HoldsUp

FoundMyFitness · 2018-10-01 · Rhonda Patrick (host), Dale Bredesen

Dr. Dale Bredesen on Preventing and Reversing Alzheimer's Disease

47 claims checked against research: 1 contradicted 5 overstated 1 needing context 35 supported 5 unverified

35

Supported by research

0:01:30Dale Bredesensupportedhigh

Alzheimer's disease is the most common cause of cognitive decline and dementia.

"Alzheimer's is the most common cause of cognitive decline, ultimately dementia." (said at 0:01:30)

Epidemiological evidence and systematic reviews consistently establish that Alzheimer's disease is the most frequent cause of progressive cognitive impairment and dementia worldwide, accounting for an estimated 60% to 80% of all dementia cases.

0:02:52Dale Bredesensupportedmoderate

Research by Rudolph Tanzi and Robert Moyer at Harvard showed that amyloid-beta possesses antimicrobial properties.

"Professor Rudy Tanzi and Professor Robert Moyer at Harvard a few years ago showed that it is an antimicrobial." (said at 0:02:52)

Research led by Rudolph Tanzi and Robert Moir (phonetically rendered as 'Moyer') at Harvard Medical School and Massachusetts General Hospital demonstrated that amyloid-beta acts as an antimicrobial peptide (AMP). In a 2010 study (Soscia et al.), they demonstrated in vitro that amyloid-beta inhibits the growth of multiple clinically relevant pathogens with potency comparable to LL-37, a classic human antimicrobial peptide, and that antimicrobial activity in Alzheimer's brain homogenates correlated with amyloid-beta levels. In a 2016 follow-up (Kumar et al.), they further showed in vivo in transgenic mouse and Caenorhabditis elegans models that amyloid-beta expression protects against microbial infection via oligomerization and entrapment of pathogens.

0:03:05Dale Bredesensupportedhigh

Research by Ashley Bush showed that amyloid-beta binds divalent metals including copper, zinc, and iron.

"as Professor Ashley Bush showed a number of years ago, it's actually quite a good binder of divalent metals like copper and zinc and things like that, iron." (said at 0:03:05)

The claim is supported by published biochemical literature co-authored by Ashley I. Bush demonstrating that amyloid-beta (Aβ) binds divalent metal ions, including copper, zinc, and iron. Bush and colleagues characterized specific metal-binding sites on Aβ, showing that Cu²⁺ and Zn²⁺ directly bind the peptide, inducing aggregation and oligomerization (PMID 10936205, PMID 11274207). Review literature authored by Bush further synthesizes these findings, noting that Aβ and its precursor protein (APP) interact with metal ions such as zinc, copper, and iron, and that high concentrations of these biometals accumulate in amyloid plaques in diseased brains (PMID 15709482, PMID 17119284).

0:06:15Dale Bredesensupportedmoderate

In insulin resistance, IRS-1 phosphorylation is altered such that serine/threonine phosphorylation increases relative to tyrosine phosphorylation, altering cellular insulin signaling.

"So you actually phosphorylate your IRS-1, as showed very nicely by Professor Ed Goetzl over at UCSF, so you've changed the ratio of the serine/threonine phosphorylation to the tyrosine phosphorylation, and you're literally changing your response to insulin." (said at 0:06:15)

Research led by Edward Goetzl and colleagues demonstrated that in conditions characterized by insulin resistance (including Alzheimer's disease and type 2 diabetes), neural-derived exosomes exhibit an elevated ratio of serine-phosphorylated IRS-1 (such as pSer312-IRS-1, associated with impaired insulin signaling) relative to tyrosine-phosphorylated IRS-1 (p-panTyr-IRS-1, representing normal active signaling). This shifted phosphorylation ratio directly impairs downstream insulin receptor pathway responsiveness.

0:10:48Dale Bredesensupportedhigh

Copper and zinc compete with each other for gastrointestinal absorption.

"copper and zinc actually are competitive, for example, in their absorption. And so too much of one actually is often associated with too little of another." (said at 0:10:48)

Copper and zinc exhibit well-characterized competitive interactions during intestinal absorption. High intake of zinc upregulates the intestinal metal-binding protein metallothionein, which preferentially binds dietary copper, trapping it inside enterocytes and preventing its systemic absorption. This mutual antagonism is clinically significant: excessive zinc supplementation is a classic cause of secondary copper deficiency and copper deficiency anemia, and is clinically utilized in the treatment of Wilson's disease to block copper absorption.

0:11:00Dale Bredesensupportedmoderate

Approximately 1 billion people worldwide are estimated to suffer from zinc deficiency.

"There are actually about a billion people on Earth as the estimate for zinc deficiency." (said at 0:11:00)

The claim that approximately 1 billion or more people worldwide suffer from zinc deficiency (or are at risk of inadequate zinc intake/deficiency) is supported by published global epidemiological models and reviews. A widely cited 2012 review by Ananda S. Prasad on human zinc deficiency states that "nutritional deficiency of zinc may affect nearly 2 billion subjects in the developing world" (PMID: 22664333). Furthermore, global food balance modeling by Wessells and Brown (2012) estimated that 17.3% of the world's population—representing over 1.2 billion people based on global population figures—was at risk of inadequate zinc intake (PMID: 23209782).

0:11:10Dale Bredesensupportedmoderate

Proton pump inhibitors and reduced gastric acidity impair zinc absorption.

"if you have poor gastric acidity, which is common as we age, if you're taking PPIs for GERD, if you're taking something for reflux, you won't absorb the zinc very well." (said at 0:11:10)

Clinical studies show that proton pump inhibitors (PPIs) and reduced gastric acidity can significantly reduce the intestinal absorption of zinc, particularly from supplemental sources, and long-term PPI use is associated with lower circulating zinc levels. In a controlled trial evaluating acute zinc absorption, omeprazole significantly reduced zinc absorption compared to baseline. Another study comparing healthy controls to long-term PPI users found that supplemental zinc absorption was markedly blunted (a 37% plasma zinc increase in PPI users compared to a 126% increase in controls), and baseline plasma zinc was 28% lower in PPI users.

0:11:38Dale Bredesensupportedmoderate

Literature from over 30 years ago documented that individuals with elevated copper-to-zinc ratios have a higher incidence of dementia.

"And in fact, it was noted over 30 years ago that people with high copper-to-zinc ratios tended to have dementia more than those with normal copper-zinc ratios." (said at 0:11:38)

Literature published over 30 years ago (meta-analysing studies dating back to 1984) confirms that patients with Alzheimer's disease and related dementias demonstrate altered trace element profiles, specifically characterisable by elevated serum copper and reduced serum zinc levels, resulting in a higher copper-to-zinc ratio in affected individuals compared to healthy controls.

0:12:19Dale Bredesensupportedhigh

Copper generates free radicals because it possesses an unpaired d-orbital electron, a characteristic zinc lacks.

"copper is a generator of free radicals. Copper can act like iron in that sense: it has a free electron in the d-orbital, which does not occur with zinc." (said at 0:12:19)

The speaker's statement is supported by biochemical literature. Copper, like iron, is a redox-active transition metal capable of driving Fenton-like redox cycling and generating reactive oxygen species such as hydroxyl radicals. Chemically, cupric copper (Cu2+) has an incomplete d-subshell electron configuration ([Ar] 3d9) containing an unpaired d-electron, allowing it to easily alternate oxidation states (Cu+ / Cu2+). In contrast, zinc exists as Zn2+ with a completely filled d-subshell ([Ar] 3d10) lacking unpaired d-electrons, rendering zinc redox-inactive and incapable of participating in free radical-generating Fenton reactions.

0:14:35Dale Bredesensupportedmoderate

Approximately 75 million Americans (around 25% of the population) carry a single copy of the ApoE4 allele.

"75 million Americans have a single copy of ApoE4... about a quarter of the population, so about 75 million Americans, have one copy of ApoE4" (said at 0:14:35)

Population genetic studies in the United States show that approximately 20% to 25% of the population carries an APOE ε4 allele (predominantly heterozygous, carrying a single copy), which corresponds to roughly 75 to 80 million people in the U.S. population. While carrier prevalence varies somewhat by ancestral background (e.g., ~25% among non-Latino White Americans and lower in some other groups), the stated overall estimate of ~25% (about 75 million Americans) is well-aligned with epidemiological data.

0:15:20Dale Bredesensupportedmoderate

Individuals with no copies of the ApoE4 allele (such as ApoE 3/3) have an estimated lifetime risk of Alzheimer's disease of about 9%.

"Now, if you have a zero copy, so if you're, for example, a 3/3, your overall lifetime risk for Alzheimer's is about 9%, so not terribly common disease, but not zero." (said at 0:15:20)

Large epidemiological studies calculating genotype-specific lifetime risks for Alzheimer's disease estimate the baseline lifetime risk by age 85 to be approximately 11% in males and 14% in females overall. Because carrying one or two APOE4 alleles significantly increases lifetime risk (to 23–30% for APOE 3/4 and 51–60% for APOE 4/4), non-carriers of APOE4 (such as APOE 3/3 carriers) have a lower baseline lifetime risk of approximately 9%.

0:15:32Dale Bredesensupportedhigh

Carrying a single copy of ApoE4 confers an estimated lifetime Alzheimer's risk of approximately 30%, whereas homozygosity confers a risk greater than 50% and up to 90% in some studies.

"On the other hand, if you have a single copy of ApoE4, your lifetime risk is about 30% or so. If you have two copies, if you're homozygous, your lifetime risk is over 50%, and in some studies, as high as 90%." (said at 0:15:32)

The speaker's estimates are well-supported by epidemiological and genetic literature on Alzheimer's disease risk. In large cohort studies and meta-analyses, individuals carrying a single APOE ε4 allele have an estimated lifetime risk of Alzheimer's disease of approximately 20% to 30% (compared to ~10–15% in non-carriers), with odds ratios around 3-fold. For APOE ε4 homozygotes, lifetime risk estimates in population studies typically exceed 50% to 60%, and in clinic-based or biomarker-defined cohorts, cumulative risk and biological penetrance approach 80% to over 90% by age 85–90.

0:24:20Dale Bredesensupportedlow

Research by Caleb Finch showed that ApoE4 carriers have survival advantages in pathogen- and parasite-rich environments, such as the Tsimané in Bolivia and populations in Ghana.

"ApoE4 gives you an advantage in that you have a hair-trigger, essentially, for inflammation... so if you live in a squalid environment like the Tsimané Indians that Professor Caleb Finch studied, for example, or the Ghana tribe that Caleb also has studied, you are in better shape if you're ApoE4-positive." (said at 0:24:20)

Published research co-authored by Caleb Finch in the indigenous Tsimané population of Bolivia supports the claim that the ApoE4 allele can confer health and cognitive advantages in pathogen- and parasite-rich environments. An observational study of Amazonian forager-horticulturalists (PMID 28031319) demonstrated that older adult ApoE4 carriers with high parasite burdens maintained or improved cognitive performance compared to non-carriers, who showed cognitive decline under high pathogen loads. Further research in this population (PMID 34586066) showed ApoE4 is associated with lower baseline C-reactive protein and higher lipid levels that may buffer the metabolic costs of immune activation during infection.

0:25:10Dale Bredesensupportedmoderate

ApoE4 is significantly underrepresented among centenarians.

"And as you know, ApoE4 is actually underrepresented in centenarians, so it has been a short-gevity gene, as it were." (said at 0:25:10)

A systematic review and meta-analysis comparing 2,776 centenarians with 11,941 younger controls across 13 studies found that carriage of the APOE ε4 allele is significantly underrepresented among centenarians compared to younger populations (pooled odds ratio of reaching exceptional longevity = 0.43; 95% CI 0.36–0.50), with an even lower likelihood for homozygous ε4/ε4 carriers (OR = 0.18; 95% CI 0.08–0.39).

0:26:20Dale Bredesensupportedhigh

Dr. Ritchie Shoemaker characterized Chronic Inflammatory Response Syndrome (CIRS) as an illness linked to exposure to water-damaged buildings, molds, and mycotoxins.

"Dr. Ritchie Shoemaker, who's done so much work over the years on mold and mycotoxins and described what he calls CIRS, chronic inflammatory response syndrome." (said at 0:26:20)

Dr. Ritchie Shoemaker published extensively describing and defining Chronic Inflammatory Response Syndrome (CIRS), particularly in the context of exposure to water-damaged buildings (CIRS-WDB), mold, biotoxins, and mycotoxins.

0:31:54Dale Bredesensupportedmoderate

The glymphatic system alters brain architecture during sleep to clear waste products from the brain.

"Of course, the glymphatic system—you actually have a change in the architecture of your brain as you're sleeping. You're actually essentially sweeping this stuff out." (said at 0:31:54)

The speaker's statement accurately reflects research on the glymphatic system. Groundbreaking in vivo rodent studies by Xie et al. (2013) demonstrated that during natural sleep or anesthesia, the interstitial space in the brain expands by approximately 60%, resulting in a significant increase in convective fluid exchange between cerebrospinal fluid and interstitial fluid and facilitating the clearance of metabolic waste products such as amyloid-beta.

  • supports: Sleep drives metabolite clearance from the adult brain. (Science (New York, N.Y.) 2013) · cited 5440x in the literature
    "Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep." (abstract, results, passage verified)
    pubmedfull study (doi)
0:32:53Dale Bredesensupportedhigh

Bruce Ames developed the Ames test to identify chemical carcinogens.

"Of course, Bruce Ames, with whom you trained, developed the Ames test, which allows us now to look at carcinogens." (said at 0:32:53)

Bruce Ames and colleagues developed the Salmonella/mammalian-microsome mutagenicity assay (the Ames test) in the 1970s. The bacterial reverse-mutation assay combines histidine-dependent Salmonella strains with metabolic activation (mammalian liver homogenate) to assess the mutagenic and potential carcinogenic potential of chemical agents.

0:37:11Rhonda Patrick (host)supportedvery low

A study by Eric Verdin published in Cell Metabolism showed that feeding animals a cyclic ketogenic diet improved healthspan, cognitive function, and brain aging.

"Dr. Eric Verdin at the Buck Institute—I had spoke with him a few months back on a very interesting paper he had published, I believe it was Cell Metabolism, where he had done—he had given animals a cyclic ketogenic diet. And there was just, you know, improvement in healthspan in general, but what was really, really robust was the—the improvements in cognitive function and brain aging" (said at 0:37:11)

A 2017 study co-authored by Eric Verdin at the Buck Institute and published in Cell Metabolism evaluated the effects of a cyclic ketogenic diet (alternated weekly with a control diet) in aging mice. The study demonstrated that the cyclic ketogenic diet reduced midlife mortality, improved memory performance in old age, and modestly improved composite healthspan measures. Because the findings derive entirely from an animal model, certainty for human application is very low.

  • supports: Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice. (Cell metabolism 2017) · cited 516x in the literature
    "We find that Cyclic KD, KD alternated weekly with the Control diet to prevent obesity, reduces midlife mortality but does not affect maximum lifespan. A non-ketogenic high-fat diet (HF) fed similarly may have an intermediate effect on mortality. Cyclic KD improves memory performance in old age, while modestly improving composite healthspan measures. ... In all, we show that a non-obesogenic ketogenic diet improves survival, memory, and healthspan in aging mice." (abstract, results, passage verified)
    pubmedfull study (doi)
0:42:40Dale Bredesensupportedlow

In a blood test developed by Milan Fiala at UCLA, peripheral blood mononuclear cells from Alzheimer's disease patients showed defective phagocytosis of amyloid-beta compared to healthy controls.

"there was a really interesting test developed by Professor Milan Fiala at UCLA, developed about almost 10 years ago. And how—and what he was looking at was taking peripheral blood mononuclear cells. So you're essentially taking the, you know, blood macrophages, and you're now simply challenging them. He would give them amyloid and just look to see how good are they at phagocytosis, at eating and getting rid of the amyloid. And the surprise was all the people who have Alzheimer's are very poor at eating and getting rid of this amyloid." (said at 0:42:40)

Research led by Milan Fiala at UCLA demonstrated that monocytes and macrophages derived from the peripheral blood of Alzheimer's disease patients exhibit impaired phagocytosis and degradation of amyloid-beta compared to healthy age-matched controls. In subsequent work developing a flow cytometric assay for amyloid-beta phagocytosis, Fiala and colleagues found defective phagocytosis in 94% of tested Alzheimer's disease patients compared to 0% of healthy control participants.

0:44:50Dale Bredesensupportedvery low

In Milan Fiala's research, an M1 to M2 macrophage ratio of approximately 2.5 to 1 was associated with optimal amyloid clearance outcomes.

"And so, in fact, getting the right level, about 2.5 to 1, was associated with the best outcomes." (said at 0:44:50)

Milan Fiala and colleagues investigated macrophage polarization in patients with mild cognitive impairment and subjective cognitive impairment by defining an M1M2 phenotype index (the ratio of pro-inflammatory markers CD54/CD80 to pro-resolution markers CD163/CD206). Their research found that an intermediate, balanced M1-M2 macrophage phenotype (the intermediate 'green zone' centered around ~2.5) was associated with active amyloid-β (Aβ 1-42) phagocytosis and favorable cognitive outcomes, whereas extreme polarization into either M1 (red zone) or M2 (white zone) phenotypes was associated with impaired clearance and poorer cognitive trajectory. However, the evidence comes from a small, open-label, uncontrolled pilot study, limiting certainty.

0:45:55Rhonda Patrick (host)supportedvery low

A study co-authored with Milan Fiala demonstrated that supplementation with omega-3 fatty acids, antioxidants, and vitamin D improved peripheral monocyte phagocytosis of amyloid plaques and improved cognition in APOE4-negative individuals.

"And you had done a small study where you had given people some omega-3 supplements along with some antioxidants and vitamin D, and it improved their phagocytosis of the amyloid plaques in the periphery and also, I think, their cognition. Some—some individuals had improved cognition—APOE4-negative ones. Right. And so that was—so I was a co-author on that paper with Professor Fiala" (said at 0:45:55)

A 2017 pilot study co-authored by Dale Bredesen and Milan Fiala evaluated nutritional supplementation (omega-3 fatty acids, antioxidants, and resveratrol/vitamin D) in patients with mild or subjective cognitive impairment. The study found that peripheral monocyte/macrophage phagocytosis of amyloid-beta 1-42 significantly improved, and cognitive scores (MMSE) improved at a median rate of 2.2 points per year specifically in APOE3/3 (APOE4-negative) individuals, whereas cognition did not improve overall in APOE4 carriers. However, the certainty of evidence is very low because the study was an uncontrolled, small open-label pilot series.

0:46:20Dale Bredesensupportedhigh

Charles Serhan at Harvard demonstrated that specialized pro-resolving mediators like resolvins and maresins derived from omega-3 fatty acids are critical for resolving inflammation.

"And of course, Professor Serhan from Harvard has shown that resolution is a critical part. You have the inflammatory part, but then you have to have that resolution part. And if you don't have that resolution part, again, a change in mode, then you're stuck with this chronic inflammatory state. And so things like omega-3s and omega-3-derived maresins and things like that are actually involved with the resolution—resolvins, named for that very event of resolving inflammation." (said at 0:46:20)

Charles N. Serhan and colleagues at Harvard Medical School/Brigham and Women's Hospital discovered and characterized specialized pro-resolving mediators (SPMs)—including resolvins, protectins, and maresins—derived enzymatically from omega-3 essential fatty acids such as EPA and DHA. Their work established that the resolution of inflammation is an active, biochemical process mediated by these signaling molecules, and that failure of endogenous resolution pathways contributes to chronic inflammatory states.

  • supports: Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. (The Journal of clinical investigation 2018) · cited 1345x in the literature
    "This Review focuses on the resolution phase of inflammation with identification of specialized pro-resolving mediators (SPMs) that involve three separate biosynthetic and potent mediator families, which are defined using the first quantitative resolution indices to score this vital process. These are the resolvins, protectins, and maresins: bioactive metabolomes that each stimulate self-limited innate responses, enhance innate microbial killing and clearance, and are organ-protective." (abstract, passage verified)
    pubmedfull study (doi)
  • supports: Resolution of inflammation: An organizing principle in biology and medicine. (Pharmacology & therapeutics 2021) · cited 334x in the literature
    "The resolution of inflammation has emerged as a critical endogenous process that protects host tissues from prolonged or excessive inflammation that can become chronic. Failure of the resolution of inflammation is a key pathological mechanism that drives the progression of numerous inflammation-driven diseases. Essential polyunsaturated fatty acid (PUFA)-derived autacoid mediators termed 'specialized pro-resolving mediators' (SPMs) regulate endogenous resolution programs by limiting further neutrophil tissue infiltration and stimulating local immune cell (e.g., macrophage)-mediated clearance of apoptotic polymorphonuclear neutrophils, cellular debris, and microbes" (abstract, passage verified)
    pubmedfull study (doi)
  • supports: E-series resolvin metabolome, biosynthesis and critical role of stereochemistry of special… (Seminars in immunology 2022) · cited 89x in the literature
    "The SPMs biosynthesized from the major omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are coined Resolvins (resolution phase interaction products; E series and D-series), Protectins and Maresins (macrophage mediators in resolving inflammation). Their biosynthesis and stereochemical assignments are established and confirmed (>1,441 resolvin publications in PubMed.gov) as well as their functional roles on innate immune cells and adaptive immune cells" (abstract, passage verified)
    pubmedfull study (doi)
0:48:35Rhonda Patrick (host)supportedvery low

Research by Norman Salem showed a defect in DHA transport across the blood-brain barrier in animals carrying human APOE4 compared to APOE2 and APOE3.

"One—one from Salem, Norman—Norman Salem, sorry. He had—he had shown in animals, you take animals and give them human APOE3, 4, 2, and then feed them DHA orally, there was a transport defect in DHA across the blood-brain barrier." (said at 0:48:35)

A 2014 study co-authored by Norman Salem Jr. evaluated docosahexaenoic acid (DHA) transport across the blood-brain barrier using human APOE-targeted replacement mice (carrying human APOE2, APOE3, or APOE4). Brain uptake of radiolabeled [14C]-DHA via in situ cerebral perfusion was found to be 24% lower in APOE4-expressing mice compared to APOE2-expressing mice. Because the finding is derived exclusively from animal models, the overall GRADE certainty is very low.

0:49:06Rhonda Patrick (host)supportedhigh

DHA is transported across the blood-brain barrier in phospholipid form via the MFSD2A transporter.

"One is through a free fatty acid, the other one's through an actual transporter called the MFSD2A transporter, which is actually in a phospholipid form—DHA is in a phospholipid form." (said at 0:49:06)

The speaker accurately describes the transport mechanism of docosahexaenoic acid (DHA) across the blood-brain barrier. The transmembrane transporter MFSD2A (Major Facilitator Superfamily Domain Containing 2A), expressed in the endothelial cells of the blood-brain barrier, specifically transports DHA esterified as a lysophospholipid—lysophosphatidylcholine (LPC-DHA)—rather than as an unesterified (free) fatty acid.

0:49:45Dale Bredesensupportedlow

Richard Wurtman from MIT showed that synaptic formation nutritionally requires both DHA and citicoline.

"And Professor Wurtman from MIT has spent years looking at what does it actually take nutrition—nutritionally to make synapses. And his point was you need the DHA and you need citicoline as well." (said at 0:49:45)

Richard Wurtman and colleagues at MIT conducted extensive research demonstrating that the synthesis of brain phosphatides, synaptic proteins, and dendritic spines depends on rate-limiting dietary precursors in the Kennedy pathway. Specifically, their work showed that co-administering docosahexaenoic acid (DHA), a pyrimidine source (such as uridine or cytidine), and choline (which are provided together by citicoline/CDP-choline) synergistically accelerates synaptic membrane formation and increases synapse density. While this mechanism is well-established in preclinical animal models, translational cognitive outcomes in human clinical trials remain variable.

0:50:20Rhonda Patrick (host)supportedvery low

DHA is required for proper functioning of glucose transporters at the blood-brain barrier.

"The other interesting thing is that DHA, and I, you know, didn't know this previously until I had been digging into the literature, is also seems to be important for some of the glucose transporters on the blood-brain barrier. and so if you're DHA deficient, those glucose transporters aren't working as well and you're not getting glucose into the brain" (said at 0:50:20)

Preclinical animal and cell-culture studies support the claim that docosahexaenoic acid (DHA) and omega-3 fatty acid status modulate glucose transporters at the blood-brain barrier. In rodent models, dietary n-3 polyunsaturated fatty acid deficiency leading to membrane DHA depletion significantly decreases the expression and binding activity of endothelial GLUT1 (the primary glucose transporter at the blood-brain barrier) and reduces brain glucose uptake by approximately 30%. Conversely, supplementing cultured brain endothelial cells with DHA enhances basal glucose uptake and GLUT1 expression. However, direct evidence for this mechanism is currently derived from animal and in vitro models, which limits the certainty to very low.

0:54:40Dale Bredesensupportedvery low

In Dr. Bredesen's clinic, a physician with PET-confirmed early Alzheimer's disease and hippocampal atrophy maintained successful clinical outcomes four years into the personalized protocol.

"One of the first people who came through was a very intelligent physician, and as we went through each thing, he said to me, "Well, you know, I believe that no, that's not a cure for Alzheimer's. That's not a cure for Alzheimer's." He had well-documented early Alzheimer's: PET scan proved amyloid PET positive, FDG-PET positive, hippocampal atrophy, the whole nine yards... And actually, he's done extremely well, and he's now four years into the program and still doing very, very well." (said at 0:54:40)

Published case reports and uncontrolled case series by Bredesen and colleagues describe individuals with biomarker-supported early Alzheimer's disease (including amyloid PET, FDG-PET, and volumetric MRI evidence of hippocampal atrophy) who experienced sustained symptomatic and cognitive improvements across multiple years of follow-up on personalized multimodal protocols (such as MEND/ReCODE). However, because these findings derive entirely from uncontrolled case reports and case series rather than randomized controlled trials, certainty in the efficacy of the protocol remains very low due to high risks of selection bias, practice effects, and lack of a control group.

0:59:30Dale Bredesensupportedvery low

Tau hyperphosphorylation causes tau to dissociate from microtubules, leading to structural microtubule and synaptic collapse.

"And what does the phosphorylation of tau do? It allows it to pop off the microtubules, so you have a rapid collapse of the structure. So no surprise, when you're in this mode of you're trying to fight this off, you're trying to change, you're trying to pull back on your structure, you're going to phosphorylate your tau, pop it off the microtubules, and you're going to die back." (said at 0:59:30)

Published mechanistic and biochemical evidence supports the claim. Under physiological conditions, tau binds to and stabilizes axonal microtubules. Hyperphosphorylation reduces the affinity of tau for tubulin, promoting its dissociation from the microtubule lattice. This detachment impairs microtubule stability, leading to cytoskeletal breakdown, disruption of axonal transport, and subsequent synaptic and neuritic degeneration.

0:43:54Dale Bredesensupportedmoderate

NF-kappa-B-mediated pro-inflammatory signaling and SIRT1-mediated anti-inflammatory pathways exhibit mutual inhibition.

"One of the states you change back and forth between a pro-inflammatory state, essentially an NF-kappa-B-mediated state, and on the other hand an anti-inflammatory state that is involved more with SIRT1. These two actually have multiple sites of mutual inhibition" (said at 0:43:54)

Extensive molecular and cell biology literature documents an antagonistic crosstalk and mutual inhibition between NF-κB-driven inflammatory signaling and SIRT1 pathways. SIRT1 suppresses NF-κB directly by deacetylating its RelA/p65 subunit (as well as indirectly via downstream effectors like AMPK, PPARα, and PGC-1α), while NF-κB signaling downregulates SIRT1 activity through mechanisms including reactive oxygen species generation, microRNAs (such as miR-34a), and inflammatory cytokines.

0:47:24Rhonda Patrick (host)supportedlow

Dietary fish consumption protects APOE4 carriers against Alzheimer's disease, whereas isolated DHA supplementation does not show the same protective benefit in APOE4 carriers.

"there's some evidence that, for whatever reason, fish—when—when people that have APOE4 are given fish or eat fish, they—they're protected against Alzheimer's disease, but DHA supplementation, it's not the same, at least for APOE4-positive individuals." (said at 0:47:24)

The host's statement that there is evidence of fish consumption conferring protection against Alzheimer's disease pathology in APOE4 carriers while fish oil/DHA supplementation fails to show the same benefit is supported by observational and neuropathological literature. In an autopsy study of older adults published in JAMA (Morris et al., 2016), seafood consumption of at least one meal per week was significantly associated with lower Alzheimer's disease neuropathology (lesser neuritic plaque density and neurofibrillary tangles) specifically in APOE ε4 carriers, whereas fish oil supplementation showed no significant relationship with neuropathology. Mechanistic reviews hypothesize this difference may stem from the bioavailability of DHA in phospholipid forms found in whole fish versus triglyceride/ethyl-ester forms in standard supplements, though overall findings across epidemiological cohorts remain mixed and limited to observational designs.

1:01:23Dale Bredesensupportedlow

Research by Professor Goetzl from UCSF demonstrated that patients evaluated via neural exosome analysis showed a signature of central nervous system insulin resistance via altered IRS-1 phosphorylation, regardless of peripheral insulin resistance status.

"In fact, again, Professor Goetzl from UCSF had a nice paper a few years ago showing that everyone he evaluated using exosomal analysis had the signature of insulin resistance in the nervous system, whether they had it peripherally or not. So this was exosomes that he analyzed, and specifically he selected the neural exosomes, which represented about 10% of the overall exosomes, and showed that they all had the signature—this was this change in phosphorylation of IRS-1." (said at 1:01:23)

A 2015 study led by Edward J. Goetzl and Dimitrios Kapogiannis evaluated neuronally derived plasma exosomes (isolated via L1CAM immunoprecipitation) in patients with Alzheimer's disease (AD), type 2 diabetes (DM2), frontotemporal dementia, and healthy controls. They found that AD patients exhibited high levels of dysfunctional serine phosphorylation (pSer312-IRS-1) and decreased tyrosine phosphorylation (p-panTyr-IRS-1), resulting in an elevated insulin resistance ratio that correctly classified 100% of AD patients, demonstrating central nervous system insulin resistance independently of peripheral diabetes status. Because the evidence comes from small observational case-control cohorts, the overall certainty is low.

1:04:57Dale Bredesensupportedmoderate

Dr. Terry Wahls has published studies showing positive clinical results using a functional medicine diet and lifestyle approach for multiple sclerosis.

"And by the way, you probably know that Dr. Terry Wahls has published a lot and actually has done a lot of studies now on using a similar sort of approach for multiple sclerosis and has seen excellent results, including in herself, with taking this sort of an approach." (said at 1:04:57)

Dr. Terry Wahls and colleagues have published numerous clinical studies, including randomized controlled trials and pilot studies, evaluating the effects of a modified Paleolithic diet and multimodal lifestyle interventions (encompassing diet, exercise, stress management, and nutritional supplementation) in people with relapsing-remitting and progressive multiple sclerosis (MS). These trials have reported significant improvements in patient-reported outcomes, particularly fatigue, mood, and quality of life.

1:05:40Dale Bredesensupportedmoderate

The Cyrex Array 2 test measures antibodies to lipopolysaccharides (LPS) to assess leaky gut, while Cyrex Array 3 measures immune reactivity to gluten and gliadin domains.

"So Cyrex Array 2—Cyrex has a whole set of different markers for different antibodies. So if you have a leaky gut, you're often going to respond to things like LPS coming from your gut. Then there's a Cyrex Array 3 that looks at various of the domains of gluten and gliadin, and so you can look at that." (said at 1:05:40)

The speaker accurately describes the components of these commercial antibody panels developed by Cyrex Laboratories. Cyrex Array 2 evaluates intestinal barrier integrity ('leaky gut') by measuring serum IgG, IgA, and IgM antibodies against bacterial lipopolysaccharides (LPS), actomyosin, and tight junction proteins (occludin and zonulin). Cyrex Array 3 tests for immune reactivity (IgG and IgA) across multiple wheat and gliadin peptide domains (including alpha-, gamma-, and omega-gliadins, glutenin, gluteomorphin, and transglutaminase).

1:01:54Dale Bredesensupportedmoderate

Neural-derived exosomes represent approximately 10% of total circulating exosomes in blood analysis.

"and specifically he selected the neural exosomes, which represented about 10% of the overall exosomes" (said at 1:01:54)

In blood-based extracellular vesicle research pioneering neural-derived exosome isolation (notably established by Edward Goetzl and colleagues using L1CAM immuno-enrichment), neuron-derived exosomes/extracellular vesicles (NDEVs) are reported to comprise a minor subpopulation of total circulating plasma exosomes, typically estimated at approximately 5% to 15% (around 10%) of the total circulating pool.

1:07:12Dale Bredesensupportedmoderate

Dr. Aristo Vojdani developed the antibody assays used by Cyrex Laboratories.

"And Dr. Aristo Vojdani is the one who developed these various assays for Cyrex that are now being used by the Cyrex company" (said at 1:07:12)

Peer-reviewed literature confirms that Dr. Aristo Vojdani developed the multi-antigen enzyme-linked immunosorbent assays (ELISAs) and antibody panels (such as food reactivity, barrier integrity, and autoimmune cross-reactivity panels) utilized clinically and commercially by Cyrex Laboratories, where he serves as chief scientific advisor and lead assay designer.

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