Alzheimer’s, Brain Health, and Biomarkers

Adam: Our genes likely determine whether or not we're going to get Alzheimer's disease. What we want to do is maximize our brain health despite that. All these things that we're talking about maximize the potential of our brain health, which includes controlling blood pressure very high on the list, along with other factors as well.

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 Adam Brickman about brain health. We talk specifically about Alzheimer's and dementia, and really dive deep into the biomarkers and blood tests that can help us understand the health of our brain.

Brent: Doctor Brickman is a professor at Columbia University. He's the associate director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and co-director of the Columbia University Alzheimer's Disease Research Center. Doctor Brickman has spent 30 years studying brain health, looking at Alzheimer's, dementia, and the factors that help us understand the health of our brains, whether through MRI, blood tests, or genetic profiling.

Brent: He's a wonderful guest to help us think through what we should be measuring to understand our brain health, what we shouldn't be measuring, and how we should be making those decisions.

Brent: Doctor Adam Brickman, welcome to the show.

Adam: Thanks so much. I'm happy to be here.

Brent: Today I want to focus the conversation on brain health, and specifically ask about the biomarkers used to understand the health of our brains. We will dive into all of that, but before we do, can you give us a sense of your background and a brief bio?

Adam: Sure. I am a neuropsychologist by training and a professor of neuropsychology at Columbia University. I've been studying cognitive and brain aging, dementia, and Alzheimer's disease for almost 30 years. I use a lot of different techniques in my work, but I'm very passionate about it and love talking about brain and cognitive aging.

Brent: Okay. I'd like to start by going through some of the biomarkers that help us understand the health of the brain. We can talk about these one by one, but the obvious place to start is with genetic markers—specifically APOE. I'm an APOE4 carrier; I've got a single E4 allele.

Brent: I have a single copy of the E4 allele. My grandmother passed away from Alzheimer's, so I spend a lot of time thinking about this. Could you give us a sense of what the APOE test is, and how someone like you thinks about the test and its value?

Adam: Sure. APOE is a gene. We each carry two copies of the APOE gene—one from our mother and one from our father. It comes in three different alleles or varieties: E2, E3, or E4.

Adam: Generally speaking, if you carry a copy of the E4 allele, you are at an increased genetic risk for developing Alzheimer's disease. If you have two copies of the E4 allele, one from each parent, your risk for developing Alzheimer's disease in the future is even higher.

Adam: There is some debate about this, but these are not deterministic genes—they simply increase risk. If you inherit two copies of the E4 allele, you are not guaranteed to get Alzheimer's disease. Likewise, if you don't inherit an E4 allele, you aren't necessarily protected from developing Alzheimer's disease in the future.

Adam: It's simply one of those genes that increases or decreases risk. There is also an E2 allele, which is thought to be somewhat protective. The risk associated with the APOE gene varies somewhat by race and ethnicity, so there is variability across different backgrounds with respect to risk.

Brent: Do you see that as primarily related to socioeconomic factors? Race can sometimes be a poor proxy for socioeconomic status. In life expectancy, we tend to see that higher socioeconomic status correlates with living longer. We see this in CDC life expectancy tables, which often report by race rather than socioeconomic status.

Brent: Is it something specific from race to race, or do you think it is more closely tied to socioeconomic status?

Adam: That is a very important question, and we don't know the exact answer. Today in science, race and ethnicity are conceptualized as social constructs rather than biologically meaningful categories, but they do correspond with different ancestral backgrounds. There might be a genetic ancestry component that moderates the effect of APOE.

Adam: We don't fully know why it varies by race and ethnicity, but generally speaking, when discussing differences in dementia risk across racial and ethnic groups, these are usually socially patterned risks rather than biologically driven ones.

Brent: That's interesting. You mentioned earlier that there is some controversy regarding whether APOE4 increases the probability of Alzheimer's versus APOE2 being protective.

Brent: When you say there is controversy around APOE, what do you mean?

Adam: The controversy I was referring to stems from a recent major paper suggesting that inheriting an E4 allele from both parents (the E4/E4 genotype) is a deterministic genetic profile for Alzheimer's disease. While it significantly increases risk, I would argue that it is not strictly deterministic.

Adam: But it's not quite deterministic. I think that that's that's the controversy that I was referring to.

Brent: Deterministic meaning diagnostic—meaning if you have E4/E4, you will definitely get Alzheimer's.

Adam: That's right. Yeah. Yeah. That's what we mean by deterministic.

Brent: So your odds are much higher than average, but it isn't guaranteed.

Adam: That's right.

Brent: That is based on your view of the broader research on the topic, suggesting that particular study may have overstated its conclusion?

Adam: I wouldn't say wrong, but the reported strength of the association was likely inflated.

Brent: Do you know your own APOE status? Do you recommend that people in middle age find out their APOE profile?

Adam: It's a deeply personal decision. I do not know my APOE status, despite having had many opportunities to learn it. I personally prefer not to know if I am at an increased risk for Alzheimer's disease. Others may view it differently; knowing their risk might lead them to live their lives differently.

Adam: Some people might focus on preventive strategies, while others might experience significant anxiety. Early in my career, I decided I didn't want to know those details. When I reached a certain age, despite conducting a lot of MRI research, I decided not to get scanned myself. I prefer to focus on living the best version of my life without the anxiety of knowing what my brain looks like.

Brent: That stands out to me because you're the second researcher to mention this—Dr. Marilyn Albert said the same thing recently, despite having studied Alzheimer's for 30 years. To me, that indicates how early we still are with preventive strategies. If you suspect strep throat, you get tested immediately because it's simple to treat with antibiotics.

Brent: Here, the complexity is that you might find out you're at risk for something you can't prevent. Is this a sign that you're skeptical about our current ability to prevent or delay the onset?

Adam: Yes and no. The advice we would give today to mitigate risk or delay onset is the same whether or not you carry an E4 allele. The best recommendations for middle-aged individuals interested in reducing Alzheimer's risk are: exercise regularly, eat well, manage stress, keep blood pressure under control, manage vascular risk factors like diabetes, sleep well, and stay cognitively and socially active.

Adam: We recommend those lifestyle habits regardless of APOE status. If knowing you carry an E4 allele motivates you to adopt those healthy behaviors, then that could be a positive reason to get tested.

Adam: However, carrying the E4 allele shouldn't be the sole motivation for taking these preventive steps, because those measures benefit overall brain and cognitive aging for everyone.

Brent: I agree it's a personal decision. Knowing that risk is heavy, and like many people, I fear Alzheimer's and cognitive decline even more than death. However, I'm not entirely convinced by the argument that we would make the same recommendations either way.

Brent: An analogy would be driving down the highway: you can either know if there's a wreck ahead or not. By that logic, one might say, "Drive safely and stick to the speed limit either way; you don't need to know about the wreck." But if I know there's a wreck ahead, I'm going to be more cautious and attentive in that moment.

Brent: While I agree there are valid reasons not to know, I've never fully found that argument persuasive.

Brent: And so while I agree there are reasons to not not know, I've never loved respectfully, I've kind of never loved that argument.

Adam: It comes down to personal choice. If the marker were strictly deterministic, that might change things. Carrying the E4 gene doesn't guarantee you will develop Alzheimer's, but if knowing catalyzes positive behavioral changes, that's a valid choice. Personally, whether I have the E4 gene or not won't alter how I exercise, eat, or stay socially engaged.

Adam: I understand your analogy, though I might tweak it to compare it to routine car maintenance—changing your oil, checking your fluids, and ensuring your windshield wipers work. Performing regular maintenance affects how the car runs regardless of whether there's an accident ahead.

Adam: Make sure that you know, your fluids are your windshield wipers work? Well, that you know that you're keeping it semi clean. That that that's what I'm talking about. And that'll have an impact on how you drive that car, irrespective of whether there's an accident up ahead.

Brent: To push slightly further on that: high cholesterol isn't deterministic either. Having high cholesterol doesn't guarantee heart disease, yet most people know their cholesterol levels or get tested for it.

Brent: At the core of this question, the difference seems to be that while we believe Alzheimer's can be mitigated, the science is still young and the knowledge is heavy. With cholesterol, the science is mature—you can take a statin with well-understood, low side effects.

Brent: There are simply more direct interventions available for cholesterol than for knowing your genetic predisposition to Alzheimer's.

Adam: I agree. Cholesterol is an interesting example because maintaining healthy cholesterol levels also decreases your risk for dementia later in life. Ideally, when discussing cholesterol or blood pressure management with your primary care physician, those conversations wouldn't just focus on heart disease and stroke, but also on brain health.

Adam: All of those medical treatments and healthy lifestyle behaviors directly contribute to brain health as well, helping mitigate the risk for Alzheimer's disease or dementia.

Adam: In the future, hopefully we will have true primary prevention strategies for Alzheimer's disease. But today, brain health and overall body health go hand in hand, and those conversations with doctors should be connected.

Brent: Heart health is brain health, particularly regarding blood pressure. Let's move on to the next biomarker: p-tau217. This simple blood test can help measure the amount of plaque in the brain.

Brent: Can you explain what this test measures and how you view its role?

Adam: This is a major development in the field of Alzheimer's disease. When I entered the field in the '90s, we used to tell patients that the only definitive way to diagnose Alzheimer's disease was post-mortem, by examining brain tissue under a microscope for plaques and tangles.

Adam: Plaques are composed of beta-amyloid protein aggregating outside of cells, while tangles consist of tau protein aggregating into neurofibrillary tangles inside cells. Historically, we had no way to detect these features in living patients.

Adam: Over time, specialized PET scans were developed using radioactive tracers to visualize plaques and tangles in living brains. We also learned to measure these proteins via spinal fluid from a lumbar puncture.

Adam: Today, we have highly sensitive blood tests that measure these same proteins to infer what is happening in the brain. Moving from post-mortem diagnosis to a routine blood test that detects plaques and tangles has transformed the field.

Adam: These blood tests allow us to determine with high confidence whether a patient has plaques and tangles. Consequently, the field now views Alzheimer's disease primarily as a biological entity.

Adam: A person can have the underlying biology of Alzheimer's disease without exhibiting cognitive or functional impairment. Older adults can now consult their doctor and determine if the disease biology is present before symptoms appear.

Adam: If highly effective treatments existed, early detection would allow prompt intervention, which is how current clinical trials are designed.

Adam: However, many available treatments only modestly impact clinical symptoms. We have become very proficient at diagnosing the biology of Alzheimer's, but less effective at treating it; we can remove plaque pathology, but it hasn't proven to be a complete cure.

Adam: But it doesn't seem to be the panacea that we all hoped it would be in terms of treatment.

Brent: Do you recommend testing? I've taken the test myself out of curiosity, but do you recommend that asymptomatic individuals get tested?

Brent: Even if someone is experiencing symptoms, is testing recommended?

Adam: Recommendations vary among medical centers. Generally, if an individual has cognitive concerns, they should see a specialist for an evaluation, which may include biomarker testing using blood tests, CSF analysis, or PET scans.

Adam: However, for completely asymptomatic individuals, diagnostic biomarker testing is generally not recommended.

Adam: This is partly because FDA-approved medications are currently indicated only for individuals demonstrating cognitive impairment.

Brent: So a positive p-tau217 result alone, without cognitive symptoms, wouldn't make a patient eligible for those medications?

Adam: Correct, approved treatments would not be indicated in that scenario.

Brent: Since current treatments are most effective in the early stages, wouldn't that support knowing your p-tau level early? Delaying testing might miss the window where treatment is beneficial.

Adam: That argument is frequently raised, and biologically, earlier intervention should yield better outcomes. However, the evidence that current treatments work significantly better in mild versus more severe stages is limited.

Adam: There is currently minimal clinical trial evidence showing that treating asymptomatic individuals with positive biomarkers produces better outcomes than treating mildly symptomatic individuals.

Brent: In preventative health and longevity, there's a growing trend to move beyond formal guidelines—such as getting elective full-body scans, even when oncologists note that research doesn't support them for general screening.

Brent: It raises the question of downside risk. While full-body scans carry notable downsides, many people seek out diagnostic tests independently without a doctor's recommendation.

Brent: What is the downside for a middle-aged person taking a p-tau217 test, even if it isn't formally recommended?

Brent: Many people are doing it across the board. What's the downside?

Adam: It is similar to the conversation around genetic testing: do you want to know if Alzheimer's biology is present in your brain? Currently, a positive test in an asymptomatic person cannot predict when symptoms will begin.

Adam: Autopsy studies show that roughly 35% of older adults who die without cognitive symptoms still display Alzheimer's pathology in their brains. A person can test positive for Alzheimer's biology and yet never develop symptoms during their lifetime.

Adam: It comes back to personal preference: do you want to know, and will that knowledge cause significant anxiety? The test confirms the presence of biology, but it cannot predict if or when clinical symptoms will manifest.

Brent: Unlike APOE, which is static and tested once, p-tau can change over time. Someone might argue that establishing a baseline in middle age could provide valuable clinical data as science advances over the next few decades.

Brent: Playing devil's advocate: what do you think of the argument that gathering baseline data now could be useful later?

Adam: I understand that perspective. People naturally want information about their health. However, there is little actionable use for that data in middle age currently, and out-of-pocket testing can be expensive.

Adam: Consider Huntington's disease as a clearer comparison: inheriting the gene means a 100% chance of developing the condition. A child of an affected parent has a 50% chance of inheriting it.

Adam: Ever since the gene was discovered, individuals at risk have faced the choice to test at age 20. Some choose to test because it fundamentally shapes their life planning, while others choose not to know.

Adam: These choices are deeply personal, and the same applies to Alzheimer's biomarkers. If effective disease-preventing treatments emerge in three to five years, I would advocate incorporating these tests into routine primary care visits. Today, however, the choice remains nuanced.

Adam: And then I'd be singing a very, very different song. I'd say absolutely. It should be part of primary care. It should be part of your wellness visit when you see your, your, primary care physician, etc.. But I think today it's still, it's still much more nuanced.

Brent: It is a one-way door decision—a concept Jeff Bezos popularized at Amazon regarding irreversible choices.

Brent: Two-way door decisions can be reversed, but one-way doors cannot. Once you know your biomarker status, you cannot un-know it, so it requires careful thought.

Brent: What are your thoughts on neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) as biomarkers for brain health?

Adam: NfL and GFAP reflect neurodegeneration—the loss of brain cells—and astrocytic activation linked to inflammation. These markers indicate general brain injury or insult, but they are non-specific.

Adam: Elevated NfL and GFAP levels appear in Alzheimer's disease, but also in head trauma, stroke, and other neurological conditions. While not specific enough for clinical diagnosis, they are valuable research tools for measuring neurodegenerative and inflammatory changes via blood tests.

Adam: Knowing your personal GFAP or NfL levels does not currently offer actionable clinical insight into your brain health.

Brent: It's not diagnostic like p-tau, nor risk-indicative like APOE. It signals that the brain is responding to injury, but without specifying the cause, making it most useful in population-level research.

Brent: Across a large cohort, it can highlight directional trends, even if it isn't definitive for an individual.

Adam: Yeah, that that's the argument that I'd make today. Yeah.

Brent: Lastly, what about the Omega-3 Index? While usually associated with cardiovascular health, given the connection between heart and brain health, does this blood test offer meaningful insight?

Adam: I have not worked extensively with the Omega-3 Index in my research. Generally, my work focuses on the intersection of vascular and brain health. Preserving cardiovascular and cerebrovascular health clearly benefits brain health.

Adam: However, I don't know enough about this specific biomarker to comment on its individual utility.

Brent: What do you think about using AI to integrate personal health data? Given how fragmented healthcare is, could feeding more biological data into AI uncover insights that doctors previously missed?

Brent: But just hey, the more I know about my biology, the more I have to feed into AI and the more dots it can connect and the smarter the output.

Adam: AI is a prominent topic everywhere, and its potential is enormous. We can now measure thousands of proteins in blood and cerebrospinal fluid, creating datasets too complex for traditional statistical methods to interpret easily.

Adam: AI excels at combining massive data streams across populations to generate hypotheses about disease pathways in Alzheimer's, cognitive aging, and dementia.

Adam: The goal of inputting all personal health data into an algorithm to receive an accurate diagnostic risk score is still in development. These models remain exploratory, and we are still learning how to interpret them.

Adam: While AI is opening exciting research avenues, it is not yet ready for individual clinical application.

Adam: From an individual perspective.

Brent: There is also the treatment challenge. For type 2 diabetes, high blood sugar is treated with metformin. High cholesterol is treated with statins, and hypertension with antihypertensives. We have clear treatments for those conditions.

Brent: Unfortunately, that clear link between diagnosis and effective treatment doesn't yet exist for brain health. Let's discuss the connection between brain and heart health. Heart health often focuses on cholesterol and plaque build-up, alongside hypertension.

Brent: Hypertension appears to correlate more strongly with brain health and dementia risk than cholesterol does, though both play a role. How do you view the vascular connection to brain health?

Adam: Hypertension tops the list of vascular risk factors, followed by high cholesterol, diabetes, and smoking. The brain is our most vascularized organ, relying on a complex network of blood vessels to meet its intense metabolic demands.

Adam: Ignoring the vascular system and how it supplies energy to the brain is a mistake. I view this through two lenses: peripheral vascular health and endogenous brain vascular health.

Adam: Conditions like heart disease, high cholesterol, and hypertension affect the brain, and their impact is visible on MRI scans. I also suspect an endogenous vascular component in Alzheimer's disease—an intrinsic vessel malfunction, possibly driven by inflammation, separate from systemic hypertension or high cholesterol.

Adam: This intrinsic vascular change could drive cognitive decline and contribute to plaque and tangle formation in Alzheimer's disease.

Brent: So you're suggesting a potential vascular issue in the brain that operates independently of standard hypertension or cholesterol, which research is only beginning to uncover?

Adam: Yes, there is clear evidence. In studies of Alzheimer's patients without hypertension, diabetes, high cholesterol, or heart disease, we still observe brain changes indicative of vascular dysfunction.

Adam: These include microvascular strokes and white matter hyperintensities, which reflect cerebrovascular damage. People with or at risk for Alzheimer's show increased cerebrovascular damage compared to healthy controls, independent of traditional vascular risk factors.

Adam: There is a distinct vascular signal present, and researching the underlying mechanisms is both exciting and challenging.

Brent: That parallels heart disease: high cholesterol itself isn't heart disease, but rather the buildup of plaque in the arteries. Someone can have high cholesterol without plaque, or low cholesterol with significant plaque.

Brent: While not an absolute rule, higher cholesterol generally increases plaque risk. Similarly, maintaining healthy blood pressure reduces the likelihood of developing Alzheimer's symptoms, even if it isn't an absolute guarantee.

Brent: Having healthy blood pressure lowers your risk, but it does not guarantee you will avoid or significantly delay Alzheimer's.

Adam: Exactly. Most researchers view the link between high blood pressure and Alzheimer's as indirect. Blood pressure doesn't directly alter amyloid plaque or tau tangle levels; rather, if those pathologies develop, high blood pressure causes cognitive symptoms to appear earlier and more severely.

Adam: Blood pressure relates more directly to general cognitive aging and clinical dementia than to Alzheimer's pathology specifically.

Brent: Two patients can show identical levels of brain pathology on scans, yet Patient A may function significantly better than Patient B. Managing blood pressure may not alter underlying brain pathology, but it can change how symptoms impact daily life.

Brent: And that's what you're saying is the connection to blood pressure is healthy. Blood pressure is not necessarily going to change the pathology, but it might change how the disease manifests itself in terms of impacting your life.

Adam: Correct. Other moderating factors, such as cognitive reserve and resilience, also influence the relationship between pathology and clinical symptoms. This remains a rich area of research.

Brent: To summarize simply: is actively managing blood pressure currently one of the single best ways to delay the onset of Alzheimer's symptoms?

Adam: It is near the top of the list. Complex genetic interactions largely determine whether someone develops Alzheimer's disease.

Adam: Our goal is to maximize brain health despite genetic risk. Controlling blood pressure is one of the most effective ways to maximize that potential, alongside other lifestyle factors.

Brent: Switching gears, tell us about the multivitamin study using Centrum Silver, which produced surprising results.

Adam: In collaboration with Harvard researchers, we conducted a randomized trial evaluating the cognitive effects of a daily multivitamin compared to a placebo.

Adam: Participants completed online cognitive tests without knowing which pill they received. While the overall effect size was modest, participants taking the multivitamin showed statistically significant improvements in memory compared to the placebo group.

Adam: I was initially skeptical due to mixed literature on multivitamins and cognition, but this study was rigorously designed, well-controlled, and subsequently replicated in a second cohort.

Adam: Having replicated the observation across two studies, the evidence now supports the idea that taking a daily multivitamin can modestly benefit cognitive function.

Brent: Do you take a multivitamin?

Adam: I hadn't taken one since childhood, but the results of my own study changed my behavior, and now I take one every morning.

Brent: The study used a standard, mass-produced multivitamin rather than a specialized supplement. Which multivitamin do you take?

Adam: We used standard Centrum Silver in the study because it was readily accessible, and most commercial formulations are similar. I don't hold stock in the manufacturer, but I personally took standard Centrum after the study and transitioned to Centrum Silver after turning 50.

Adam: Since we completed.

Brent: Centrum Silver is formulated for ages 50 and up. What about other practices for brain health, like saunas?

Adam: I don't have an expert opinion or familiarity with the scientific literature on saunas and brain health, though I personally enjoy using them.

Brent: The multivitamin study received attention because taking a low-cost, daily pill is simple to integrate into an existing routine compared to broader lifestyle interventions.

Adam: That simplicity explains the public interest. Taking a pill sounds much easier than exercising, maintaining a healthy diet, staying socially connected, or limiting social media use.

Adam: Because the effect of a multivitamin is modest, it should complement—not replace—a healthy lifestyle. There is no simple pill that replaces effort when it comes to maintaining brain health.

Brent: More isn't always better. Studies show that cancer patients taking certain unproven supplements can experience worse outcomes, and oncologists often advise stopping them during treatment.

Brent: Multivitamins stand out as an exception where evidence shows a clear, safe benefit, whereas many other supplements lack efficacy or carry potential risks.

Adam: I advise consulting a physician before starting any multivitamin or supplement, as certain health conditions or medications may render specific supplements inappropriate or harmful.

Brent: Could you share details about your research in South Africa using portable MRI machines in rural communities?

Brent: So give us a sense of that.

Adam: Neuroimaging via magnetic resonance imaging (MRI) is central to my research. Standard MRI scanners are multi-ton, multi-million-dollar machines housed in specialized hospital facilities, making them inaccessible in under-resourced regions.

Adam: An innovative team developed a portable ultra-low-field MRI scanner that operates without specialized infrastructure. Collaborating with colleagues at Wits University in Johannesburg and Harvard University, we brought this technology to rural South Africa.

Adam: How could you can't you have to leverage these huge magnets to to to take these brain images. But but a very, very smart group, and company, developed, a portable MRI system, that can that's very small and it can be put into more rural environments without all that architecture and equipment. And so I have a very, strong collaboration with, with, colleagues at Fitts University in South Africa, in Johannesburg and at Harvard University.

Adam: Supported by an NIH grant, we deployed the portable scanner to study cognitive aging, dementia, and vascular disease in rural populations. Navigating the logistics of international shipping, transport regulations, and customs was a major undertaking.

Adam: Now installed, the scanner enables systematic research into brain aging, vascular risk factors, cognitive outcomes, and Alzheimer's biomarkers in this rural population.

Adam: So we're really, really excited about this study. It's a it's a wonderful collaboration.

Brent: Does this connect back to the multivitamin study? In lower-income rural areas with different dietary patterns, nutritional deficiencies might affect brain health. Could similar mechanisms be at play here?

Brent: Possibly. Or am I thinking about the wrong way.

Adam: Dietary habits, education, poverty, and healthcare access are key variables in our research. Interestingly, high-resource settings often feature processed foods and convenient diets, whereas in rural South Africa, fresh and whole foods are more common.

Adam: I often eat a healthier diet while working in rural South Africa than I do at home. Comparing these distinct environments offers valuable insights into lifestyle factors and brain health.

Brent: Longevity isn't limited to wealthy areas like Monaco or Palo Alto; Blue Zones exist in places like rural Costa Rica. Doctor Adam Brickman, thank you for advancing the science and for sharing your time with us today.

Brent: And thank you for the time today.

Adam: Thank you so much. I enjoyed it.

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.