Alzheimer’s Prevention

Marilyn: There's a lot of evidence to suggest that what we need to be able to do is intervene early—intervene when people are cognitively normal—so that we delay things so much that maybe you would progress, but you never get dementia. You have some cognitive problems, but you're still able to manage independently.

Brent: Welcome to the Life Lab by Death Clock. I'm your host, Brent Franson. The mission of Death Clock is to help 100 million people live ten years longer. Today, we speak with Doctor Marilyn Albert about Alzheimer's prevention. Doctor Albert is director of the Division of Cognitive Neuroscience in the Department of Neurology at Johns Hopkins University School of Medicine, and the director of the Johns Hopkins Alzheimer's Disease Research Center.

Brent: She's been studying Alzheimer's, dementia, and specifically what we can do in terms of prevention for decades. She's a really great guest because she does a good job of separating what we know from the research from what might work in the future. She helps us understand: what do we know about Alzheimer's? What do we know about the biomarkers that help us understand Alzheimer's?

Brent: What does the research say about what prevents it and what doesn't? So if you want to know for yourself how to prevent Alzheimer's, what works, what doesn't work, this is a really good primer.

Brent: Doctor Marilyn Albert, welcome to the show.

Marilyn: My pleasure. It's good to talk with you today.

Brent: So today we're going to talk about Alzheimer's prevention and something called cognitive reserve. This is near and dear to my heart: my grandmother on my mom's side died of Alzheimer's, and I am an ApoE4 carrier—we'll get into what that means in a minute. I spend a lot of time thinking about this for myself, as well as in the context of my grandmother and my family.

Brent: But before we get into that, will you give us a sense of your background and your day job?

Marilyn: I've been working in the field of Alzheimer's disease and cognitive aging for many decades. As the field has progressed, I have focused earlier and earlier in the course of disease. Now, my own research focuses on the very earliest stages of Alzheimer's disease, which lends itself to studying lifestyle factors that might influence cognitive decline.

Brent: Can you sketch the spectrum of the disease? You're talking about the earliest stages, which most of us are not familiar with because they're not something you would notice in someone the way you would later stages. So when does it start, what does the progression look like, and how does it end?

Marilyn: There are two things to think about when we talk about the start of the disease. The first is the pathology that causes the disease. The basic pathology consists of what we call plaques and tangles. The primary component of the plaques is a substance called amyloid, and the primary component of the tangles is a substance called tau.

Marilyn: What we know now—that we didn't know until quite recently—is that those markers start to develop when people are in middle age. Tau begins to develop when people are in their 30s and 40s, and amyloid when they're in their 40s and 50s. As you indicated before, there is a gene called ApoE4, and amyloid deposits earlier in people who carry it.

Marilyn: We now know that that pathology progresses for a very long time before there are symptoms, which is an important distinction to make. Symptoms usually begin with people becoming more forgetful: forgetting conversations, repeating themselves, having trouble keeping track of recent events, or managing day-to-day tasks like paying bills or driving.

Marilyn: Those symptoms begin slowly. In the beginning, people can compensate for them. During that phase, we call it mild cognitive impairment: you have symptoms, but you're able to overcome them and manage independently. Eventually, it gets to the point where you can't compensate anymore, and you become dependent on others for daily life.

Marilyn: And that's what makes the disease so distressing and difficult for everybody.

Brent: If we start at the beginning, let's first talk about what ApoE4 is and how your ApoE status changes your risk profile. We should mention that this is a simple blood test if you want to know your ApoE4 status, though there's a broader conversation around whether or not you actually want to know.

Brent: There is a psychological burden to knowing—I can speak to that. But let's hit the basics: what is ApoE4? What are the different results you can get from that test, and how do those results indicate your risk of Alzheimer's?

Marilyn: ApoE is a gene with three main versions, which we call ApoE2, ApoE3, and ApoE4. Each of us has two ApoE genes. Having one ApoE4 gene increases your risk for Alzheimer's disease.

Marilyn: If you have two ApoE4 genes, it increases your risk even more. Most people in the world have ApoE3. Having ApoE2 is actually protective, putting you at lower risk for developing Alzheimer's disease. We now know that ApoE4 increases risk because amyloid starts to deposit earlier, shifting the entire timeline forward.

Marilyn: Once amyloid builds up sufficiently, we think it accelerates the production of tau. As both proteins become more abnormal and abundant, they begin damaging nerve cells—and that's when symptoms start to appear.

Brent: So to reiterate, we each have two alleles in this genetic setup. Everyone has a specific pair. Being E2/E2 would be ideal—if you could wave a magic wand for your kids, you'd give them E2/E2.

Brent: That is not only the lowest risk of Alzheimer's, but it's protective. Someone who is E2/E2 rarely gets Alzheimer's. Or you could be E2/E3—having one E2 is better than none.

Brent: As we move up the risk spectrum, E3/E3 is the most common—you don't have the protective E2, but you don't have the higher-risk E4 either. Then there's E3/E4, which is my status: I have one higher-risk allele. Or you could be E4/E4, which carries the highest risk.

Brent: So E2/E2 is best, and E4/E4 carries the highest risk. Everyone has some combination of these. A simple blood test tells you which one you have. Do we consider E3/E3 the baseline average risk? If so, what is the average risk of developing Alzheimer's, and how does that change with one E4?

Brent: In terms of percentages, what is the risk with one E4 versus two E4s?

Marilyn: I don't have those exact percentages at the top of my head, but I don't think that's what people should focus on. What matters most is that prevalence increases significantly with age. Very few people under age 65 get it. These genes represent risk factors, not a guarantee.

Marilyn: They are not deterministic—they simply modify your overall risk. There are rare gene mutations where carrying them guarantees you will develop the disease, but ApoE alleles simply adjust your risk level.

Marilyn: That risk exists alongside your lifestyle factors and environmental exposures, which also influence your overall odds. At age 65, disease prevalence is about 5%, and it increases dramatically over time. Over age 80 or 85, roughly 1 in 3 people have dementia.

Marilyn: We're talking about a very large number of people. That is what people should keep in mind when evaluating risk, age, and genetics.

Brent: Do you recommend that people find out their ApoE status? I'm glad I know mine because conversations around prevention are evolving, and there's more optimism about delaying symptom onset. But knowing can feel heavy.

Brent: I'm not the best sleeper, so I worry—I have kids and I don't want them to see me go through Alzheimer's. Many people fear Alzheimer's more than death, because losing cognitive awareness while alive feels worse than dying.

Brent: What is your recommendation? Should everyone know their status to be proactive, or is it a deeply personal choice you wouldn't necessarily advise?

Marilyn: It's a very personal decision. If we had highly effective treatments that worked better for ApoE4 carriers, knowing genetic risk would be crucial. For instance, my father died of colon cancer, so getting colonoscopies early is important for me as a preventive measure.

Marilyn: We're not at that point with Alzheimer's disease yet. With the treatments approved in 2023 and 2024, carrying an ApoE4 allele increases the likelihood of side effects, making genetic testing relevant in that context. However, we don't yet know if lifestyle factors—like cognitive or physical activity—offer differing levels of benefit depending on ApoE status.

Marilyn: Because we don't know that yet, it makes sense to practice risk-reducing habits regardless of your genetics. I suspect I might carry at least one ApoE2 allele, given that my mother lived to 101 and my grandmother lived to 99 with clear cognition.

Marilyn: My father died of colon cancer, but his sister recently turned 100. It's likely I carry an ApoE2 allele, though I haven't tested myself.

Brent: That choice sounds intentional. Having spent decades in this research, and given that a blood test takes minutes to get, you've decided not to know your status because the recommended preventative steps remain the same either way.

Marilyn: Exactly right. For dominant genetic mutations, testing is critical to prevent passing the disease to future generations. But ApoE status simply modifies your probability of developing it.

Brent: What are your thoughts on other blood tests for brain health? Before we dive in, let's clarify what these involve. You mentioned amyloid plaque accumulation and tangles in the brain during pathological evaluations.

Brent: These pathology markers can develop long before symptoms appear. Could you explain what plaque and tangles actually are? When I hear 'plaque,' I think of dental plaque or arterial plaque.

Marilyn: Dental plaque is a helpful analogy. Amyloid accumulates outside nerve cells as a very sticky substance that forms large, circular clumps. Tau builds up inside nerve cells as a tangled structure. Diagnosing Alzheimer's disease requires abnormal levels of both amyloid and tau.

Marilyn: We think they interact over time, and understanding that interaction is central to research. We are fortunate in this field to have indirect ways to measure them—unlike many neurological conditions where primary pathologies cannot be detected in blood, cerebrospinal fluid, or imaging.

Marilyn: But in Alzheimer's disease, we can.

Brent: What is your perspective on accessible blood tests, such as p-tau 217 or neurofilament light chain, which check for tau buildup prior to symptom onset? Research suggests tau begins accumulating in midlife.

Brent: What are these additional biomarkers besides ApoE? When do concerning signs show up in these readings, and would you advise average middle-aged individuals to get tested?

Marilyn: The FDA has approved a blood test measuring the amyloid-to-tau ratio, but only for individuals exhibiting symptoms. Elevated levels relative to specific cutoffs indicate abnormality, though many results turn out indeterminate.

Marilyn: Because it is only approved for symptomatic individuals, we do not recommend asymptomatic people in their 50s or 60s get this blood test. Diagnostic focus remains on when symptoms actually appear.

Marilyn: We hope to eventually have reliable blood tests for healthy individuals that indicate future risk alongside effective preventative treatments, but we do not have that yet.

Brent: I am 44 with an ApoE4 allele. I tested my p-tau and amyloid ratios, and everything came back in the normal range. Why wouldn't you recommend someone in my situation run these inexpensive, accessible tests?

Brent: Why shouldn't others in a similar position run these tests?

Marilyn: These tests are not validated for asymptomatic individuals, so their accuracy in that context is unknown and could yield misleading results. I firmly support evidence-based science and relying on validated data. Blood tests are validated for symptomatic individuals,

Marilyn: but they are not yet considered sufficiently accurate for asymptomatic individuals.

Brent: To play devil's advocate: proponents of elective full-body scans—despite a lack of mortality data—argue that tracking findings year-over-year helps establish trends and guide decisions on follow-ups.

Brent: The same logic could apply to tracking tau baseline levels over time to monitor progression.

Brent: People similarly track baseline cognitive scores before symptom onset to observe trajectory over time. How do you evaluate the idea of connecting multi-test data points over time to track overall directional trends?

Marilyn: That perspective is reasonable. However, improved diagnostic blood tests will likely render today's results non-comparable within a couple of years. Tracking cognitive baselines over time makes sense because identifying early changes is essential.

Marilyn: If you suspect an issue, cognitive testing can be useful. Researchers are actively working on superior blood tests for Alzheimer's disease, and once more accurate options become available, tracking them over time may be more practical.

Marilyn: In my view, we aren't quite there yet. However, for individuals heavily focused on brain health who prefer to track these metrics, it may be a personal preference.

Brent: I don't necessarily recommend it myself either. Some days I wish I didn't know my status, but knowing motivates me to prioritize brain health. It remains a heavy realization that you can't undo.

Brent: We removed ApoE panels from our app so users wouldn't stumble into results without careful consideration of the pros and cons.

Brent: It's an irreversible decision. I've personally experimented with low-dose lithium—which I suspect you might view cautiously relative to my experimental approach.

Brent: Some early research suggests certain medications or supplements, such as low-dose lithium or lithium orotate, might help prevent disease progression. What is your evaluation of preventative pharmacological interventions?

Marilyn: Evaluating efficacy requires randomized controlled trials comparing substances against placebos or existing therapies. Taking unproven substances based on preliminary ideas carries risk and can cause harm.

Marilyn: For example, early observational data suggested estrogen therapy might lower Alzheimer's risk, but rigorous follow-up studies disproved it. Taking drugs without demonstrated efficacy is inadvisable.

Marilyn: Currently approved medications target symptomatic individuals and carry side effects. Any genuinely effective Alzheimer's drug will likely carry side effects, though preventative options remain unproven.

Brent: In the longevity space, figures like Bryan Johnson spend millions experimentation-testing protocols on themselves. For instance, we recently discussed hyperbaric oxygen therapy on the podcast.

Brent: A guest from Duke noted a lack of clinical evidence for hyperbaric oxygen in prevention, yet Bryan Johnson uses it regularly alongside low-dose lithium. Do you see self-experimentation based on rodent studies as problematic?

Brent: Or is your perspective simply that it isn't something you would personally do?

Marilyn: I wouldn't call it reckless, but it isn't an approach I would take. Relying on validated clinical data is essential. History in Alzheimer's drug research shows multiple instances where trials were halted early due to unforeseen harm from interventions assumed to be helpful.

Marilyn: I favor a more conservative approach, though individual choices vary.

Brent: Are you optimistic about GLP-1 receptor agonists like semaglutide? A recent trial suggested limited risk reduction for Alzheimer's specifically, but interventions reducing systemic inflammation and supporting cardiovascular health offer broader benefits. Heart health and brain health are closely aligned.

Brent: Given that GLP-1s lower inflammation and improve metabolic and vascular health, could they indirectly delay or prevent Alzheimer's onset? Are you hopeful about this class of drugs despite early data?

Marilyn: GLP-1s are a notable example: observational data showed promise, but large clinical trials did not bear that out. Maintaining cerebral vascular health remains critical regardless.

Marilyn: Managing blood pressure, cholesterol, weight, smoking, and diabetes directly protects brain vasculature. Combining vascular disease with Alzheimer's pathology leads to significantly worse outcomes.

Brent: Before moving to cognitive reserve, medications like statins, antihypertensives, or metformin offer secondary preventative benefits. Improving vascular and metabolic health lowers overall Alzheimer's risk.

Brent: Managing markers like hs-CRP to reduce systemic inflammation likely yields secondary risk reduction for cognitive decline.

Marilyn: Managing those factors reduces the overall risk of all-cause dementia. Most older adults present with multiple co-occurring brain pathologies, and controlling vascular risk factors lowers general dementia risk.

Marilyn: It may not modify Alzheimer's pathology directly, but preventing additive vascular damage avoids compounding cognitive decline.

Brent: Could you clarify the distinction between dementia and Alzheimer's disease?

Marilyn: Dementia describes progressive cognitive decline severe enough to interfere with independent daily living. It has various underlying causes, with Alzheimer's disease being the most common—accounting for at least 70% of cases.

Marilyn: Whether vascular disease accelerates Alzheimer's pathology remains unproven, but having both conditions undeniably worsens outcomes.

Brent: Before discussing cognitive reserve—where research supports delaying symptom onset—let's cover sleep, diet, and exercise.

Brent: Sleep helps clear amyloid buildup and waste from the brain. Sleep duration and quality correlate with dementia and Alzheimer's risk.

Brent: What does current research tell us about sleep's role in preventing or delaying symptom onset?

Marilyn: Sleep research is complex: poor sleep can increase amyloid, while elevated amyloid disrupts sleep patterns, creating a bi-directional cycle. Prioritizing quality sleep is important, though exact needs vary by individual.

Marilyn: Targeting seven to eight hours per night is generally advisable.

Brent: How do diet and exercise impact long-term brain health and lower risk? Do they operate primarily through cardiovascular pathways, or are direct neuroprotective mechanisms involved?

Brent: Do we know the specific mechanisms?

Marilyn: Evidence links healthy diets—such as the DASH or Mediterranean diets—to cardiovascular and cerebrovascular health. They preserve blood vessel integrity in the brain much like they do in the heart.

Marilyn: Physical exercise may offer unique advantages. Research shows physical activity enhances brain function independently of vascular health, suggesting additional neuroprotective benefits.

Brent: Sleep, diet, and exercise offer broad health benefits, including protecting brain function. You don't need genetic testing to justify prioritizing them to reduce dementia risk.

Marilyn: Exactly right. Exactly right. Yes.

Brent: How does community engagement and social interaction factor in? People often note that Supreme Court justices frequently live long lives, perhaps due to ongoing cognitive challenge and interacting with new cohorts of young law clerks.

Brent: Continuous mental engagement as you age may extend cognitive vitality. How important is cognitive stimulation—whether through reading, learning languages, or solving puzzles—relative to social connection?

Marilyn: Substantial evidence shows mental activity reduces cognitive decline risk. Regarding Supreme Court justices, their core framework of legal knowledge remains relatively stable over decades.

Marilyn: Unlike scientific fields where knowledge shifts rapidly, professions like law or musical conducting rely on established foundational knowledge, allowing individuals to leverage long-term expertise alongside ongoing activity.

Brent: Maintaining cognitive reserve seems analogous to preserving muscle mass as we age. Because muscle loss accelerates over time, strength training builds a physical buffer for longevity.

Brent: Does that muscle analogy apply to cognitive reserve? Should we actively build neural resilience through learning, puzzles, and social interaction to slow age-related decline?

Brent: Building brain capacity helps buffer against inevitable age-related changes.

Marilyn: That's a helpful model. I frame it around brain connectivity and neural pathways. Cognitive activity fosters redundant neural connections, providing alternative functional pathways if primary networks experience damage.

Marilyn: That functional redundancy underpins cognitive reserve, though viewing it like a muscle is also a practical concept.

Brent: Your research shows that two patients can have identical levels of brain pathology—such as amyloid or p-tau—yet the individual who regularly builds cognitive reserve displays fewer clinical symptoms.

Brent: Is that correct? If so, what specific exercises or routines best build cognitive reserve to mitigate potential symptoms?

Brent: Well—

Marilyn: Studies quantify cognitive reserve using metrics like education and literacy levels. Individuals with higher reserve experience delayed symptom onset. Biologically, higher cognitive reserve appears to buffer against lower levels of tau pathology, postponing clinical manifestations.

Marilyn: Targeted cognitive training exercises have also been shown to reduce long-term dementia risk over multi-year periods.

Brent: Are these memory tasks like flashcard recall? What specific exercises constitute an effective cognitive training regimen?

Marilyn: My colleagues and I recently published findings on a computerized cognitive task called speed of processing training. Participants focus on central screen objects—like identifying a car versus a truck—while simultaneously pinpointing peripheral symbols.

Marilyn: The task dynamically adapts to user performance, increasing in complexity as accuracy improves. Long-term follow-up showed participants engaging in this speed of processing training had significantly lower dementia risk 20 years later.

Brent: That sounds similar to modern video games, which were historically criticized. Fast-paced first-person shooters require spatial tracking, dynamic navigation, and processing changing visual stimuli quickly.

Brent: These mechanics demand rapid information processing and working memory. Could commercial video games on platforms like Xbox or PlayStation offer cognitive benefits, or are specialized tasks necessary?

Brent: So are you optimistic about the more entertainment style video games, the Xbox, the PlayStation, video games? Or would you say no, no. These need to be games that are specifically created for cognitive reserve.

Marilyn: Our documented results stem specifically from divided attention tasks that require rapid multi-target processing. That specific training lowered long-term dementia diagnosis risk compared to general memory or reasoning exercises.

Marilyn: Commercial video games sharing those divided-attention mechanics might yield similar benefits, but that requires direct scientific study.

Brent: What about activities like learning languages or social engagement? Navigating social settings requires tracking conversations, remembering names, and managing active dialogue, making it cognitively demanding.

Brent: How do crosswords, language learning, and active socialization compare in supporting brain health?

Marilyn: Evidence indicates that loneliness and social isolation correlate with worse cognitive trajectories over time. Social interaction challenges cognitive capacity. Additionally, feeling agency over one's life—what psychologists term self-efficacy—is vital when facing stressors.

Marilyn: Social support networks reinforce self-efficacy by providing collaborative problem-solving resources during difficult periods.

Marilyn: Maintaining that sense of self-efficacy plays a key role in overall well-being.

Brent: Looking ahead, what upcoming developments make you most optimistic? Public figures like RFK Jr. have claimed Alzheimer's would already be cured if not for institutional missteps at the NIH.

Brent: Are there emerging research avenues that could lead to genuine cures in the next 10 to 20 years?

Marilyn: I am very optimistic. Congressional leaders recognized that unchecked growth in Alzheimer's and related dementias would strain healthcare infrastructure. With 1 in 3 adults over 80 affected, expanding research funding became a necessity.

Marilyn: Significant funding increases over the past decade accelerated our scientific understanding. This progress coincides with technological advances across imaging and analytics.

Marilyn: PET scans, advanced MRI, artificial intelligence, and sophisticated genomics now integrate to drive discoveries that were previously impossible. Progress relies on both direct funding and broader technological evolution.

Marilyn: These combined tools continually speed up discovery across the field.

Brent: If you had to predict 50 years into the future, will Alzheimer's disease be cured?

Marilyn: I focus primarily on prevention rather than cure. Intervening early in cognitively normal individuals can delay disease progression enough that patients maintain independent function throughout life without developing dementia.

Marilyn: Developing diagnostic tools to assess 5-to-7-year progression risks alongside targeted early treatments offers a realistic goal. Preventing functional decline takes priority over reversing late-stage dementia.

Marilyn: Delaying onset achieves effective prevention.

Brent: Embryo screening technology already allows selecting against ApoE4 alleles in favor of protective ApoE2 pairs. Eliminating high-risk variants genetically presents a theoretical pathway to population-level risk reduction.

Brent: Is widespread genetic selection against ApoE4 a plausible future scenario?

Marilyn: Consider Huntington's disease, which stems from a single deterministic mutation carrying a 50% inheritance risk. Despite available genetic testing, many affected families choose not to screen embryos or select against the mutation.

Marilyn: We are far from seeing widespread adoption of embryo selection for susceptibility genes like ApoE4.

Brent: Is there an obscure research domain today that could yield surprisingly major breakthroughs over the next 50 years?

Marilyn: Lifestyle factors warrant expanded scientific study. Conducting randomized controlled lifestyle trials is challenging, but momentum is building, and unexplored lifestyle interventions may significantly lower risk.

Marilyn: Considerable potential remains in rigorous lifestyle medicine research.

Brent: Societal trends show declining smoking and alcohol consumption alongside growing awareness of sleep, diet, and exercise. Thank you, Dr. Marilyn Albert, for sharing your research and insights with us.

Brent: Your work in Alzheimer's and dementia prevention is deeply important, and we appreciate your time and perspective.

Marilyn: A pleasure to talk with you today.

Brent: The Life Lab by Death Clock is recorded in Boulder, Colorado, and San Francisco, California. Produced by Patrick Gudino, music by Patrick Lee, and hosted by Brent Franson, founder and CEO of Death Clock.