain biology along trajectories that increase the risk” of developing Alzheimer’s, he says.
In this, and in his effort to more broadly examine neurodegeneration, Irimia has harnessed the power of ar- tificial intelligence. His team has used a neural network — an AI model that “learns” through intensive, complex data analysis — to identify novel aspects of aging that may predispose people to developing Alzheimer’s. Irimia has also mapped how genetics interact with brain structure to increase or decrease Alzheimer’s risk. “Obviously, there’s a lot more work to do” with neural networks, he says. “This is a very new field.”
One day, physicians may be able to use such deep, detailed brain imaging to identify people whose brains are aging quickly or abnormally, while they are still cognitively normal.
“It could reduce the risk for Alzheimer’s for individuals who might be at higher risk,” he says, “but who may, by virtue of these interventions, be assigned to a trajectory of aging that does not eventually lead to dementia.”
Anthropology and genetics provide leads
Irimia’s quest to understand dementia has led him to the Amazon basin in Bolivia, where he’s studied the Tsimane people, who live a preindustrial lifestyle that features high levels of physical activity and a healthy diet devoid of highly processed foods. “Despite the fact that they have more infectious disease, due to lack of access to modern medicine, they also have far lower rates of dementia,” he says.
It appears that their lifestyle is protective of brain health in a way our industrialized lifestyle is not, he says. “The Tsimane, and other preindustrial societies where being sedentary is not the norm, can teach us a lot about how lifestyle and factors related to industrialization, the consumption of processed foods that is so pernicious in modern societies — how all these factors can actually influence dementia risk,” he says.
University Professor Caleb Finch, the ARCO/William F. Kieschnick Chair in the Neurobiology of Aging, also studies the Tsimane and the long-term effects of modern society on the brain. It’s part of Finch’s lifelong quest to understand the mechanisms of human aging — including the roots and triggers of Alzheimer’s.
Even in our more sedentary, industrialized societies, exercise and diet mitigate Alzheimer’s disease risk, Finch says. “We were the first to show that if you take an ordi- nary mouse with human Alzheimer’s genes and put it on a low-fat diet, there are much fewer Alzheimer’s changes in the mouse’s brain,” he says.
Those same mice had to work in their cage to get food, and they were incentivized because they were hungry, he says. Similarly, people who are physically active and have low body fat are at lower risk for dementia than those who are more sedentary and heavier, he says. Another known risk for Alzheimer’s is air pollution. Finch’s research traced the pathways in the mouse brain that air pollution uses to accelerate Alzheimer’s-like changes. His findings showed this can happen in mice who are only exposed prenatally.
Over and over, Finch’s research points to one weapon against Alzheimer’s: lifestyle prevention.
“We don’t really have any interventions for Alzhei- mer’s other than lowering the risks by lowering the risk of heart disease,” he says. “All of what is good for the heart is good for the brain, and what is bad for the heart is bad for the brain.”
Historically, Alzheimer’s has been a rare condition, he says. Only a “very few and rare genes” destine a small number of people to develop the disease, usually in their 30s and 40s, he says. But in modern societies, “we can see at least a fivefold increase in the risk of serious cognitive impairment at later ages,” he says. “This is environmental.”
A gene called APOE4, which is known to increase the likelihood of Alzheimer’s in industrialized populations, doesn’t appear to get triggered in that way in the Tsimane. Instead, it seems to have some- what of a protective function, Finch says.
Young Tsimane women who have the gene are able to bear more children, despite the highly infectious environment, he says. “So in some conditions, the Alzheimer risk gene is protective from infections,” he says.
Understanding the role of the APOE4 gene — and its companions, APOE3 and APOE2 — looks increasingly like an important piece of the Alzheimer’s puzzle, says Christian Pike, professor of gerontology and assistant dean of research.
Pike began his career studying beta amyloid, the protein that forms the plaques found in Alzheimer’s brains. These days, though, his attention and his research are centered on the family of APOE genes because they are “a really significant regulator of longevity,” he says.
The APOE3 gene is neutral for Alzheimer’s; the APOE2 gene is protective against the disease; and the APOE4 gene increases the disease risk, to the extent that people who carry two copies of APOE4 have a 60% chance of developing Alzheimer’s by age 85. Much of Pike’s recent research looks at diet and pharmaceutical interventions that can blunt or even reverse the effects of the APOE4 gene in genetically engineered mice.
One intriguing study looked at what happened when mice bred with human versions of APOE genes were treated with an estrogen-related molecule called 17a-estrodial. Certain mice that were given this drug at the onset of middle age later showed improved cognition and reduced brain damage from destructive proteins, Pike says. The benefits of the drug were limited to mice who had the APOE4 gene, and the effects were stronger in male mice than in female ones, Pike says.
In other studies, Pike and Associate Professor of Gerontology Changhan Lee are looking at the impact of a fasting diet on Alzheimer’s, as well as the effects of a microprotein called MOTS-c, which may also have a role in obesity and diabetes, according to research by USC Leonard Davis School Dean and Distinguished Professor Pinchas Cohen.
The work is complex because mice are not exact stand-ins for humans, Pike says. For instance: Female mice, like almost every other animal on the planet besides humans, don’t go through menopause. And male mice don’t age in the same way male humans do, either. “They’re models, and incomplete models, because they can only model specific components of a condition,” he says. “When you get something as complicated as Alzheimer’s disease, you can’t include all the different components that you want.”
So, one experiment will look at the effects of aging, and another at Alzheimer’s pathology, but marrying the two in one experiment can be tricky if not impossible, given other variables, he says.
“You can only answer so many different questions at a time, and then you try to make conclusions based on some sort of composite of several different pieces, but we can’t put it all together yet,” he says.
Untangling neurotransmitters, hormones and endocrine disruption
Mara Mather, professor of gerontology, psychology and biomedical engineering, is investigating the role and functions of the locus coeruleus, a small part of the brain stem that plays a large part in dementia. The tiny bluish region (its name translates as “blue spot”) is one of the first places where Alzheimer’s pathology occurs in the brain. (Mather cites research from 2011 that showed precursors of Alzheimer’s in brains of people in their 30s.)
Mather’s lab is analyzing pupil dilation, since that is one indication the locus coeruleus is activated. Per- haps these and other signs of locus coeruleus function could be used as early indicators of Alzheimer’s, she says.
“The ideal next step would be to target the locus coeruleus in interventions,” she says. “Can you be doing things that really benefit the locus coeruleus in particular?”
The locus coeruleus produces neurotransmitters that activate the brain’s hippocampus region, a site of learning and memory. The hippocampus is another site in the brain where Alzheimer’s disease first becomes apparent, and a region that Teal Eich, assistant professor of gerontology and psychology, studies as she tries to unravel a bedeviling scientific mystery: Why does Alzheimer’s affect more women than men?
A 2021 pilot study shed some light. Women’s cognitive abilities were associated with levels of a key neurotransmitter, gamma-aminobutyric acid (GABA), in the hippocampus, such that lower levels of GABA predicted worse memory. This wasn’t the case for men. The pilot study involved only 20 participants, but preliminary data from a larger study of more than 300 participants is showing the same results, Eich says.
“That led to the question: What might be happening in women versus men?” she says.
Alzheimer’s researchers have found that women’s susceptibility to many frailties and diseases increases significantly after menopause, when estrogen levels drop dramatically. But estrogen levels can’t be the only reason behind the GABA results, because all women who live long enough go through menopause, but not all of them get Alzheimer’s, Eich says.
“There have to be other factors that are influencing this, that are changing the trajectory of estrogen or the timing of it or how it’s impacting brain function,” she says.
That set Eich on a new research path, one she’s still in the process of funding: How are pollutants and human-made toxicants impacting menopausal women, and what connection might that have to GABA levels in the brain?
Many of these chemical compounds are endocrine disruptors, “and there’s a lot of work on how they impact fetuses in utero and how they affect childhood development,” she says, referring to research showing possible links between such chemicals and changes such as childhood obesity and early puberty.
“But there’s almost no research of how [endocrine disruptors] affect women in menopause,” Eich says. She’s hoping to change that by studying whether exposure to certain toxins affects women’s hormone levels in midlife, and how that, in turn, might impact brain function, she says.
Once the function of GABA, and its relationship with estrogen, is better understood, researchers may be able to target GABA levels with pharmaceutical interventions, Eich says. This gets to a larger question of aging, she says. Just as one person’s skin wrinkles faster than another’s, or one person’s hair goes grayer earlier than a friend’s does, so, too, may other, less visible parts of our bodies age at different rates, researchers are starting to understand.
Eich wonders about endocrine age, especially as it applies to women. If GABA levels predict cognitive function in women but not in men, that could mean GABA is also connected to women’s hormone levels. And that could mean, Eich says, “that maybe endocrine age is going to be a good predictor of brain health.”
Putting the pieces together for prevention
Exercise and how the body’s fitness affects the brain is a key focus of research for another USC Leonard Davis school scientist, Constanza Cortes.
“The ultimate goal of my lab is to develop what I like to call ‘exercise in a pill,’” says Cortes, assistant professor of gerontology.
One of the most powerful preventions against dementia is exercise, Cortes says, but in our often-sedentary society, few people move enough. Some people find themselves constrained by work and care obligations, others by access to gyms or safe outdoor spaces. Older people may have mobility challenges on top of that, she says.
“If we could develop a pill that gives you those same benefits, you can just take that drug and get the benefits of exercise, hopefully, without having to get on a treadmill,” she says.
For too long, she says, neuroscience research has ended at the neck. But scientists know that when the body moves, one system starts talking to the other: the muscles to the endocrine system, the organs to the blood. “Now, we’re starting to see that the brain is actually involved in those conversations much more deeply than we ever knew,” she says.
This may be coming into play with the plaques that show up in the brains of Alzheimer’s patients. Cortes compares the plaques to trash that builds up in sections of the brain. “We think that one of the ways that exercise is good for you is that it is telling the brain — essentially, the trash truck — to ‘Hey, go pick that trash up; it’s sitting over there,’” she says.
Cortes models Alzheimer’s in mice, and she’s found that when they run on wheels in their cages, plaques in their brain shrink, and even disappear. “That gives us a really good target so we can modulate and change these disease-associated markers,” she says.
The next step is to pinpoint messengers between the muscles and the brain, because “if we can figure out what the messengers are, I can mimic it with a drug and make a pill for it that mimics the effects of exercise,” she says.
Recently, Cortes’ lab has found one that seems to work in mice. “We’re pretty excited because that means we have a target to go after,” she says. In the coming year, her lab will begin work on developing a version of the medicine for humans, she says.
Eventually, she hopes, physicians will hand at-risk patients a pair of prescriptions: one an exercise-imitating pill, and another a personalized exercise plan. Even with a drug at hand, movement will remain important, she says, and it’s never too late to start.
“No matter how old you are, or how sedentary you are, any kind of increase in your physical activity levels will give you a benefit,” she says. “Even if the only thing you can do is walk around your apartment for a couple of minutes every day, that is better than not doing it.”
Mather also has a whole-body perspective as she investigates how the nervous system’s “fight or flight” mechanism plays a role in dementia.
The autonomic nervous system has two parts: the sympathetic and the parasympathetic. The sympathetic is what we use to move, to generate energy and ideas, and, in times of crisis, for emergency responses like “flight or fight.” The parasympathetic nervous system is responsible for helping us digest food, calm down and rest. In other words, it undoes the excitable work of the sympathetic nervous system. Both branches of the nervous system are essential for health and emotional well-being, but as we age, the parasympathetic begins to deteriorate.
“You can think of it like, if you’re doing a really hard physical workout, the sympathetic system is involved quite a bit,” says Mather. “But if you worked out to the max every day without resting, your body would completely fall apart.”
Rest is important for restoring that damage; the trouble, she says, is when your body becomes less effective at making that rest happen.
“My question is, how much can we restore that balance, and how will that influence the progression towards [preventing] neurodegenerative disease?” she says.
To that end, Mather studies heart rate variability, which decreases as the parasympathetic system deteriorates. Simple breathing exercises can increase heart rate variability while simultaneously decreasing in the blood the proliferation of the amyloid beta peptides linked to the Alzheimer’s disease process, Mather and colleagues found in a 2023 study.
All in all, the data on Alzheimer’s points increasingly in one direction, Mather says. “It suggests that we all should be thinking about [Alzheimer’s] more as a general health issue,” she says. “The health of our brain.”
Brain health — it’s a relatively new concept, but within it may lie the key to unlocking many of dementia’s greatest mysteries. How do vascular changes impact brain health? Traumatic brain injuries? A declining parasympathetic nervous system? Sex hormones?
We already know that sleep, diet, exercise and stress can impact our brains as we age. But what else are we missing? And what more can yet be done?
One day, Pike predicts, his and others’ work will probably result in a pill or pills to reduce or eliminate the symptoms of Alzheimer’s. But even then, he adds, physicians will probably still tell patients to maintain two tried-and-true prevention practices.
“We’ve known for a long time that the best prevention is diet and exercise,” he says. “It’s not that I don’t believe in beta amyloid anymore. I absolutely do. At the same time, I think of this more holistically: that Alzheimer’s is not just a brain disease; it’s a whole-body disease.”
