Can You Delay Alzheimer’s?

Yaakov: So there's a whole set of these different lifetime exposures that can really add up and make a difference. Does it guarantee that you will not get Alzheimer's disease? No. But what it might mean is that you get it later.

Brent: Welcome to Death Clock. I am your host, Brent Franson. Today we speak with Doctor Yaakov Stern about Alzheimer's and dementia. Doctor Stern is the Florence Irving professor of neuropsychology at Columbia University Medical Center. He's also the chief of the cognitive neuroscience division in the Department of Neurology. It's a really good conversation about what we know about Alzheimer's today and how we think about testing and prevention.

Brent: If you want to be proactive about prevention of Alzheimer's or dementia, you've got Alzheimer's in the family or you just want to know more, Doctor Stern is a wonderful guest.

Brent: Doctor Yaakov Stern, welcome to the show.

Yaakov: Nice to be here.

Brent: Today we're going to talk about Alzheimer's, dementia, and cognitive aging. I want to spend a bunch of time understanding how we prevent Alzheimer's and dementia, which is a little bit more complicated than the other three of the four horsemen: heart disease, cancer, diabetes, and then Alzheimer's or dementia. But before we do that, will you give us a sense of your bio, your day job, and the focus of your career?

Yaakov: I used to be called a neuropsychologist, sometimes a neuroscientist. I work at Columbia University and the Columbia Presbyterian Medical Center. I am chief of the cognitive neuroscience division within the Department of Neurology. Most of my work centers around cognitive aging and dementia.

Brent: Can we hit the basics of how we define dementia? Where does Alzheimer's sit underneath that umbrella? How do we think about the categorization of these things and what they are and are not?

Yaakov: Dementia is a very general term for the loss of cognitive and behavioral function, impact on day-to-day activities, not just cognitive functions. There are multiple causes of dementia. Alzheimer's disease is by far the most common cause, but there are many other dementing diseases out there as well.

Brent: Is Alzheimer's the most scary and fatal, or are they all equally scary and fatal with different causes and manifestations?

Yaakov: I think they're all bad. Dementia represents a loss of cognition that impacts people's day-to-day life so they can't do the things they always did before. Most of these dementing illnesses occur later in life, but some can occur earlier as well.

Yaakov: That's why everyone is so worried about it. I think Alzheimer's gets the most publicity because it's the most well-known. No one wants to end up in a nursing home being taken care of. We can talk about the severity that dementia can reach.

Yaakov: Initially, most dementias—and Alzheimer's is a good example—are slow-moving with subtle signs at first, and then they tend to get worse over time.

Brent: Alzheimer's tends to be in a unique category. I fear Alzheimer's more than I fear death from something that is not Alzheimer's. My grandmother died of Alzheimer's, so I've got a genetic predisposition.

Brent: If you tell me I'm going to die of heart disease or something, that scares me a lot less than dying of Alzheimer's or related complications, because of the slow-moving living-dead state that happens—maybe that's a bit harsh, but it's slow-moving.

Brent: There is a long period where you're alive, but your quality of life is severely limited.

Yaakov: Exactly. My father had Alzheimer's disease as well. It was very frustrating as someone involved in research for a lot of my career to feel like there was nothing I could do. It's very hard to watch. It starts with subtle cognitive changes, forgetfulness, things that might happen to anyone.

Yaakov: As it advances, it gets worse and worse. A lot of us are familiar with the forgetfulness, but later on in the disease, you really can't do anything. You can't walk, you can't talk, you can't eat anymore. It becomes a horrible thing to see.

Brent: Let's talk about what actually happens in the brain of somebody who has Alzheimer's.

Yaakov: It's called Alzheimer's disease because it was first described by Dr. Alois Alzheimer. What he described was a specific familial form of Alzheimer's disease occurring at an early age. The Alzheimer's disease that older people get wasn't recognized as the same thing for quite a while.

Yaakov: What Alzheimer described in his patient with cognitive problems was amyloid plaques in the brain upon autopsy. That is one of the hallmarks of Alzheimer's disease: a set of brain changes over time associated with cognitive and functional decline.

Yaakov: I was there during the transition when people started to recognize that many older people also have amyloid in their brain, making Alzheimer's disease very prevalent. I remember the National Institute on Aging pushing researchers to enter that area.

Yaakov: With my colleague at Columbia, we tried to get things going, but at first people didn't want to work with us because they felt it was a rare disease. Only later was it recognized as a widespread disease of aging.

Brent: What is a plaque? Is this the same plaque that shows up in blood vessels and heart disease, or is it specific to the brain?

Yaakov: They call it plaque, but it's a specific substance called amyloid. At this point, we can image it with a special PET scan. Originally, it was only visible upon death, but it's not like cardiovascular plaque.

Yaakov: It's a specific brain change made of amyloid. Now there are even blood tests to see if you have amyloid, which is usually the initial change. Then there is tau, which forms tangles within neurons.

Yaakov: That's the second specific brain change. We can image it and test for it in blood. Many feel amyloid is the first and most important step. Two new drugs recently approved for Alzheimer's attack this amyloid to remove it.

Yaakov: Besides amyloid and tau, there are other brain changes occurring simultaneously; it may be multiple disease processes going on at once.

Yaakov: Those are the two main markers people discuss: amyloid and tau, followed by neurodegeneration, meaning the brain isn't working as well as before. Those are the three steps people focus on.

Brent: Is amyloid located in the blood vessels or elsewhere in the brain?

Yaakov: It's in the brain tissue. Tau is inside the neurons, while amyloid accumulates outside the cells.

Brent: On the testing side, traditional tests relied on cognitive evaluations over time with a neurologist, which can have some subjectivity.

Brent: Now we have blood tests and cerebrospinal fluid tests. How has testing evolved?

Yaakov: Things have changed significantly. Early on, we couldn't see inside the brain to check for amyloid or tau, so we relied strictly on observing cognitive and functional changes over time.

Yaakov: There is a specific pattern of cognitive change with Alzheimer's. Neuropsychologists give battery tasks testing memory, reasoning, and language to identify these specific progression patterns.

Yaakov: For years, diagnosis was "probable Alzheimer's disease" because we couldn't confirm pathology in life. PET scanning developed later to image amyloid and tau in the living brain.

Yaakov: PET scans were expensive, but now blood tests offer easier characterization. Originally, Alzheimer's was defined as a cognitive/behavioral syndrome caused by plaques and tangles.

Yaakov: Many now want to redefine Alzheimer's biologically by the presence of amyloid and tau. In my study tracking people aged 20 to 80, we give amyloid PET scans to participants over 55.

Yaakov: Some people have amyloid in their brain yet remain cognitively intact for a long time. Biological changes take time to manifest as clinical symptoms. With new targeted drugs available, confirming amyloid presence is crucial so patients aren't misdiagnosed.

Yaakov: There are other causes of dementia besides Alzheimer's, so you don't want to prescribe an Alzheimer's drug for a different condition.

Brent: Is amyloid a surrogate marker—like cholesterol for heart disease, where there is correlation but not absolute causation?

Yaakov: No, amyloid is directly involved in the pathological cascade leading to cognitive decline, though it's not the only factor. Many believe amyloid buildup triggers subsequent tau tangle development.

Yaakov: It's considered a direct driver, which is why trial treatments target it. However, removing amyloid doesn't completely reverse or cure the disease.

Yaakov: Current anti-amyloid drugs slow cognitive decline significantly compared to placebos, but they don't halt the disease entirely. Multiple pathological processes are occurring simultaneously.

Yaakov: Amyloid is certainly a critical part of the picture.

Brent: For younger individuals with amyloid in their brain, is it a matter of rate of progression toward Alzheimer's, or can you have amyloid without ever developing Alzheimer's?

Yaakov: You can have some amyloid and never develop dementia. If it progresses slowly, people may pass away from other causes before symptoms occur. Having amyloid isn't a guaranteed sentence for Alzheimer's.

Yaakov: Two people can have identical amounts of pathology like amyloid and tau, yet one is much more affected than the other. Some individuals possess greater resilience.

Brent: Is that related to the work you pioneered on cognitive reserve?

Yaakov: Yes, exactly. That's the concept of cognitive reserve, alongside other forms of resilience.

Brent: Which speaks to its multifactorial nature. Two people with identical amyloid levels can present with very different symptom severity.

Yaakov: Right. Cognitive aging is a normal part of life, just like physical aging. Take basketball players—at a certain age, physical and cognitive shifts naturally alter performance.

Yaakov: Structural brain changes happen naturally with age independent of amyloid and tau. Two people with identical age-related brain changes can perform cognitively at different levels.

Brent: Are amyloid and tau a normal part of typical age-related brain changes, or are they distinct to Alzheimer's?

Yaakov: Even without amyloid and tau, the brain shrinks slightly with normal aging, and white matter connections alter. These normal changes affect cognition independently of Alzheimer's disease.

Yaakov: We can show that greater age-related structural brain change correlates with cognitive changes, completely separate from dementia.

Brent: Does everyone develop plaque in their brain over a lifetime, or are there two distinct paths: an Alzheimer's path with plaque and a non-Alzheimer's path with zero plaque?

Yaakov: A significant number of people never develop amyloid plaques. Others develop them late or in amounts insufficient to cause cognitive impairment or dementia during their lifetime.

Yaakov: It's a wide spectrum, separate from other conditions that might impact cognition.

Brent: With blood tests and PET scans replacing invasive spinal taps, is the recommended age for testing changing?

Brent: Since new medications are most effective early, should someone at 43 with a genetic predisposition get a blood test for Alzheimer's?

Yaakov: It's a personal choice. If we had a definitive cure, early tracking would be essential. To put it in perspective:

Yaakov: Many people live with full-blown Alzheimer's without receiving a formal diagnosis. Doctors are supposed to ask about cognition during annual checkups, but many don't. Does your doctor screen your cognition?

Brent: My primary care doctor doesn't, though I speak with many doctors in my line of work.

Yaakov: Physicians have many areas to cover and aren't always specialized in cognitive evaluation, so many individuals go undiagnosed.

Yaakov: Universal screening isn't feasible currently. Available drugs are expensive and invasive. Typically, patients with noticeable impairment who consult specialists get screened and evaluated for treatment.

Yaakov: If we had a magic-bullet cure, testing recommendations would differ. At age 71, I could easily get tested through studies or private doctors, but I haven't sought it out.

Yaakov: I haven't felt the need to find out.

Brent: Are you an ApoE carrier? Have you checked for a genetic predisposition given your father's history?

Yaakov: I've never checked. Both my father and grandfather had Alzheimer's, but everyone evaluates these decisions individually.

Brent: That makes sense. With heart disease, clear preventive steps exist. With Alzheimer's, knowing your genetic status or plaque levels might create psychological stress without providing clear intervention options.

Brent: Given your work on cognitive reserve and individual differences, knowing plaque status doesn't guarantee you will develop clinical symptoms, so why endure the psychological strain?

Yaakov: Exactly. Personally, I focus on lifestyle choices associated with better prognosis, coping with underlying pathology longer and more effectively.

Brent: Even with a family history, less invasive blood tests, and promising early-stage medications, you choose not to get tested.

Brent: These medications are most efficacious in early stages, yet you prefer not to get a blood test.

Yaakov: If I experienced noticeable functional deficits, my response would be different. Available treatments target people who already exhibit measurable cognitive decline.

Yaakov: They are indicated for individuals presenting clear cognitive symptoms alongside amyloid presence.

Brent: What defines "early stage"? In your 70s or 80s, distinguishing normal cognitive aging from early Alzheimer's might seem challenging, but early-stage Alzheimer's is clinically distinct from typical age-related changes.

Yaakov: Neuropsychological tests evaluate memory and language against age-matched norms. Individuals developing Alzheimer's score significantly lower across multiple standardized tests.

Yaakov: The key differentiator is daily functional impairment: trouble managing appliances, getting lost, or struggling with financial tasks beyond minor, occasional forgetfulness.

Yaakov: Dementia involves cognitive deficits that compromise daily independent functioning, progressing gradually over time.

Brent: There is more optimism now regarding prevention. While it used to be controversial, lifestyle factors like sleep, diet, and exercise are recognized as influential.

Brent: What is your perspective on lifestyle factors and prevention, alongside genetics?

Yaakov: Multiple factors support successful aging and buffer against Alzheimer's pathology. Highly educated individuals can still develop Alzheimer's, but these factors help maintain cognitive function longer.

Yaakov: Delaying onset allows people to live out their natural lifespan without experiencing severe dementia.

Yaakov: Early in my career, skeptics doubted that exercise or cognitive stimulation could counteract brain disease. Today, lifetime exposures are widely accepted as key drivers of successful cognitive aging.

Yaakov: It doesn't guarantee you won't get Alzheimer's, but it can delay symptom onset and reduce severity.

Brent: How would you rank these preventative lifestyle factors (sleep, exercise, diet) to delay onset?

Yaakov: Each factor offers distinct benefits; good sleep doesn't replace the need for physical exercise. In research, we track lifetime exposures starting from childhood socioeconomic status and schooling.

Yaakov: Education, cognitive complexity at work, physical activity, diet, and social networks all contribute cumulatively throughout life.

Yaakov: These accumulated exposures influence outcomes in cognitive aging and dementia. The Lancet regularly publishes reviews summarizing key evidence-backed interventions.

Yaakov: Sleep, exercise, diet, and social engagement all work together additively.

Brent: What about claims surrounding supplements or environmental detoxing?

Yaakov: Studies link environmental factors like pollution and noise exposure to cognitive health. However, I am unfamiliar with specific commercial detox programs and cannot speak to them.

Yaakov: It's probably meaningful that I don't know anything about them.

Brent: What about alcohol or blood pressure management? Taking care of cardiovascular and metabolic biomarkers benefits overall health regardless of Alzheimer's risk.

Brent: You're going to have better cardiovascular biomarkers and metabolic biomarkers. You want to be taking care of those things anyway, whether you're trying to prevent Alzheimer's disease or not. So just do those things. And it's a little bit of a two for one.

Yaakov: Doing what keeps you healthy overall is key. I stay intellectually engaged through research, stay active, maintain social networks, and monitor my diet.

Yaakov: While not a guaranteed prevention, these habits reliably help individuals tolerate higher levels of brain pathology before functional impairment appears.

Brent: What emerging developments excite you? Are new medication trials promising, and what is your outlook on eventually curing Alzheimer's?

Yaakov: We continue to learn rapidly. Look at oncology, where targeted treatments address specific cancer sub-types successfully.

Yaakov: Alzheimer's treatment will likely evolve similarly through numerous concurrent trials exploring diverse pathological targets beyond just amyloid.

Yaakov: Progress won't rely on a single magic pill, but on therapies tailored to a patient's specific combination of underlying brain pathologies.

Yaakov: Beyond plaques and tangles, many concurrent processes occur during disease progression.

Yaakov: Early expectations hoped for a single treatment akin to L-dopa for Parkinson's disease, but Alzheimer's is far more complex and heterogeneous.

Yaakov: Patients present differently—some experience psychiatric symptoms, others motor signs. It requires individualized precision medicine like cancer, so a full cure will take time.

Yaakov: But, you know, this is a whole area of study that I've been interested in. Also, different people have different problems. Some people have psychiatric problems, some people don't. Some people have motor problems, tremors and some there's it's a very heterogeneous disease. And so it is like cancer, except we're farther behind. So, you know, I think medicine is doing the best it can.

Yaakov: I would say it's still going to be a while before we have a real a real cure.

Brent: We've moved into a phase with an increased likelihood of scientific breakthroughs, supported by technological progress and AI.

Brent: Given the brain's complexity, a definitive breakthrough like the polio vaccine may still be ahead, but the momentum is promising.

Yaakov: Treatment will ultimately be highly individualized. Sustained progress relies heavily on continued research funding.

Yaakov: Basic science is actively expanding targets beyond amyloid and tau, identifying up to 15 different pathological factors to balance for individual patient care.

Brent: How much research relies on public funding subject to budget shifts?

Yaakov: Almost all basic science research. Pharmaceutical trials carry enormous costs—screening participants alone with PET scans costs thousands per person.

Yaakov: It's remarkable that drug companies persist, but having two approved treatments on the market shows progress.

Yaakov: So it's it's a process.

Brent: Public funding remains vital for baseline discovery.

Yaakov: University laboratories worldwide depend on grants to conduct foundational research.

Yaakov: Budget constraints jeopardize international collaborations and reduce overall research funding pool sizes.

Brent: Cross-disciplinary global collaboration combines specialized expertise to solve complex problems faster.

Brent: Both sides need funding to reach actionable answers.

Yaakov: Collaborations bring together complementary skill sets—combining expertise in cognitive psychology, neuroimaging, and biochemistry.

Yaakov: That interdisciplinary environment is a key strength of university research settings.

Brent: Where can listeners find reliable resources on Alzheimer's and prevention?

Yaakov: The Alzheimer's Association provides excellent, up-to-date resources online for the general public.

Yaakov: Several dedicated organizations maintain reliable information as new scientific findings emerge daily.

Brent: Doctor Yaakov Stern, thank you so much for your work and for joining us today.

Yaakov: My pleasure to be here.

Brent: Death Clock is recorded in Boulder, Colorado, and San Francisco, California. Produced by Patrick Gudino, music by Patrick Lee, hosted by Brent Franson.

Brent: Founder and CEO of Ma.