Does eating healthy, exercising, staying socially and mentally engaged, and managing your cardiovascular health protect your brain from cognitive decline? A major U.S. trial put this idea to the test with encouraging results. But there’s a catch: everyone in the trial received some level of lifestyle intervention. So, what does US-POINTER really tell us, and why are some brain-health practitioners calling it evidence that lifestyle changes can prevent dementia?

In this Field Note, we examine the 2025 US-POINTER trial and what it suggests about reducing your risk of cognitive decline. As we’ll see, the results require taking a close look, or it’s easy to see things that aren't really there.

First, let’s get the acronym soup out of the way. The OG for all of this research is FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability), a Finnish study published in 2015. I’m focusing on the US-POINTER trial from 2025, which is based on FINGER.

POINTER is a convoluted acronym that would take half this blog to explain. There is also a related LatAm-FINGERS trial, recently presented at this year’s Alzheimer’s conference. It’s probably a good thing that these scientists work in research institutions rather than on Madison Avenue.

What I love about US-POINTER is that the objective is clear: “Can multidomain lifestyle interventions improve or protect cognitive function in older adults at risk of cognitive decline and dementia?” So, let’s get into the research:

• It’s a randomized two-year trial of 2,111 older adults at risk of cognitive decline or dementia.

• There were two groups. Both were encouraged to eat a healthy diet, exercise, engage mentally and socially, and have their cardiovascular health tracked.

• The big difference between the groups was intensity. The high-intensity group had coaching and frequent meetings. The low-intensity group was provided with information on lifestyle changes and a handful of meetings over the two-year trial.

• Two things to note about the trial:

  • US-POINTER did not compare implementing lifestyle change with doing nothing, so there was no true no-intervention control group.

  • The trial did not address sleep, a major contributor to cognitive health as well as dysfunction.

After two years, cognitive scores improved for both groups, with the high-intensity group doing slightly better. When researchers looked more closely at individual cognitive functions, however, there was no clear advantage for the high-intensity group in episodic memory performance. I find this disappointing because memory loss is a primary concern for most people. Executive function was the only area where the high-intensity group clearly outperformed the low-intensity group.

The overall findings are consistent with FINGER and LatAm-FINGERS, suggesting this isn't simply a one-off finding.

So, why all the excitement in the blogosphere over US-POINTER? The difference passed the statistical gate, but how much difference are we talking about?

Participants in the high-intensity group improved more than the low-intensity group by only 0.029 standard deviations per year. I think about it this way: Imagine your pediatrician tells you that your daughter moved from the 79th percentile in height to the 81st since the last visit. That’s a measurable change against all the other babies her age, but you wouldn’t look at her and think, “It’s time to start calling WNBA scouts.”

That's roughly the scale we're talking about with US-POINTER. Even the study authors acknowledged that the difference was so small that “assessing clinical significance is challenging.”

What I find fascinating is that both groups improved. Why? On the one hand, maybe lifestyle behavior education and minimal encouragement helped participants adopt healthier behaviors, leading to modest cognitive performance improvement. On the other hand, much of this improvement may be due to a known learning curve with repeated cognitive testing, especially over a short time frame like two years.

Still, even taking the improvement at face value, we need to be careful that we don’t read more into the results than is there:

• Despite what you may hear about US-POINTER, the trial measured changes in cognitive performance, not whether the intervention prevented dementia. Nearly all participants were cognitively normal when the trial started.

• The trial did not separate the effects of the individual lifestyle interventions. We don’t know whether we need to do them all or only one to achieve the same gain. I do find it interesting that executive function was the only metric that showed a clear benefit, and previous research has shown that exercise can improve executive function. Unfortunately, US-POINTER can’t tell us if exercise did indeed play an outsized role.

So, my bottom line is that a highly structured lifestyle program appears to provide a small additional benefit over a less intensive, self-guided program. Regardless, we should exercise, eat healthy, stay socially and mentally engaged, manage our cardiovascular risk, and get our sleep in order. These are low-risk interventions with benefits that extend well beyond cognition.

I’m excited that there are some actionable takeaways in this Field Note:

• Don’t confuse better test scores with preventing dementia.

• Don’t pay someone to enroll you in the “US-POINTER Protocol.” This is not Coca-Cola’s secret recipe. None of this is proprietary.

US-POINTER — Baker et al., JAMA (2025): Structured vs Self-Guided Multidomain Lifestyle Interventions for Global Cognitive Function: The US POINTER Randomized Clinical Trial

FINGER — Ngandu et al., The Lancet (2015): A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER)

LatAm-FINGERS (2026): Lifestyle Program Improves Brain Health Among Older Adults at Risk for Dementia Across Latin America

OK, I’ll acknowledge that for the past few Field Notes I’ve changed where I’m going next after diving into the research. However, this time, I’m pretty confident that in the next Field Note we’ll be shining a light on photobiomodulation and attempting to separate hype from reality.

At the end of Field Note 3, I said I’d next move into FINGER and POINTER, two major studies on cognitive decline and Alzheimer’s disease. But as I dug into those studies, I realized we were missing a key part of the story: brain energy metabolism, one of the primary targets of these studies.

I first encountered brain metabolic health listening to Christopher Palmer, MD, on the Huberman Lab podcast. Palmer argues that metabolic dysfunction may underlie schizophrenia, bipolar disorder, and some depression — and, as I noted in Field Note 3, it may play a role in Alzheimer’s as well.

If that holds, a failure in brain energy metabolism could sit upstream of symptoms we currently treat one at a time.

This brings us to this Field Note, which focuses on brain cell metabolism. To illustrate the story, I’m using the ketogenic diet as a lens into a much bigger question: how does the brain produce energy, and how do we measure it?

One of the more intriguing paradoxes in brain health is that many medications used to treat severe mental illness improve symptoms while simultaneously worsening metabolic health. Weight gain, insulin resistance, and metabolic syndrome are common side effects of antipsychotics, antidepressants, and mood stabilizers.

The consequences are far from trivial. As Shebani Sethi, MD, and colleagues point out, metabolic syndrome is extremely common in people with severe mental illness, who die an estimated 10–25 years earlier than the general population, largely because of premature cardiovascular disease. Dr. Sethi is a leader in the field of metabolic psychiatry, having coined the term.

Against this reality, Sethi and her team ask a straightforward question: If we improve metabolic health in patients with schizophrenia and bipolar disorder, do psychiatric outcomes improve as well? I’ll admit I read that the way most people would: metabolic health is metabolic health. When you improve the bloodwork, you improve the metabolic health of the body and the brain. They chose the ketogenic diet to treat metabolic dysfunction.

My intro to ketogenic therapy was reading Georgia Ede, MD’s book Change Your Diet, Change Your Mind. Through her work, I also discovered Iain Campbell, PhD, whose personal experience with keto and bipolar disorder led him into metabolic psychiatry research. I’ll return to Dr. Campbell’s work in a future Field Note.

Ketogenic therapy is hardly new. It’s been used to treat drug-resistant epilepsy, particularly in children, since the 1920s. Testing it in psychiatry is a logical step because several anti-epileptic medications are common bipolar disorder treatments.

As with the patients we discussed in Field Note 2 (vagal nerve stimulation for treatment-resistant depression), participants in the Sethi study were severely ill. Thirty-eight percent had previously attempted suicide. Participants completed extensive psychiatric testing and metabolic assessments before beginning the ketogenic diet and returned for ten follow-up visits over four months.

The improvements, on the surface, appear striking.

• 29% met the criteria for metabolic syndrome at the beginning of the study. By the end, none did.

• Clinical Global Impression severity scores improved by an average of 31%.

• Roughly one-third of participants were in recovery at baseline. By the end of the study, approximately three-quarters met recovery criteria, and all adherent participants met the study’s recovery criteria.

• Nearly 80% of symptomatic participants experienced clinically meaningful improvement.

• For participants who adhered closely to the diet, estimated 10-year cardiovascular disease risk fell by about 11%: triglycerides decreased, HDL cholesterol increased, and blood pressure decreased. One exception was that LDL cholesterol went up 21% on average.

Viewed in isolation, these results make the ketogenic diet look remarkably effective. But do they tell the whole story?

Both psychiatric and metabolic benefits are real, and in a population with decades of illness behind them, patients suffering less is something to celebrate. But Sethi’s paper sent me in a different direction than I expected.

The metabolic and psychological improvements are encouraging, but there was no control arm, so we can’t say ketosis caused them. Weight loss alone might have. Very low-calorie diets and GLP-1 medications improve many of the same markers, and Sethi’s participants lost about 10% of their body weight. We also know from other studies that severely ill people improve simply by receiving close attention and fresh hope: reasons unrelated to the treatment itself.

At this point, I was ready to end the Field Note. Interesting pilot. Too many limitations. Wait for a bigger trial.

And yet, something was bugging me. What if the improvements, especially in mood, came from something ketosis does inside the brain that weight loss alone can’t explain? What if Sethi’s markers captured only part of the picture? What if something was happening in the brain that blood tests were never going to see?

What’s Going on Upstairs?

The markers Sethi’s team measured (insulin resistance, HbA1c, triglycerides, weight, waist circumference, and metabolic syndrome) tell us a great deal about the body’s metabolic state.

Think of it like checking the thermostat in your living room. If it reads 75°F, you have a pretty good idea the entire house is comfortable. But it doesn’t tell you whether the bedroom upstairs is the right temperature for sleeping. You don’t know until you go up.

Blood tests are much the same. For all their detail, they can’t tell us whether neurons on the other side of the blood-brain barrier can still take up glucose and convert it into usable energy. Good metabolic health in the body doesn’t necessarily mean the brain is using energy normally.

This may be the foundation of why neuroscientists are so interested in ketosis. We already know ketones readily reach the brain; ketogenic therapy has treated epilepsy for a century. And it does something no weight-loss diet can: it gives neurons a second fuel, ketones, alongside glucose.

Keto may be less a way to improve metabolic health than a way to ask a deeper question: how does the brain produce energy, and what role might that play in mental health? This may prove to be one of the more important questions in neuroscience.

These ideas are also central to some clinical practice. One of the best-known examples is Dale Bredesen, MD’s ReCODE (REversal of COgnitive DEcline) protocol, which includes nutritional ketosis as one element in a multidomain strategy.

I’ll devote a future Field Note to ReCODE because it raises a bigger question: Can a collection of biologically plausible interventions become more than the sum of its parts?

• The Sethi study showed dramatic improvements in systemic metabolic health, but without a control group, we can’t determine how much of that benefit was attributable to ketosis versus weight loss. In other words, weight loss is a great step toward reversing metabolic dysfunction, and keto is one way to get there.

• The psychological improvements are encouraging, but a larger controlled trial is needed to determine how much of the benefit was due to ketosis itself.

• Ketosis has become scientifically interesting because it provides the brain with an alternative fuel.

• If you try keto, watch your LDL: it rose 21% here. That’s a real cardiovascular flag to track with your doctor.

Scientific Paper

Sethi S, et al. Ketogenic Diet Intervention on Metabolic and Psychiatric Health in Bipolar and Schizophrenia: A Pilot Trial. Psychiatry Research. 2024;335:115866.

Books & Researchers

• Georgia Ede, MD Change Your Diet, Change Your Mind

• Christopher Palmer, MD

• Iain Campbell, PhD (research and public writing on metabolic psychiatry)

Podcast

• Huberman Lab Podcast – Dr. Christopher Palmer: Diet & Nutrition for Mental Health

If blood tests only provide a hint of what’s happening inside the brain, what opens that window? Next, we’ll explore cerebral glucose hypometabolism and how imaging of an aging brain reveals metabolic changes long before symptoms appear.

I was surprised to learn that 85% of Alzheimer’s Disease cases involve a reduced sense of smell (hyposmia). Why does the sense of smell degrade? As you’ll read, hyposmia might be the canary in the memory coal mine. Notably, unlike in Field Notes 1 and 2, inflammation is not the lead actor here.

Meyer and colleagues set out to answer a simple question: What actually causes smell loss early in Alzheimer’s disease? The central player in this research is once again the locus coeruleus, previously discussed in Field Note 2. This small brainstem nucleus sends noradrenaline nerve fibers throughout the brain, including to the brain’s smell-processing center, the olfactory bulb.

They hope that understanding the mechanisms linking the locus coeruleus to the loss of the sense of smell can lead to earlier detection of Alzheimer’s and potential treatment. Of course, this is a mouse study, and as I wrote previously, Mickey ain’t me. We’ll get back to this later.

For the research, the team used mice predisposed to Alzheimer’s (at least as far as mice Alzheimer’s goes). These mice express three mutations that promote the accumulation of amyloid beta. While no mouse fully reproduces human Alzheimer’s disease, this model captures several features researchers believe are important in the earliest stages of the disease.

In case you’re wondering, how do you ask Mickey to “smell” something? They did two things. First, they timed the mice to find buried food. Second, they ran experiments to measure the function of the locus coeruleus and the olfactory bulb while exposing mice to various scents (e.g., vanilla, lemon, banana).

Their primary discovery is that mouse hyposmia results from the loss of locus coeruleus connections to the olfactory bulb, occurring well before detectable amyloid plaques appear: neurons survive, but their axons degenerate. I assumed inflammation would be a factor. Instead, it turns out it’s the brain’s trash collectors, the microglia, doing their day jobs.

But why? And why is it first happening in the olfactory bulb, even though the locus coeruleus connects to multiple brain regions, including the hippocampus?

The researchers think that the brain’s smell-processing center may be more vulnerable to this cleanup process than other regions. One possible reason is that it is one of the few regions that undergoes ongoing neurogenesis and remodeling.

Here’s the entire story in four simple steps:

1. A normally functioning locus coeruleus neuron provides a regular pulse to the olfactory bulb, helping to modulate its function. Think of it like a volume knob on a radio. In Alzheimer’s mice, these neurons act abnormally.

2. Meyer postulates that the dysfunctional axon exposes an “Eat Me” signal. I think of it like a giant Post-it note that catches the attention of nearby microglia. This signal is phosphatidylserine on the axon surface.

3. The microglia detect the signal and destroy the axon. In other words, the microglia are not inflamed; they are just doing their job.

4. The connection is lost. The smell signal weakens. The mouse takes longer to find buried food.

To validate their findings, the researchers used additional techniques. For example, they used specially bred mice whose microglia can’t destroy the axon, even when the “eat-me” flag is up. These mice kept their sense of smell intact into “old age.”

If these findings translate to humans, the earliest signs of Alzheimer’s may be the loss of these connections to the brain’s smell-processing center. If so, it could give researchers a new window into the earliest stages of the disease. Whether that leads to earlier diagnosis or treatment is unknown, but it offers another clue about where to look. After all, hyposmia may occur long before cognitive decline.

Though Meyer presents an elegant study of mouse Alzheimer’s-like brain dysfunction associated with olfactory loss, it is just a mouse study. Even so, it provides another clue for researchers investigating the role of the locus coeruleus in Alzheimer’s and other conditions, including Parkinson’s disease, and Lewy body dementia.

In terms of inflammation, I’ve listened to a few recent lectures by well-known experts in this space discussing “good” and “inflamed” microglia, a bit of a Jekyll and Hyde view of the brain’s janitors. Meyer’s research suggests that this early mechanism may not fit neatly into the good-versus-bad microglia framework at all.

Last week, a good friend said, “I find your blog very interesting, but I’m not sure what to do with it. There’s nothing actionable.” I get it, and I realized that I’m missing an opportunity to be helpful. So, starting today, I’m adding this “Key Takeaways” section. Rather than a list of things to do – or not do – it’s a way to put the research in context. Sometimes it will be actionable, but many times, as in this field note, it will hopefully just be reassuring.

Here are my three takeaways from this research:

1. Next time your smeller is out of whack, don’t panic. There are many reasons (e.g., COVID, sinus infection, allergies) that can reduce your sense of smell. The odds are in your favor. Millions of people experience olfactory deficits; this is rarely due to neurological problems. However, if it persists, you should seek medical advice.

2. One unreplicated mouse study cannot tell us what happens in humans. It does, however, provide another clue for further research.

3. This study adds to growing evidence that brain dysfunction may begin long before any cognitive deficit. The main takeaway is that loss of smell may be an early clue. This finding gives me some hope that researchers are looking more upstream than ever before.

Meyer, C., Niedermeier, T., Feyen, P.L.C., et al. “Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer’s disease.” Nature Communications 16, 7338 (2025). https://doi.org/10.1038/s41467-025-62500-8

As I look out onto the Field Notes horizon, I’d like to understand better why the locus coeruleus is such a central figure in brain dysfunction and explore the upstream processes (e.g., mitochondrial dysfunction) that may be at play. If Meyer’s research ultimately applies to humans with underlying biological changes beginning long before cognitive decline, is there anything we can do about it?

I’m hopeful that the answer is “yes.” My next Field Notes will explore two major human research studies, FINGER and POINTER, to see if they offer any new clues about preserving brain health before symptoms appear.

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Ever since doing research for Field Note 1 on how gut bacteria, the vagus nerve, inflammation, and short-term memory interact in mice, my Facebook feed has been overflowing with ads for vagus nerve stimulators. Beware, you, too, are now destined for the same advertising purgatory!

It’s intriguing to me that the vagus nerve paradoxically appears to be a major contributor to both mental illness and wellness, leading me to this two-year study on Vagal Nerve Stimulation (VNS) for people with Treatment-Resistant Depression (TRD).

My impression has always been that one is labeled with TRD only until they find the right treatment. But what’s the right number of treatments to try? The patients in this trial went through an average of 13.5 lifetime failed antidepressant treatments. Approximately 41% had a prior suicide attempt, and had lived roughly half their lives in depression; many had also failed Transcranial Magnetic Stimulation (TMS) or Electroconvulsive Therapy (ECT). To underscore the severity of the situation, 72% of participants were unemployed.

My heart goes out to these people. Study qualification requires “failing four or more antidepressants,” which I think is backward because it places the burden on the patient. The treatments failed them, fitting into my upstream hypothesis.

The way I see it, every downstream depression treatment available today is a hammer. For most people, finding the right hammer for their nail works. With TRD, your depression is more like a screw, and, with only hammers to choose from, you are screwed.

As the authors touch on, TRD may be a totally different beast than other types of depression, which raises the question of whether the standard tools for measuring depression are the right ones for this population.

VNS has a 20-year regulatory history, originally developed for drug-resistant epilepsy. Researchers later discovered its antidepressant effects, leading the FDA to approve VNS for TRD in 2005. This VNS is not something you clip to your ear or wear on your neck. It’s a surgical procedure that, despite FDA approval, is largely unavailable because, in 2007, the Centers for Medicare & Medicaid Services (CMS) ruled that the evidence for VNS was insufficient, blocking Medicare coverage. Typically, when Medicare blocks coverage, so too do the commercial insurance companies. The RECOVER trial’s goal is to settle the coverage question, hopefully making VNS much more readily available.

Led by a team from Washington University in St. Louis, the RECOVER study was initially a one-year, double-blind study of 493 participants across 84 US sites, randomized to active VNS or a sham (unit implanted but not activated). The VNS units, made by the sponsor, LivaNova, were implanted subcutaneously in the chest with a lead wrapped around the left cervical vagus nerve.

The primary endpoint for the research was the percentage of time a participant spent “in response,” defined as a >= 50% improvement on the MADRS, a standard for measuring depression.

The disappointing news from the first-year trial was that there was no significant difference in MADRS scores between the active and sham arms. In contrast, the other measures showed a statistically significant, “modest,” difference between the groups. Conway and colleagues call this out, acknowledging that MADRS may not be the right measure for this population.

Yet the two-year follow-up study highlights impressive durability. As shown in the chart below, among patients who showed at least meaningful benefit at 12 months, 85% still had it at 24 months. The stronger responders held even better: of those with substantial benefit at 12 months, 92% still had at least meaningful benefit at 24 months. Not shown in the chart, but worth calling out, is that about a third of patients with no benefit at 12 months gained benefit during year two. Relapse was rare, and there were no safety issues.

To interpret these results, it’s important to understand the initial 12-month trial. The trial had two arms. Everyone (493) received an implant and underwent the standard interviews and screenings across four measures: clinician impression (CGI-I), patient self-report (QIDS-SR), a masked, off-site clinician rating (QIDS-C), and MADRS. Half the patients had the device turned on and calibrated over months 1-3.

At the end of the first year, all patients had their devices turned on, but the researchers only included the first-year active group scores in their durability analysis. This decision is a real limitation that we’ll return to below.

What grabbed me about the RECOVER results is both the promise of VNS and the challenges of TRD. VNS isn’t a medication targeting neurotransmitters; rather, it’s an intervention that stimulates an entire regulatory system tied to the vagus nerve. This distinction is particularly important for this population, given their lifelong challenges of being continually disappointed by medications.

For me, the obvious question is, given that VNS shows some benefit, what is it doing? Surprisingly, the researchers did not investigate this question. They only speculate on this, with likely candidates including changes in neurotransmitter signaling, neuroplasticity, and the vagus nerve’s anti-inflammatory effects.

The inflammation angle aligns with my first Field Note, where I discussed its role in altering vagal nerve signaling and driving cognitive decline in mice. I understand why RECOVER didn’t measure any inflammatory markers. Its design focused not on how VNS works, but how well it works.

This thread led me to a very small Canadian study by Lespérance et. al. that measured inflammatory markers in TRD patients receiving VNS. This trial comes with two key disclaimers: it involved only 6 patients, and the patients’ level of depression was less severe than that of the RECOVER group.

The Lespérance team found a reduction in inflammatory markers, but not those typically associated with damaging inflammation and depression: TNF-α and IL-6. Neither marker moved noticeably. What changed were other inflammation markers related to signaling pathways that recruit immune cells into the brain, as well as proteins that govern the blood-brain barrier.

The authors interpreted this (pure speculation) to mean that VNS may not directly reduce inflammation; rather, it influences the underlying inflammatory machinery. For example, augmenting the blood-brain barrier and reducing the signals that summon immune cells to cross it.

In Field Note 1, we saw how bacterial metabolites suppressed vagal nerve signaling, leading to neuroinflammation and downstream memory loss in mice. With RECOVER, we might be seeing the flip side of the same biology, though it’s impossible to verify because RECOVER didn’t measure any inflammatory markers, and Lespérance included only 6 patients.

From an upstream perspective, aspects of both depression and cognitive decline might overlap at the intersection of the vagus nerve, the blood-brain barrier, and inflammation. And certainly, there is strong evidence that midlife depression associates with cognitive decline later in life. But does having depression in midlife cause later cognitive decline, or are they both symptoms of the same upstream dysfunction? It’s a question worth revisiting.

Plausible isn’t proven, and this section is where I work through the gap with three concerns about how to interpret these results.

First, we don’t know why VNS is triggering the results the authors found. Their best guesses are:

• Changes in neurotransmitter signaling would involve the locus coeruleus, a small brainstem nucleus that’s a principal source of norepinephrine and one of the structures that project to the hippocampus, a structure I wrote about in Field Note 1.

• Neuroplasticity, which seems to be a catch-all these days for both brain dysfunction and its potential recovery.

• The anti-inflammatory pathway.

Second, because there was no control arm in year two, there is no way to tell if durability is due to VNS. Certainly, scores (non-MADRS) remained high and even rose in some cases, but without a sham-control group, we don’t know whether VNS was the reason.

Third, the relationship between the responses of the sham and active stimulation groups is odd. The sham group's scores increased in the last three months of the first-year trial, and the authors speculate that sham participants became more optimistic as the activation date approached. There's clearly much more going on than just vagal stimulation, and even the authors noted that the sham group scored higher than in comparable trials.

On the surface, this research looks like a story about whether VNS works for severe depression, and according to the standard depression scale (MADRS), it doesn’t. My take is that the researchers chose the wrong primary endpoint for patients with TRD. For the meaningful subset of patients who responded on the other three measures, the vast majority maintained that response two years out. Again, these were people who had spent half their lives with treatments failing them. So, while this trial suggests some benefit from VNS, it clearly highlights the challenge of measuring TRD in the first place.

• Conway et. al. Vagus nerve stimulation in treatment-resistant depression: A one-year, randomized, sham-controlled trial. Brain Stimulation. 2025;18:676–689.

• Conway et. al. Durability of the benefit of vagus nerve stimulation in markedly treatment-resistant major depression: a RECOVER trial report. International Journal of Neuropsychopharmacology. 2026;29:pyaf080.

• Lespérance et. al. Vagus Nerve Stimulation Modulates Inflammation in Treatment-Resistant Depression Patients: A Pilot Study. International Journal of Molecular Sciences. 2024;25:2679.

For my next Field Note, I want to further look into the blood-brain barrier and its possible role in cognitive decline and depression. Suffice it to say, it’s time to take out the trash.

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Here it is! My inaugural Field Note. After 25 years in cybersecurity analysis—learning to explain upstream risks before they became crises—I’m now applying that same mindset to brain health. I’ve often written for clients about “shifting left” to find vulnerabilities at the source before they reach production. Brain health needs the same rethink: many current treatments target downstream effects such as low serotonin levels and amyloid plaques rather than root causes. We need to focus upstream!

In this first Field Note, I’m writing about a new study in mice that links gut bacteria to memory loss, and potential ways to reverse that loss. BTW, my interest in the gut-to-brain connection started a few years ago after reading about a patient who developed depression following a poop transplant (it’s a thing!) from a donor with undisclosed depression.

If these mouse study results prove relevant to humans, treatment strategies for cognitive decline could fundamentally change. Below, I explain why understanding this pathway is essential.

Age-related memory decline is top of mind. My family history makes me extra sensitive. For example, recently, when I couldn’t immediately recall the name of the Canadian singer who went to school with my Uncle (Leonard Cohen), I freaked! Friends told me, “Happens to me all the time.” But why do our memories fade and become harder to reach with age?

Researchers at the University of Pennsylvania suggest that what we call “brain aging” may partly stem from a breakdown in gut-to-brain communication. The gut bacterium Parabacteroides goldsteinii in mice produces medium-chain fatty acids. These activate receptors on peripheral immune cells, triggering inflammation. This inflammation damages vagal nerve impulses to the hippocampus (where new memories are made).

What’s intriguing is that this finding is consistent with another area of research in humans: peripheral inflammation is linked to cognitive decline, and may cause it. Two large meta-analyses found that higher levels of inflammatory markers significantly increase the risk of cognitive decline in older adults. Even more striking, a long-term study found that people with higher inflammation in their 20s performed worse on cognitive tests in middle age. However, while these studies suggest an association, they do not confirm causation or the exact mechanisms involved. Still, inflammation is increasingly hard to ignore.

What excites me about this paper is the level of detail in the biological pathway. This isn’t just generic advice about “gut health” — it’s a description of a specific molecular pathway.

The researchers tackled causation versus correlation head-on using multiple approaches. Young mice developed memory problems after exposure to aged mice and their gut bacteria. Germ-free mice receiving microbiomes from older mice showed a similar decline. Researchers also isolated specific bacterial species to test their direct effects.

Researchers linked cognitive decline to reduced activation of hippocampal neurons. They identified medium-chain fatty acids as an active molecule that could reproduce memory deficits when given directly.

Further, they tested specific interventions. A bacteriophage targeting bacteria improved memory in aged mice. Inhibiting a specific cell-surface receptor involved in inflammation triggered by the medium-chain fatty acids restored cognitive function. Finally, Vagal nerve stimulation with capsaicin restored memory performance.

The mouse research is quite interesting to me because it relates to drugs that millions of people already take. Researchers showed that liraglutide (similar to Ozempic and Wegovy) improved memory in aged mice. This finding may relate to human findings. Strikingly, observational studies have linked GLP-1 drugs for diabetes to lower dementia risk. Impressive, right, though this may be correlation more than causation.

Late last year, Novo Nordisk announced that its EVOKE trials, the largest GLP-1 studies conducted in Alzheimer’s, did not slow cognitive decline, prompting Novo to end the program. This doesn’t kill the GLP-1 hypothesis, but it complicates it significantly.

I’m intrigued by the way GLP-1 drugs sit at the intersection of metabolism, inflammation, and cognitive decline. Researchers increasingly suspect that insulin resistance, impaired glucose metabolism, and chronic inflammation may all contribute to cognitive decline and Alzheimer’s disease. This is one reason some researchers describe aspects of Alzheimer’s as “Type III diabetes,” since many Alzheimer’s brains show disrupted glucose utilization.

It’s important to note that the observational studies tracked people taking GLP-1 drugs before dementia onset. The EVOKE trials tested the drugs in people who already had early-stage Alzheimer’s. In other words, the drugs may still have value for prevention even though they don’t reverse existing damage. This difference—between prevention and treatment, and between causation and correlation—highlights a research gap that will require more targeted trials to resolve.

What makes this worth paying attention to is that brain aging may be driven in part by modifiable factors. Aged, germ-free mice experience delayed cognitive decline. This makes the upstream focus personally urgent. And by targeting defined actors along the pathway, researchers suggest a possible route to truly tackle the causes—not just the symptoms—of cognitive decline, at least in mice. Interestingly, the researchers did not find increased intestinal permeability (“leaky gut”) in the mice experiencing cognitive decline, suggesting the effects may be more closely tied to inflammation and vagal signaling.

How cool is it that specific approaches can restore memory function in aged mice? This could open a path toward new treatments targeting inflammation and gut-to-brain pathways in humans.

• Primary study — Cox et al., Nature, March 2026

• GLP-1 and dementia meta-analysis — 26 trials, 160,000+ patients

• The EVOKE trial did not slow Alzheimer’s progression

• Early inflammation and cognitive decline — Yaffe/UCSF, Neurology 2024

• IL-6 and cognitive decline meta-analysis — 15,828 participants

• Inflammation and cognition: a systematic review

I’m intrigued by the possibility that the gut-to-brain pathway has an impact beyond memory and cognition. This investigation will continue as I explore the vagus nerve’s role in treatment-resistant depression. If it turns out that high inflammation and vagal signaling suppression contribute to both cognitive decline and mood disorders, these pathways may prove more relevant than we currently understand.

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