HoldsUp

DavidPerlmutterMD · 2021-08-09 · David Perlmutter (host), Dale Bredesen

Doctor explains how Alzheimer's Reversal is Real-with Dr.Bredesen | The Empowering Neurologist EP130

33 research-tied claims examined: 1 overstated 1 context 28 supported 3 unverified

28

Supported by research

0:01:35David Perlmutter (host)supportedvery low

A 9-month proof-of-concept trial of the Bredesen protocol showed that approximately 80% of patients improved in cognitive measures including MoCA, CNS Vital Signs, and AQ-C scores, and had better MRI volume outcomes than typical decline.

"Dr. Bredesen has a new study out that we are going to review, a 9-month study that had an 80% improvement, rather 80% of the individuals in his program undergoing his treatment protocol improved" (said at 0:01:35)

A 9-month proof-of-concept trial of a multi-modal precision medicine protocol (the Bredesen protocol) in 25 patients with mild cognitive impairment or early dementia evaluated outcomes using MoCA, CNS Vital Signs Neurocognitive Index, the Alzheimer's Questionnaire Change score (AQ-C), and brain MRI volumetrics. The published pilot study reported statistically significant improvements across all of these cognitive measures and MRI volumetric parameters over the 9-month intervention. However, because this was a small, open-label pilot study without a randomized, parallel control group, the certainty of evidence for clinical efficacy is very low due to potential risks of practice effects, placebo effects, and regression to the mean.

0:08:50David Perlmutter (host)supportedhigh

Eli Lilly's monoclonal antibody donanemab was shown to slow the decline of Alzheimer's disease by 32%.

"Eli Lilly's new monoclonal antibody, donanemab, that it was so great that the stock of Eli Lilly went up billions of dollars with an announcement that it actually slowed the decline of Alzheimer's by a third, 32%." (said at 0:08:50)

In the double-blind, randomized Phase 2 TRAILBLAZER-ALZ clinical trial funded by Eli Lilly and published in the New England Journal of Medicine, donanemab slowed cognitive and functional decline in early symptomatic Alzheimer's disease by approximately 32% at 76 weeks on the primary composite outcome, the Integrated Alzheimer's Disease Rating Scale (iADRS). The change from baseline was -6.86 in the donanemab group compared to -10.06 in the placebo group (difference: 3.20 points, P = 0.04), representing a 31.8% (rounded to 32%) reduction in decline.

0:18:30Dale Bredesensupportedvery low

Research by Rudolph Tanzi and Robert Moir demonstrated that beta-amyloid is an antimicrobial peptide with antiviral and antifungal properties.

"our colleague Rudy Tanzi, along with the late Robert Moir, showed a number of years ago that amyloid is actually quite a good antimicrobial peptide. Interestingly, it has antiviral properties and antifungal properties." (said at 0:18:30)

Preclinical studies led by Robert Moir and Rudolph Tanzi demonstrated that amyloid-beta (Aβ) functions as an antimicrobial peptide in the innate immune system. In 2010 and 2016, they showed in vitro and in animal models (mice and nematodes) that Aβ inhibits clinically relevant pathogens, protecting against bacterial and fungal infections (such as Candida albicans). In 2018, they demonstrated antiviral properties, showing that Aβ oligomers bind herpesvirus surface glycoproteins (HSV-1 and HHV-6) and entrap viral particles in cell culture and transgenic mouse models. Because these findings are derived from cell cultures and animal models, the certainty of evidence is very low.

0:22:06David Perlmutter (host)supportedhigh

In the donanemab trial, the treatment group showed measurable brain tissue loss (atrophy) compared to the placebo group.

"First, the donanemab study, interestingly, in the treated group demonstrated measurable loss of tissue, atrophy, if you will, in comparison to the placebo group." (said at 0:22:06)

Randomized clinical trials evaluating anti-amyloid monoclonal antibodies, including donanemab (e.g., TRAILBLAZER-ALZ trials), demonstrated that participants in the active treatment group experienced accelerated brain volume loss (greater decreases in whole brain and cortical volume, along with greater ventricular enlargement) on MRI compared to the placebo group. While the precise biological mechanisms behind this phenomenon continue to be studied (e.g., clearance of amyloid plaques, reduction in inflammation-associated edema, or pseudoatrophy vs. neurotoxicity), the finding of measurable excess brain volume reduction in the treated arm relative to placebo is well-documented.

0:22:40David Perlmutter (host)supportedlow

Research by Ruth Itzhaki demonstrated colocalization of beta-amyloid with herpes simplex virus.

"And even prior to Rudolph Tanzi, Ruth Itzhaki in England showed colocalization of beta amyloid to herpes simplex, indicating exactly what you said, that the amyloid is a response element." (said at 0:22:40)

Ruth Itzhaki and colleagues published a 2009 study using in situ polymerase chain reaction (PCR) combined with immunohistochemistry or thioflavin S staining in post-mortem human brain sections, demonstrating that herpes simplex virus type 1 (HSV-1) DNA was specifically localized within amyloid-beta plaques (found in 90% of plaques in Alzheimer's disease brains). The authors concluded this direct association suggests HSV-1 infection leads to amyloid accumulation as a response.

0:23:40Dale Bredesensupportedvery low

Research by Stuart Lipton showed that anti-amyloid antibodies trigger an inflammatory response in the brain.

"And Stuart found that when you look at the brains when you give these antibodies, it actually causes inflammation." (said at 0:23:40)

Research from Stuart Lipton's laboratory (Trudler et al., PNAS 2021) demonstrated that complexes of antibodies with misfolded target proteins (including amyloid-β and α-synuclein) paradoxically activated the NLRP3 inflammasome and exacerbated interleukin-1β secretion and neuroinflammation in human iPSC-derived microglia and in humanized mouse brains. Because the findings derive from cell culture and animal models rather than direct human clinical trials, the GRADE certainty is very low.

0:26:11David Perlmutter (host)supportedhigh

Insulin-degrading enzyme (IDE) degrades both insulin and beta-amyloid.

"We can upregulate insulin-degrading enzyme by becoming more insulin sensitive through dietary means. And as such, you know, recognize that this enzyme that degrades insulin is also involved in the degradation of beta amyloid." (said at 0:26:11)

The host's statement that insulin-degrading enzyme (IDE) degrades both insulin and beta-amyloid, and that IDE expression and activity can be upregulated through dietary interventions improving insulin sensitivity, is fully supported by published literature. IDE (a zinc metalloendopeptidase) is well established as a primary enzyme responsible for the proteolytic degradation and extracellular clearance of both insulin and amyloid-beta (Aβ) peptides. Furthermore, animal studies demonstrate that high-fat diet-induced insulin resistance decreases IDE expression and function, whereas dietary interventions that improve insulin sensitivity (such as caloric restriction, dietary polyphenols/curcumin, or reversing high-fat diet effects) restore or upregulate hepatic and renal IDE expression and clearance activity.

0:27:45David Perlmutter (host)supportedhigh

Approximately 80 million Americans have insulin resistance or are on their way to type 2 diabetes.

"HOST: That's 80 million Americans. GUEST1: Exactly." (said at 0:27:45)

According to national surveillance data from the Centers for Disease Control and Prevention (CDC) and the National Health and Nutrition Examination Survey (NHANES), an estimated 84 million to 98 million American adults have prediabetes—an intermediate state of progressive dysglycemia characterized by insulin resistance and impaired glucose regulation that precedes type 2 diabetes. The statement that approximately 80 million Americans have insulin resistance or are on their way to type 2 diabetes accurately reflects these national epidemiological figures.

0:11:52David Perlmutter (host)supportedmoderate

Bioenergetic defects in the brain during Alzheimer's disease pathogenesis can predate the onset of clinical cognitive symptoms by 20 to 30 years.

"So, why don't we start with the notion that there is a bioenergetic defect in the Alzheimer's brain that may predate the onset of clinical symptoms by 20, even perhaps 30 years." (said at 0:11:52)

The host's statement accurately reflects the established scientific understanding of Alzheimer's disease (AD) pathophysiology. Multiple neuroimaging (such as FDG-PET) and bioenergetic studies have demonstrated that reductions in cerebral glucose metabolism, mitochondrial dysfunction, and declining ATP production can be detected during the preclinical phase, often 20 to 30 years (or decades) before the onset of overt clinical dementia and cognitive symptoms, particularly in populations at elevated risk (such as APOE ε4 carriers or perimenopausal/postmenopausal cohorts).

0:16:58David Perlmutter (host)supportedmoderate

Type 2 diabetes is associated with an increased risk of developing Alzheimer's disease.

"You know, we've known for years that there's an increased risk of Alzheimer's in type 2 diabetics, hence the call to get your blood sugar under control" (said at 0:16:58)

Large-scale prospective cohort studies and meta-analyses consistently demonstrate that individuals with diabetes mellitus (predominantly type 2 diabetes) have a significantly higher risk of developing Alzheimer's disease compared to individuals without diabetes. A meta-analysis of 17 longitudinal population-based cohort studies comprising over 1.7 million individuals found that diabetes was associated with an approximately 53% increased risk of Alzheimer's disease (RR 1.53, 95% CI 1.42–1.63). Additionally, poor glycaemic control, longer diabetes duration, and episodes of hypoglycaemia in individuals with type 2 diabetes are prospectively associated with increased risks of dementia and Alzheimer's disease.

0:25:10Dale Bredesensupportedvery low

Beta-amyloid triggers both the pathological phosphorylation of tau protein and the production of reactive oxygen species in the brain.

"you're going to continue to make the beta amyloid that is part of that innate system, and it is going to trigger the phosphorylation of tau, and trigger the reactive oxygen species you referred to, and trigger the downsizing of your brain" (said at 0:25:10)

Extensive preclinical and mechanistic research demonstrates that amyloid-beta (Aβ) exposure triggers both the hyperphosphorylation of tau protein and the generation of reactive oxygen species (ROS) / oxidative stress in neuronal and glial models. Human neuronal and cellular assays show that exposure to Aβ oligomers induces marked increases in ROS production, mitochondrial dysfunction, and pathological tau phosphorylation at Alzheimer's disease-associated epitopes. Because this evidence is derived from in vitro, ex vivo, and animal mechanistic models rather than clinical trial endpoints, the GRADE certainty is rated very low.

0:30:37Dale Bredesensupportedmoderate

Elevated fasting blood glucose levels and elevated cortisol levels are associated with hippocampal volume reduction.

"As your glucose goes up, your hippocampus shrinks down. Same for cortisol. Cortisol up, hippocampus down." (said at 0:30:37)

Human observational neuroimaging studies support the association between higher fasting blood glucose levels and reduced hippocampal volume, even within non-diabetic or subclinical glucose ranges. Similarly, studies measuring systemic cortisol levels (in healthy older adults, Alzheimer's disease patients, and individuals with hypercortisolism/Cushing's disease) demonstrate significant negative correlations between serum cortisol levels and hippocampal volume.

0:36:26Dale Bredesensupportedmoderate

Neuropathological evaluations of COVID-19 patient brains show microthrombosis, microhemorrhage, inflammatory cells, and megakaryocytes.

"And when you actually look at the brains as you indicated, you see microthrombosis, you see microhemorrhage, you see inflammatory cells. There was even a report of megakaryocytes as it being a question of one issue." (said at 0:36:26)

Postmortem and neuropathological examinations of patients who died with COVID-19 document vascular injury and neuroinflammatory changes, including cerebral infarction, microvascular thrombosis, intracranial hemorrhage/microhemorrhages, and neuroinflammation. In addition, autopsy studies have specifically identified the atypical presence of intracapillary megakaryocytes within the cerebral vasculature of COVID-19 patients.

0:38:29David Perlmutter (host)supportedvery low

Postmortem brain examinations of individuals exposed to MPTP in 1983 revealed persistent, ongoing microglial activation years after the initial exposure.

"I remember research that looked at the MPTP individuals in 1983 in Southern—was it Southern California or San Francisco?—who experimented with a synthetic Demerol and ultimately immediately by virtue of the damage to the mitochondria in the part of the brain that creates the dopamine that is involved in the motor system, these individuals developed Parkinson's. But, what's interesting, the reason I'm bringing it up, not that that's uninteresting, is that when these individuals years later passed away, there was still ongoing microglial activation." (said at 0:38:29)

A landmark 1999 postmortem neuropathological study by Langston and colleagues examined three individuals who developed severe parkinsonism after exposure to MPTP (a contaminant in synthetic opioids) in northern California in the early 1980s. Surviving between 3 and 16 years following the initial time-limited exposure, postmortem examination of their substantia nigra revealed persistent gliosis and active clustering of microglia around nerve cells alongside ongoing nerve cell loss. As this evidence comes from a small autopsy case series (n = 3), the certainty of evidence for this specific historical cohort is graded very low.

  • supports: Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1… (Annals of neurology 1999) · cited 969x in the literature
    "Survival times ranged from 3 to 16 years. Neuropathological examination revealed moderate to severe depletion of pigmented nerve cells in the substantia nigra in each case. Lewy bodies were not present. In Patients 1 and 2, there was gliosis and clustering of microglia around nerve cells. Patient 3 had a similar picture and also showed large amounts of extraneuronal melanin. These findings are indicative of active, ongoing nerve cell loss, suggesting that a time-limited insult to the nigrostriatal system can set in motion a self-perpetuating process of neurodegeneration." (abstract, results, passage verified)
    pubmedfull study (doi)
0:41:10Dale Bredesensupportedmoderate

In a 2015 study and follow-up evaluation, approximately 12.8% to 14% of World Trade Center first responders presented with cognitive decline.

"And another great example, of course, the World Trade Center first responders were evaluated in 2015, years after the original problem. And it turned out that 12.8% of them—and then actually a follow-up paper a little higher, about 14% of them—actually had cognitive decline." (said at 0:41:10)

The speaker's statement accurately reflects findings from published epidemiological studies evaluating World Trade Center (WTC) first responders. In an evaluation conducted between January 2014 and April 2015 by Clouston et al. (published in 2016 in Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring), screening of 818 WTC responders using the Montreal Cognitive Assessment (MoCA) revealed that approximately 12.8% had scores indicative of cognitive impairment (and 1.2% had scores indicating possible dementia, totaling ~14%). Subsequent analyses across WTC cohorts have continued to document similar and expanding rates of mild cognitive impairment and cognitive decline.

0:46:36David Perlmutter (host)supportedhigh

Cyanobacterial blooms produce the neurotoxin beta-N-methylamino-L-alanine (BMAA).

"we're having these incredible fish kills as a consequence of red tide, incredible overgrowth of cyanobacteria and known to produce BMAA." (said at 0:46:36)

Published environmental toxicology research and chemical analyses confirm that blooms of various cyanobacterial species produce the non-protein amino acid neurotoxin β-N-methylamino-L-alanine (BMAA) along with its structural isomers.

0:51:09Dale Bredesensupportedhigh

Familial Alzheimer's disease accounts for less than 5% of Alzheimer's cases, and APP mutations represent less than 1% of Alzheimer's disease cases in humans.

"There are different ones now, there are the 5XFAD mice, which is basically they're saying FAD, familial Alzheimer's disease. Well, that's less than 5%. The mice that we worked with were typically APP mutants. APP mutations in humans represent less than 1% of Alzheimer's disease." (said at 0:51:09)

Autosomal dominant familial Alzheimer's disease (FAD) accounts for less than 1% to 5% of all Alzheimer's disease cases. Furthermore, pathogenic mutations in the amyloid precursor protein (APP) gene are even rarer, found in a minor fraction of early-onset cases (typically less than 0.5% to 1% of all Alzheimer's disease patients).

0:57:25Dale Bredesensupportedmoderate

Sudden withdrawal of cholinesterase inhibitors can cause cognitive worsening due to compensatory upregulation of cholinesterase by the body.

"And the key thing is the people who suddenly cold turkey it could potentially get worse with their cognition because, as you know, your body now responds by making more cholinesterase, exactly what you don't want it to do. And so, if you suddenly cold turkey, you could be in a worse position than when you started." (said at 0:57:25)

Randomized trials and systematic reviews demonstrate that discontinuing cholinesterase inhibitors in patients with Alzheimer's disease is associated with significant cognitive and neuropsychiatric worsening compared to continuing treatment. A Cochrane systematic review of randomized trials found that discontinuation was associated with worse cognitive outcomes in both short-term and 12-month follow-ups. A meta-analysis of five randomized controlled trials similarly showed a statistically significant worsening in cognitive scores (Mini-Mental State Examination) and neuropsychiatric symptoms following discontinuation, leading clinical guidelines to recommend cautious tapering and monitoring when deprescribing.

  • supports: Cholinesterase inhibitor discontinuation in patients with Alzheimer's disease: a meta-anal… (The Journal of clinical psychiatry 2015) · cited 64x in the literature
    "Discontinued patients demonstrated a significant worsening of cognition (standard mean Mini-Mental State Examination difference: -0.29 [95% CI, -0.45 to -0.13], N = 300 continued/307 discontinued, P < .001), a significant worsening of neuropsychiatric symptoms (standard mean Neuropsychiatric Inventory difference: -0.32 [-0.51 to -0.12], N = 199/211, P = .001), and significantly higher dropout rates (risk ratio [RR] = 1.33 [1.11-1.59], N = 321/332, P = .002) compared to those who continued." (abstract, results, passage verified)
    pubmedfull study (doi)
  • supports: Withdrawal or continuation of cholinesterase inhibitors or memantine or both, in people wi… (The Cochrane database of systematic reviews 2021) · cited 43x in the literature
    "Compared to continuing cholinesterase inhibitors, discontinuing treatment may be associated with worse cognitive function in the short term (standardised mean difference (SMD) -0.42, 95% confidence interval (CI) -0.64 to -0.21; 4 studies; low certainty), but the effect in the medium term is very uncertain (SMD -0.40, 95% CI -0.87 to 0.07; 3 studies; very low certainty). In a sensitivity analysis omitting data from a study which only included participants who had shown a relatively poor prior response to donepezil, inconsistency was reduced and we found that cognitive function may be worse in the discontinuation group in the medium term (SMD -0.62; 95% CI -0.94 to -0.31). Data from one longer-term study suggest that discontinuing a cholinesterase inhibitor is probably associated with worse cognitive function at 12 months (mean difference (MD) -2.09 Standardised Mini-Mental State Examination (SMMSE) points, 95% CI -3.43 to -0.75; moderate certainty)." (abstract, results, passage verified)
    pubmedfull study (doi)
0:59:54David Perlmutter (host)supportedmoderate

In Parkinson's disease, alpha-synuclein pathology can propagate physically from the gut to the brain via the vagus nerve.

"You know, there's so much in the literature these days that it's making it clear even from the physicality of the connection of the vagus nerve as it relates to alpha-synuclein making its way from the gut to the brain in the Parkinson's patients." (said at 0:59:54)

A substantial body of literature, originating with the Braak staging hypothesis, demonstrates that pathological alpha-synuclein aggregates can spread transneuronally from the enteric nervous system to the brain via the vagus nerve in models of Parkinson's disease. Landmark preclinical studies have shown that injecting preformed alpha-synuclein fibrils into the gastrointestinal muscularis leads to sequential spread via the vagus nerve to the dorsal motor nucleus in the brainstem and onward to the substantia nigra, causing dopaminergic loss and motor symptoms. Furthermore, surgical severance of the vagus nerve (truncal vagotomy) completely blocks this retrograde gut-to-brain spread and subsequent neurodegeneration.

1:00:35David Perlmutter (host)supportedvery low

The dithiocarbamate pesticides maneb and mancozeb are used in laboratory research to model Parkinson's disease by damaging cellular and mitochondrial function.

"You know, I was very taken a couple of years ago to learn that there's this chemical maneb and mancozeb that are used to create Parkinson's in the laboratory animal to damage cellular function, to damage the mitochondrial function in certain human-derived cells." (said at 1:00:35)

Maneb and mancozeb are manganese- and zinc-containing dithiocarbamate fungicides widely used in experimental laboratory models of Parkinson's disease. Animal studies in rodents and in vitro studies using isolated brain mitochondria, human neuroblastoma lines, and human-derived induced pluripotent stem cells (iPSCs) demonstrate that these compounds induce dopaminergic neurodegeneration by impairing cellular respiration, inhibiting electron transport chain complex III, decreasing ATP production, and disrupting mitochondrial function.

0:35:20David Perlmutter (host)supportedmoderate

COVID-19 infection is associated with viral brain entry, blood-brain barrier disruption, increased inflammatory cytokines (including IL-1 beta, IL-6, IL-10, and TNF-alpha), NMDA receptor stimulation, and kynurenine pathway activation producing quinolinic acid.

"We now know that there is actual evidence of entry of COVID into various parts of the brain. And some of these mechanisms include excitotoxicity, NMDA stimulation, kynurenic acid pathway with quinolinic acid being produced, increased inflammation as evidenced by increased levels of, you know, interleukin-1 beta, IL-6, IL-10, TNF-alpha, the vascular issues, the blood-brain barrier disruption, et cetera." (said at 0:35:20)

Published literature confirms that COVID-19 infection is associated with blood-brain barrier disruption, neuroinflammation driven by inflammatory cytokines, and activation of the kynurenine pathway leading to elevated levels of neurotoxic quinolinic acid (an NMDA receptor agonist implicated in excitotoxicity). Clinical and biomarker studies measuring cerebrospinal fluid (CSF) and plasma in acute and post-acute COVID-19 patients demonstrate significant upregulation of indoleamine 2,3-dioxygenase (IDO), increased tryptophan breakdown, and marked elevations of quinolinic acid and other kynurenine metabolites correlating with markers of neurodegeneration and neurological symptoms.

0:44:25Dale Bredesensupportedvery low

In a clinical trial testing a multi-modal protocol for cognitive decline conducted by Dale Bredesen, Kat Toups, Ann Hathaway, and Deborah Gordon, the vast majority of participants showed clinical improvement.

"And in the trial, it was interesting. Not only did we see the vast majority of people get better, but interestingly, the few who did not get better, you could see why they weren't getting better... I do want to just quickly say that the people I work with on the trial, Dr. Kat Toups, who you know, Dr. Ann Hathaway, and Dr. Deborah Gordon, just absolutely fantastic functional medicine physicians and just did a great job." (said at 0:44:25)

A proof-of-concept pilot trial led by Kat Toups, Ann Hathaway, Deborah Gordon, Dale Bredesen, and colleagues evaluated a personalized multi-modal protocol in 25 participants with mild cognitive impairment or early dementia over 9 months. The published results reported statistically significant improvements in cognitive measures (including the Montreal Cognitive Assessment, CNS Vital Signs Neurocognitive Index, and Alzheimer's Questionnaire Change score) across the study group. Because the study was a small (n=25), uncontrolled pilot project without a randomized control arm, the certainty of the evidence for the protocol's general clinical efficacy is very low.

  • supports: Precision Medicine Approach to Alzheimer's Disease: Successful Pilot Project. (Journal of Alzheimer's disease : JAD 2022) · cited 70x in the literature
    "Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline... All outcome measures revealed improvement: statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimer's Questionnaire Change score were documented." (abstract, results, passage verified)
    pubmedfull study (doi)
1:02:27Dale Bredesensupportedmoderate

Exposure to toxins like trichloroethylene and annonacin increases the risk of Parkinson's disease.

"Absolutely huge increases, probably toxin-related, you know, trichloroethylene, things like that. Annonacin is another exposure that some people have that increases Parkinson's." (said at 1:02:27)

The claim that exposure to toxins like trichloroethylene (TCE) and annonacin increases the risk of Parkinson's disease (or parkinsonism) is supported by epidemiological studies and experimental rodent models. A population-based cohort study of US veterans who served at Camp Lejeune found that exposure to drinking water contaminated with trichloroethylene (TCE) and other volatile organic compounds was associated with a 70% increased risk of Parkinson's disease (odds ratio 1.70, 95% CI 1.39-2.07) compared to unexposed controls (PMID: 37184848). Reviews and smaller epidemiological studies also report marked increases in Parkinson's disease risk linked to occupational and ambient TCE exposure (PMID: 36938742). Regarding annonacin (a mitochondrial complex I inhibitor found in plants of the Annonaceae family such as soursop), epidemiological research in Guadeloupe linked its consumption to atypical parkinsonism. Experimental studies in rats demonstrate that systemic annonacin administration causes loss of dopaminergic neurons in the substantia nigra and mimics pathological features of parkinsonism (PMID: 14675150, PMID: 14521988). While human evidence for annonacin relies primarily on observational data and animal models of atypical parkinsonism, the body of evidence for TCE includes large human cohort data, justifying a moderate certainty grade overall.

1:04:26Dale Bredesensupportedmoderate

Whole coffee fruit extract increases brain-derived neurotrophic factor (BDNF).

"Simple things like whole coffee fruit extract, which you actually taught me about a few years ago. So, thank you for that. Very interesting, and increases BDNF and has turned out to be a very interesting supplement" (said at 1:04:26)

Clinical trial evidence demonstrates that whole coffee fruit concentrate/extract acutely increases circulating levels of brain-derived neurotrophic factor (BDNF). In a randomized human study, a single 100 mg dose of whole coffee fruit concentrate powder produced a 143% increase in plasma BDNF levels over baseline compared to control treatments, though the sample size in the initial trial was small.

1:07:05David Perlmutter (host)supportedlow

A lifestyle intervention program published by Kara Fitzgerald showed a 3.5-year reversal of the Horvath DNA methylation clock.

"Kara Fitzgerald, who recently published a wonderful paper about a 3 and 1/2 year reversal of the Horvath DNA methylation clock via an interventional lifestyle program, which was a specific program, but not uniquely personalized." (said at 1:07:05)

Kara Fitzgerald and colleagues published a pilot randomized clinical trial in 43 healthy men aged 50–72 evaluating an 8-week multimodal diet and lifestyle intervention. Compared with the control group, the intervention group demonstrated a 3.23-year reduction in biological age as measured by the Horvath DNAmAge clock (p = 0.018). Within the intervention group, the average decrease from baseline was 1.96 years (p = 0.066). While the published study matches the speaker's description, certainty is low due to the small sample size and pilot nature of the trial.

  • supports: Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot rand… (Aging 2021) · cited 371x in the literature
    "The diet and lifestyle treatment was associated with a 3.23 years decrease in DNAmAge compared with controls (p=0.018). DNAmAge of those in the treatment group decreased by an average 1.96 years by the end of the program compared to the same individuals at the beginning with a strong trend towards significance (p=0.066). To our knowledge, this is the first randomized controlled study to suggest that specific diet and lifestyle interventions may reverse Horvath DNAmAge (2013) epigenetic aging in healthy adult males." (abstract, results, passage verified)
    pubmedfull study (doi)
1:08:24David Perlmutter (host)supportedmoderate

Fructose metabolizes into uric acid, and uric acid plays a pivotal role in insulin resistance, inflammation, and non-alcoholic fatty liver disease.

"keeping people off of fructose or recommending that in what I write, because of their ultimate metabolism down to uric acid, because we're learning so much now about the pivotal role of uric acid sort of as an orchestrator of insulin resistance, inflammation, non-alcoholic fatty liver disease, etc." (said at 1:08:24)

Fructose metabolism in the liver via fructokinase (ketohexokinase) causes rapid ATP depletion, nucleotide turnover, and purine degradation, resulting in the generation of uric acid. Experimental and clinical evidence demonstrates that hyperuricemia and intracellular uric acid accumulation contribute to mitochondrial oxidative stress, low-grade inflammation, de novo lipogenesis, and impaired insulin signaling, promoting insulin resistance and non-alcoholic fatty liver disease (NAFLD/MASLD).

1:02:40Dale Bredesensupportedmoderate

Gluten consumption has an impact on intestinal permeability (leaky gut).

"And especially focusing on gluten. It's a huge issue because of its impact, especially on leaky gut." (said at 1:02:40)

Evidence from ex vivo human intestinal biopsy explants, animal models, and cell line studies demonstrates that exposure to gliadin (a major component of gluten) triggers zonulin release, tight junction disassembly, and increases intestinal permeability. While this effect occurs to some degree in non-celiac controls, it is more pronounced and sustained in individuals with active celiac disease and non-celiac gluten sensitivity.

1:08:24David Perlmutter (host)supportedhigh

Organ meats, sardines, and scallops are high sources of purines that metabolize into uric acid.

"certainly organ meats and higher sources of purines like sardines and scallops... because of their ultimate metabolism down to uric acid" (said at 1:08:24)

Dietary purines from meats and seafood (including organ meats, sardines, and shellfish) are well-established substrates that are metabolized into uric acid in humans. Large epidemiological analyses, such as data from NHANES III (PMID: 15641075), demonstrate that higher intake of meat and seafood is significantly associated with elevated serum uric acid levels.

Unverified means no publication matching the claim was located; it does not prove the claim false. Spotted an error? See the corrections policy - disputes from the people quoted are prioritized.