# Read Your Genes! APOE4, Brain Health, and Longevity | HOMe Podcast #026

An episode of [Health Optimization Medicine Podcast](https://invisiblenetwork.ai/podcast/1663974629), 9 Sep 2026, 11 min.

Audio: https://traffic.libsyn.com/secure/672d8edf-a640-45ce-ac61-cd5f898a7b27/HOMe_Podcast_026.mp3?dest-id=3824325

In this episode of the Health Optimization Medicine Podcast, Dr. Ted Achacoso, Dr. Jup Kuipers, Boomer Anderson, Dr. Allen Bookatz, and Dr. Scott Sherr explore a difficult question: can we influence the biology of an aging brain carrying APOE4 risk? APOE4 is not simply a diagnosis, and a genetic result does not tell us what is happening in someone's brain today. The team looks at how APOE4 may affect lipid transport, microglial behavior, vascular integrity, glucose utilization, mitochondrial function, circadian biology, and epigenetic maintenance. The discussion also lays out a practical three-phase framework: establish the phenotype, reduce ongoing stressors, restore circadian and bioenergetic alignment, and track whether cognitive, functional, metabolic, vascular, and biological age measures actually improve over time. Join us as we delve into: • APOE4 Risk vs Diagnosis: What one versus two APOE4 copies may mean, and why genotype is not the same as the current clinical stage. • Cellular Energy and Epigenetic Maintenance: Why disrupted energy metabolism can affect the conditions needed for normal transcription and epigenetic maintenance. • Circadian Biology, NAMPT and NAD+: How CLOCK and BMAL1 influence NAMPT and the NAD+ salvage pathway, and why disrupted circadian rhythms can affect cellular maintenance. • Health Optimization Medicine vs Disease-Centered Prevention: Why the HOMe approach focuses on the cellular environment and the conditions that create and sustain health. • The Three-Phase Clinical Framework: How to establish a baseline phenotype, reduce exposomic stressors, restore circadian and bioenergetic alignment, and track outcomes over time. • The Skeptical Position: The team considers the argument that APOE4-driven pathology may be too genetically determined for lifestyle and metabolic tuning to meaningfully change the trajectory. • What Does a "Reset" Actually Mean?: Why a reset is a claim that needs to be demonstrated through durable improvements in cognition, function, and biomarkers over time. This episode is for you if: • You have undergone genetic testing and want to better understand what an APOE4 result does and does not tell you. • You are interested in the relationship between APOE4, brain aging, metabolism, vascular health, and mitochondrial function. • You want to understand how circadian biology, NAD+ salvage, and epigenetic maintenance may intersect with brain health. • You are interested in a measurement-based Health Optimization Medicine approach to genetic risk. • You want to understand why phenotype, longitudinal tracking, and objective biomarkers matter when evaluating interventions. You can also find this episode on… YouTube: https://youtu.be/byEspMGRbtI Find more from Health Optimization Medicine and Practice (HOMeHOPe): Website: https://homehope.org/ Instagram: https://www.instagram.com/homehopeorg/ HOMeHOPe Conference 2026: https://homehope.org/homehope-conference-2026 Use PODCAST10 to get 10% OFF your purchase of the Clinical Metabolomics Module at https://homehope.org/products/clinical-metabolomics Find more from Troscriptions: Website: https://troscriptions.com/ Instagram: https://www.instagram.com/troscriptions/ Use POD10 to get 10% OFF your Troscriptions purchase at https://troscriptions.com/collections/our-products

## Transcript

[0:00] Dr. Allen Bookatz: What if the word reset is doing too much work?
[0:03] APOE4 is not trivial.
[0:06] One copy raises Alzheimer's risk, and two copies may produce a far more penetrant
[0:11] and predictable Alzheimer's biology.
[0:13] But neither a genotype nor one blood methylation score tells
[0:17] us by itself what's happening in this person's brain today.
[0:21] The stricter question is this.
[0:23] Can we improve the biology that shapes an aging brain, then show that cognition,
[0:28] function, vascular health, metabolism, and the relevant biomarkers work together?
[0:34] That is harder than selling a reset, but it's also far more useful.
[0:42] Dr. Jup Kuipers: All right, everybody.
[0:43] This is the Health Optimization Medicine podcast.
[0:45] Your clinical team here today, myself, Dr. Jup Kuipers, general practice physician
[0:50] in Amsterdam and home doctor; Boomer Anderson, our CEO of HOMeHOPe and Health
[0:56] Optimization Medicine practitioner; Dr. Allen Bookatz, chief of emergency
[1:00] medicine and home doctor as well; and Dr.
[1:03] Theodore Achacoso, the founder of Health Optimization Medicine and practice;
[1:07] and Dr. Scott Sherr, board-certified internal medicine doc and home doctor.
[1:13] Today your clinical team is going after one question: Can we reset
[1:17] epigenetic aging in an APOE brain?
[1:19] The next 25 minutes, you'll get into the cellular mechanics, the clinical
[1:23] protocol, and the one thing most practitioners get wrong about this.
[1:27] Let's go.
[1:27] Boomer Anderson: All right, gents.
[1:28] Can I get a drum roll please?
[1:30] Okay, I guess I'm the only one supplying the drum roll today.
[1:33] All right, the $64,000 question of the day.
[1:36] Can or… A cognitively normal person runs a direct-to-consumer genetics test, I know
[1:42] nobody like this- … uh, and finds that w- they have one or two APOE4 alleles.
[1:48] Should they join the message board on Reddit about how their life is ending?
[1:52] Is th- that a risk result?
[1:55] Is that a diagnosis, or is it really something in between?
[1:59] Mm. Dr. Bookatz.
[2:00] Dr. Allen Bookatz: Yeah, I, I imagine someone getting a positive APOE test
[2:04] would be quite alarmed initially by it, and if you do a quick internet search.
[2:07] And so I think to clear it up for people, they need to understand that for one
[2:11] copy, yes, it is a major risk result, and for two copies, the biology deserves,
[2:17] I think, really stronger language here.
[2:19] And so let's look at what the literature tells us.
[2:21] A 2024 cohort analysis found a much more predictable sequence
[2:25] of amyloid tau neurodegeneration and symptom onset in the APOE4
[2:31] homozygotes, so that means two copies.
[2:33] Leading authors propose that an APOE4 as a genetic form of Alzheimer's disease.
[2:40] But the genotype is still not the same as current clinical stage, and
[2:45] that's really important to understand.
[2:46] It changes the prior probability and the urgency of phenotyping
[2:51] Dr. Scott Sherr: Yeah, Allen, and we need to be clear about the contrast here.
[2:54] Pathogenesis asks which disease label should we assign and what
[2:59] drugs treat the protein byproduct?
[3:01] HOMeHOPe, as in contrast, looks at salutogenesis, which asks what
[3:06] creates and sustains health in this specific cellular network?
[3:10] Root cause is not enough if the root question is still disease.
[3:14] Boomer Anderson: All right, let's get into that mechanism, shall we, Dr.
[3:16] Dr. Jup Kuipers: Kuipers?
[3:19] the biology a bit.
[3:20] So why is the APOE4 brain metabolically and epigenetically
[3:25] more vulnerable, Dr. Ted?
[3:27] Dr. Ted Achacoso: Well, because, uh, APOE4 alters lipid transport, microglial
[3:31] behavior, and vascular integrity.
[3:34] In the cerebrovasculature and glia, lipid handling is less efficient, which alters
[3:39] membrane composition, increases oxidative stress, and impairs glucose utilization.
[3:44] When energy production slips, the cell enters a defense or cell danger response
[3:50] pattern, and the epigenetic machinery loses the metabolic stability required
[3:55] for normal transcriptional maintenance.
[3:57] Dr. Jup Kuipers: All right, Dr. Kuipers, where does chronobiology fit into
[4:00] this discussion on the metabolic side?
[4:02] So circadian transcription factors like CLOCK and BMAL1 drive the
[4:07] expression of NAMPT, the rate-limiting enzyme in the NAD+ salvage pathway.
[4:14] So when circadian rhythms are disrupted by late-night artificial light or shift
[4:18] work, NAMPT oscillations flattens.
[4:22] Cellular NAD+ pools contract and SIRT1 activity drops.
[4:27] And these sirtuins, they require NAD+ to regulate histone
[4:30] deacetylation and DNA repair.
[4:33] Disrupt circadian timing, and you impair epigenetic maintenance.
[4:36] Dr. Scott Sherr: Yeah, Yep, and here's what practitioners often
[4:38] make as a conceptual mistake.
[4:40] Preventative medicine aims to prevent disease but remains disease-centered.
[4:44] Health Optimization Medicine is health-centered.
[4:47] It measures and tunes cellular cofactors, redox balance, and a metabolic flux
[4:52] before structural damage occurs.
[4:54] Dr. Allen Bookatz: Exactly, Dr. Scott.
[4:55] And from the longevity perspective, lifespan without
[4:59] healthspan is not the win.
[5:02] The goal here isn't merely adding years to your calendar.
[5:05] It's maintaining that peak biological quality of life, and
[5:09] in this case, cognitive clarity.
[5:10] Dr. Scott Sherr: The Health Optimization Medicine Conference is happening.
[5:13] Two days of events, October 2nd and 3rd, Chicago, Illinois, at the Drake Hotel.
[5:18] CMEs available to practitioners who need them.
[5:20] Just 150 people with amazing speakers on the cutting edge of health and wellness.
[5:25] This is a community.
[5:26] It's not your average conference.
[5:28] If you're interested, go to homehope.org and save 25% on your ticket by
[5:31] using CONFERENCE25 at checkout.
[5:34] I hope to see you there.
[5:35] Boomer Anderson: All right, so now it's perhaps my favorite time
[5:37] in the podcast where we're gonna get into the one-cent solution.
[5:39] So these are the three things that you guys can do.
[5:42] How do we translate this into a structured clinical framework?
[5:46] Dr. Allen Bookatz: I think we call this phase one.
[5:48] Well, we're gonna measure and we want to unburden the cell environment.
[5:52] So first, we establish the baseline phenotype, and we do that by
[5:55] measuring things like organic acids, lipid peroxidation markers,
[5:59] NAD+ salvage metabolites and pathways, vascular markers, and
[6:04] circadian sleep-wake parameters.
[6:06] And so really talking to the person, getting a sense like what
[6:09] is, what is their lifestyle like?
[6:11] Then we wanna identify and reduce the exposomic stressors, so things
[6:15] like the lipophilic toxins, chronic nighttime light pollution, and those
[6:20] unmanaged glycemic variability.
[6:23] Hint, hint, nighttime snacking.
[6:25] Dr. Ted Achacoso: And toxic partners.
[6:26] Dr. Jup Kuipers: And,
[6:26] Dr. Allen Bookatz: and toxic partners.
[6:27] Dr. Jup Kuipers: And toxic partners.
[6:28] And once we've got rid of our toxic partners, kidding, we move
[6:31] to phase two, reestablish circadian and bioenergetic alignment.
[6:35] So align circadian cues to restore NAMPT oscillations.
[6:41] Anchor morning outdoor light within 30 minutes of waking.
[6:44] Eliminate high-intensity evening light, and maintain consistent meal timing.
[6:48] Things like this support mitochondrial substrate delivery and redox balance based
[6:52] strictly on measured metabolomic deficits.
[6:55] Dr. Scott Sherr: Hmm, yes.
[6:56] And so what phase three is, is tracking longitudinal multi-domain outcomes.
[7:01] So what this means is retesting objectively.
[7:05] Evaluate whether cognitive performance, functional capacity, vascular
[7:09] markers, metabolic flexibility, and biological age indicators move
[7:11] in unison over six to 12 months.
[7:14] An intervention is only effective if the broader biological
[7:17] network confirms improvement.
[7:19] Boomer Anderson: All right, so Dr. Ted, you know, this
[7:21] podcast comes out on Wednesday.
[7:23] What should people be doing by Monday?
[7:25] Dr. Ted Achacoso: Well, if you're a practitioner or individual addressing
[7:28] APOE4, do not start by purchasing 10 unquantified supplements.
[7:33] Boomer Anderson: Who does
[7:34] Dr. Ted Achacoso: that?
[7:36] All of us do.
[7:37] Mm-hmm.
[7:37] On Monday, audit circadian light exposure.
[7:40] Get 10 to 15 minutes of natural morning light, or if you can't do
[7:44] that, get yourself a vitamin D lamp.
[7:46] Dim evening environment after sunset.
[7:48] You know, you can have bulbs there that actually take the blue out
[7:52] gradually from your evening light.
[7:54] And schedule baseline metabolomic testing to guide any subsequent protocol, meaning
[7:59] your supplements have to be guided by the results of your metabolomic tests.
[8:04] Boomer Anderson: All right, gents, I have to ask you for MDs.
[8:06] What could we be wrong about here?
[8:08] Dr. Scott Sherr: Yeah.
[8:08] Here, so let's, let's do this deal, man, as we do all the
[8:11] time in this podcast, right?
[8:13] What, what is the skeptical position?
[8:14] So a neurologist or a geneticist might say APOE4 is a major structural
[8:18] driver of amyloid and tau pathology.
[8:21] Lifestyle and metabolic tuning cannot overcome strong monogenic penetrance
[8:25] or prevent eventual neurodegeneration.
[8:28] Dr. Allen Bookatz: Yeah, that's definitely fair, and it's an important objection.
[8:32] And I think when we understand what penetrance means, at least in this case,
[8:37] high penetrance is the… means basically that the biological slope itself is steep.
[8:42] So while we don't claim that lifestyle advice alone halts the progression to
[8:47] advanced pathology, and w- no one's claiming that here, but lifestyle advice
[8:51] becomes precision medicine when cell health markers guide the prescription.
[8:55] By optimizing the mitochondrial bioenergetics, vascular integrity,
[8:59] and circadian NAD salvage pathways, we improve the cellular terrain in
[9:03] which that genetic risk operates.
[9:05] Boomer Anderson: All right, so real quick, take home three from you guys.
[9:08] Uh, Dr. Bookatz, I'm gonna volley right back to you on this one.
[9:11] Yeah.
[9:11] Dr. Scott Sherr: Okay.
[9:12] So your genotype is not your biography.
[9:15] Dr. Allen Bookatz: So one copy of this APOE4 certainly raises risk.
[9:19] Two copies increases the penetrance.
[9:22] So phenotype early instead of being fatalistic here.
[9:26] Boomer Anderson: Dr. Ted, you get round two.
[9:28] Dr. Ted Achacoso: Yes, you cannot supplement out of circadian misalignment.
[9:34] BMAL1 drives an NAMPT.
[9:36] Light anchoring comes first.
[9:37] So wake up in the morning, anchor yourself in the morning light, and
[9:41] in the evening, decrease your blues and just like mimicking a sunset.
[9:46] Dr. Jup Kuipers: All right.
[9:46] Sorry to skip you this week, Scott, but Dr. Kuipers, you get number three.
[9:50] Okay.
[9:51] So let's take it home.
[9:52] The reset is a claim that must be earned with durable cognitive, functional,
[9:57] and biomarker improvements across time.
[10:01] And on that note, I'm gonna sign you guys off.
[10:04] Thank you all for listening to the Health Optimization Medicine podcast.
[10:07] If you're a physician or health care provider ready to learn clinical
[10:11] metabolomics, exposomics, bioenergetics, epigenetics, and chronobiology as one
[10:17] coherent system, join HOMeHOPe Certified Practitioner Program at homehope.org.
[10:22] We'll see you guys next week.
[10:25] Boomer Anderson: Sayonara
[10:27] Bye.

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