HoldsUp

DavidPerlmutterMD · 2026-02-17 · David Perlmutter (host), Sarah Marzi

Why Some Brains Never Get Alzheimer’s | Dr. Sarah Marzi

37 research-tied claims examined: 4 overstated 1 context 30 supported 2 unverified

30

Supported by research

0:04:41Sarah Marzisupportedhigh

Neurodegenerative diseases, including Alzheimer's disease, are rarely caused by a single mutation in a single gene; the vast majority of cases are caused by a combination of many hundreds or thousands of genetic risk factors interacting with environmental and lifestyle exposures.

"it's rarely ever one gene that's the smoking gun for these diseases. That happens in the minority of cases. Occasionally people will get a disease from just one mutation and one gene. But the vast majority of people that get, say, Alzheimer's disease are caused by a combination of many, many hundreds potentially or thousands of little genetic risk factors that probably interact with the environments they're exposed to and the lifestyle they lead" (said at 0:04:41)

The speaker's statement accurately reflects the established scientific consensus on the genetic architecture of Alzheimer's disease (AD) and most neurodegenerative disorders. Monogenic forms of AD—caused by highly penetrant single-gene mutations (such as in APP, PSEN1, or PSEN2)—account for a very small minority of cases (typically <1–5%, primarily manifesting as early-onset familial AD). In contrast, the vast majority of cases (late-onset sporadic AD) are multifactorial and polygenic, arising from the cumulative effect of numerous common and rare genetic variants (including APOE and dozens to hundreds of susceptibility loci identified in genome-wide association studies) interacting with environmental, lifestyle, and epigenetic factors.

0:09:44Sarah Marzisupportedhigh

Virtually all neurodegenerative diseases feature the aggregation of abnormal protein clumps either inside neurons or in the extracellular spaces between neurons.

"One of the features that neurodegenerative diseases have in common is the aggregation of different types of proteins. So proteins that build clumps that they shouldn't build and they build them either in the neurons that then eventually die or in the space between the neurons. And it can be different types of proteins in different diseases, but virtually all neurodegenerative diseases have some of these protein clumps." (said at 0:09:44)

The speaker's statement that neurodegenerative diseases share the feature of abnormal protein aggregation occurring either inside neurons or in extracellular spaces between neurons is supported by consensus neuropathology. Major neurodegenerative disorders (frequently designated as proteinopathies or protein misfolding disorders) are defined by specific protein deposits: extracellular amyloid-beta plaques and intracellular hyperphosphorylated tau neurofibrillary tangles in Alzheimer's disease, intracellular alpha-synuclein inclusions (Lewy bodies) in Parkinson's disease and Lewy body dementia, intracellular TDP-43 or SOD1 inclusions in amyotrophic lateral sclerosis (ALS), and intracellular huntingtin aggregations in Huntington's disease.

0:11:18Sarah Marzisupportedmoderate

The common non-monogenic genetic risk factors for Alzheimer's disease overwhelmingly map to genomic regions that regulate gene expression selectively in microglia rather than in neurons or other brain cell types.

"when you look at the genetics of Alzheimer's disease, so not the one gene that causes it, but these many hundreds or thousands of little risk factors that we talked about, they quite overwhelmingly, they fall into regions of the genome that are active and that are regulating expression of genes only in microglia and not in any of the other brain cell types, so not in neurons, for example." (said at 0:11:18)

Genome-wide association studies (GWAS) and cell type-specific epigenomic profiling in human brain tissue consistently demonstrate that common, non-monogenic risk variants for sporadic Alzheimer's disease are preferentially enriched within noncoding regulatory elements (such as transcriptional enhancers and promoters) active in microglia/myeloid cells rather than neurons, astrocytes, or oligodendrocytes. Functional genomics and chromosome conformation studies confirm that these noncoding risk variants modulate gene expression in a microglia-specific manner.

0:12:48Sarah Marzisupportedmoderate

Microglial phagocytosis of proteins is impaired in individuals with Alzheimer's disease.

"this eating up or phagocytosing of proteins is something that we think is or that we see is impaired actually in people with Alzheimer's disease." (said at 0:12:48)

Published human neuropathological, genetic, and preclinical evidence indicates that microglial phagocytosis and clearance of pathological proteins (such as amyloid-beta) become dysfunctional and impaired during the progression of Alzheimer's disease. Genetic risk variants associated with Alzheimer's disease (such as in TREM2 and CD33) directly modulate microglial phagocytic efficiency, and microglia transition from functional, plaque-clearing states to exhausted or dysfunctional phenotypes as disease pathology advances.

0:21:31Sarah Marzisupportedhigh

Carrying two copies of the APOE4 risk allele can increase an individual's risk for Alzheimer's disease by up to 12-fold.

"So if you have two copies of the APOE4, the risk allele, that can increase your risk for Alzheimer's by up to 12-fold." (said at 0:21:31)

Carrying two copies of the APOE-ε4 allele (homozygosity) is well established to confer an approximately 10- to 15-fold (or higher depending on ancestry) increase in the odds of developing Alzheimer's disease compared to the baseline ε3/ε3 genotype. In landmark multi-ethnic meta-analyses, ε4/ε4 homozygosity was associated with an odds ratio of approximately 14.9 in Caucasian populations and even higher in East Asian populations.

0:25:42Sarah Marzisupportedhigh

Carrying one or two copies of the APOE2 allele strongly protects against developing Alzheimer's disease.

"APOE2 is actually a strong protective factor. So people with APOE2, one copy or even two copies, very rarely get Alzheimer's disease, meaning there must be something that's really protecting them from that disease." (said at 0:25:42)

Large-scale genetic studies and meta-analyses consistently establish the APOE ε2 allele as a robust protective genetic factor against late-onset Alzheimer's disease. Relative to the common APOE ε3/ε3 genotype, carrying one or two copies of ε2 significantly reduces the odds and lifetime risk of developing Alzheimer's disease and delays age of onset, with the ε2/ε2 homozygote showing the lowest risk of Alzheimer's disease among APOE genotypes, although the magnitude of protection varies across ancestral backgrounds.

0:26:13Sarah Marzisupportedvery low

In Alzheimer's mouse models xenografted with human microglia, APOE4 microglia exhibit higher expression of pro-inflammatory cytokines, impaired protein phagocytosis, and downregulation of genes promoting cellular motility and proliferation compared to APOE2 microglia.

"the APOE4 microglia, as we've been talking about before, they are pro-inflammatory. They release a lot of pro-inflammatory cytokines. They're less good at clearing up proteins and other debris. So this ability to phagocytose is impaired. A third feature that we found was they seem to be less good at cellular motility and cellular proliferation. So normally when microglia are called into action to clear up something, they need to be motile, they need to proliferate, and they need to get to the site of injury or aggregation to clear up the proteins. And based on our gene expression results, we really see that genes that promote these kinds of processes are downregulated in the E4 microglia and actually conversely upregulated in the E2 microglia." (said at 0:26:13)

A 2025 study profiling gene expression and chromatin accessibility in human microglia xenografted into an Alzheimer's disease mouse model (APP NL-G-F) directly supports the claim. The researchers found that human APOE4 microglia showed downregulation of pathways and gene networks governing cellular proliferation and migration (motility) alongside altered immune responses, whereas APOE2 microglia exhibited enhanced phagocytic signatures and upregulation of these protective cellular functions.

0:15:24David Perlmutter (host)supportedvery low

Amyloid-beta acts as an antimicrobial peptide generated in response to microbial infections in the brain, such as herpes simplex virus type 1 or Chlamydia.

"Dr. Rudolph Tanzi at Harvard has talked about amyloid representing what we call an antimicrobial peptide, that the amyloid is produced in response to perhaps microbial infection in the brain, Chlamydia, herpes simplex type 1, and that in many ways the original formation of beta-amyloid is a way of protecting the brain" (said at 0:15:24)

The speaker accurately describes the 'Antimicrobial Protection Hypothesis' of Alzheimer's disease developed by Dr. Rudolph Tanzi, Robert Moir, and colleagues. In preclinical studies (in vitro, nematode, transgenic mouse, and 3D human neural cell culture models), amyloid-beta was shown to function as an innate immune antimicrobial peptide that oligomerizes and fibrillizes in response to pathogens—such as herpes simplex virus 1 (HSV-1), human herpesviruses, and various bacteria—entrapping them and protecting host cells from infection. However, clinical evidence in living humans remains indirect and based primarily on preclinical models and pathogen associations, conferring very low GRADE certainty for its causative role in human Alzheimer's disease.

0:17:25David Perlmutter (host)supportedmoderate

40 Hz sensory stimulation enhances gamma brainwave activity and has shown early clinical signals associated with slower cognitive decline.

"We know that when you're exposed to 40 Hz stimulation, this is linked to what we call gamma, increasing gamma activity in the brain. In other words, balance in the brain, which is really a fundamental for brain health and brain functionality. In fact, in early clinical research using what's called 40 Hz stimulation, researchers have reported signals that are consistent with a slower decline in cognitive function in some participants." (said at 0:17:25)

The claim is supported. Published clinical and preclinical studies show that 40 Hz sensory stimulation (such as flicker light, auditory clicks, or combined audiovisual stimulation) successfully entrains endogenous gamma oscillations in the brain. Early-phase clinical trials and systematic reviews in patients with mild cognitive impairment and Alzheimer's disease report preliminary signals of preserved brain volume, improved electrophysiological connectivity, and a slower rate of cognitive decline across standard cognitive assessments (e.g., MMSE, ADAS-Cog), though researchers emphasize that larger, randomized, long-term confirmatory trials remain necessary.

0:30:19Sarah Marzisupportedvery low

In protective APOE2 microglia, there is enhanced signaling via binding of the vitamin D receptor to DNA.

"And one of the strongest results that we got for these enrichments is that in the E2, in the protective microglia, there seems to be enhanced signaling via binding to the DNA of the vitamin D receptor." (said at 0:30:19)

A 2025 study profiling the transcriptomic and chromatin accessibility landscapes of human microglia xenotransplanted into a mouse model of Alzheimer's disease demonstrated that APOE2 microglia exhibited enriched DNA-binding of the vitamin D receptor alongside increased phagocytic capacity, supporting a potential mechanism for APOE2's neuroprotective role.

0:31:52Sarah Marzisupportedlow

Downstream genes regulated by the vitamin D receptor in microglia and immune cells drive an anti-inflammatory phenotype.

"in immune cells like the microglia, it really clearly has effects on immune functioning, and in particular, it has anti-inflammatory effects. So most of the genes that are downstream and that are being regulated by vitamin D receptor will drive an anti-inflammatory phenotype in microglia or other immune cells." (said at 0:31:52)

Vitamin D receptor (VDR) activation in microglia and other immune cells is well established in mechanistic, cellular, and animal models to regulate gene transcription toward an anti-inflammatory phenotype. In preclinical studies, VDR agonists such as calcitriol suppress pro-inflammatory mediator production (e.g., M1 polarization markers and cytokines) and upregulate anti-inflammatory cytokines and M2 polarization pathways. Because the evidence is derived primarily from in vitro cell models and animal studies rather than direct clinical trial endpoints, the overall GRADE certainty is low.

0:33:24Sarah Marzisupportedhigh

The vitamin D receptor heterodimerizes with the retinoid X receptor before binding to DNA.

"vitamin D receptor heterodimerizes with the retinoid X receptor before it binds the DNA." (said at 0:33:24)

The canonical mechanism of genomic vitamin D signaling involves the binding of active 1,25-dihydroxyvitamin D (calcitriol) to the vitamin D receptor (VDR), which promotes its heterodimerization with the retinoid X receptor (RXR). The resulting VDR–RXR heterodimer then binds specific DNA motifs known as vitamin D response elements (VDREs) in target gene promoters to regulate transcription.

0:35:26David Perlmutter (host)supportedvery low

Activation of the vitamin D receptor downregulates the NLRP3 inflammasome.

"we do know that there's downregulation of the NLRP3 inflammasome with activation of the VDR." (said at 0:35:26)

Preclinical in vitro and animal studies demonstrate that activation of the vitamin D receptor (VDR) negatively regulates and suppresses NLRP3 inflammasome assembly and activation. Mechanistically, ligand-activated VDR can directly interact with NLRP3 to impede its BRCC3-mediated deubiquitination and suppress downstream caspase-1 activation and pro-inflammatory cytokine (such as IL-1β) secretion. Because evidence for this molecular pathway is derived from cell culture and animal disease models rather than human clinical trials, certainty is graded as very low.

0:38:32Sarah Marzisupportedmoderate

Twin studies show that Parkinson's disease is only about 20% to 30% heritable/genetic.

"And when you do that for Parkinson's, it's only about 20 to 30% genetics, meaning likely the environment that you're exposed to plays a much bigger role." (said at 0:38:32)

Large population-based twin registry studies confirm that overall heritability for Parkinson's disease is roughly 20% to 30%. In a 20-year follow-up of the US Veteran Twins Registry, overall heritability was estimated at 0.27 (27%), though it was markedly higher (0.83) for early-onset cases diagnosed at age 50 or younger (PMID: 30786044). Similarly, a longitudinal study from the Swedish Twin Registry estimated heritability for Parkinson's disease at 34% (PMID: 21482443). These findings support the conclusion that environmental and non-genetic factors account for the majority of risk in typical late-onset Parkinson's disease.

0:41:39Sarah Marzisupportedmoderate

Epidemiological evidence shows that rotenone exposure increases the risk of Parkinson's disease substantially in humans.

"and there is strong epidemiological evidence that it increases Parkinson's risk quite substantially in humans." (said at 0:41:39)

Epidemiological findings from the Farming and Movement Evaluation (FAME) study, a case-control study nested within the large prospective Agricultural Health Study (AHS), demonstrated that human exposure to rotenone was associated with an approximately 2.5-fold increase in the odds of developing Parkinson's disease (OR = 2.5; 95% CI: 1.3–4.7). This confirms the claim that human epidemiological data link rotenone exposure to a substantially increased risk of Parkinson's disease.

0:43:10Sarah Marzisupportedhigh

In Parkinson's disease, dopaminergic neurons in the substantia nigra of the midbrain die.

"So in Parkinson's, a type of neuron called dopaminergic neuron dies. It's called this because it primarily uses a neurotransmitter called dopamine. And these dopaminergic neurons that die in Parkinson's sit in a very specific area right in the center of our brain, in the midbrain, in an area called the substantia nigra." (said at 0:43:10)

The speaker's statement is completely accurate and describes the defining neuropathological hallmark of Parkinson's disease. In Parkinson's disease, there is selective and progressive degeneration and loss of dopamine-producing (dopaminergic) neurons located in the substantia nigra pars compacta of the midbrain. This loss leads to the hallmark dopamine depletion in the striatum responsible for the classic motor symptoms of the disorder.

0:44:11Sarah Marzisupportedhigh

The pesticide rotenone specifically targets and impairs mitochondrial functioning.

"and rotenone, this pesticide, specifically targets and impairs mitochondria." (said at 0:44:11)

Rotenone is a well-established classical inhibitor of mitochondrial complex I (NADH:ubiquinone oxidoreductase) in the electron transport chain. By specifically binding within the ubiquinone-binding site (Q-channel) of complex I, rotenone blocks electron transfer to ubiquinone, impairing oxidative phosphorylation, reducing ATP synthesis, and elevating reactive oxygen species production.

0:44:41Sarah Marzisupportedvery low

In a rotenone rat model, there is a striking upregulation of the complement cascade and C1q in the substantia nigra.

"And uniquely in the substantia nigra, we actually see quite a striking upregulation of immune-related pathways, probably coming from the microglia, including an upregulation of an immune response called—so we see an upregulation of the complement cascade and potentially the C1q." (said at 0:44:41)

A 2025 study evaluating regional epigenomic and transcriptomic changes in a rotenone rat model of Parkinson's disease found region-specific immune alterations, specifically demonstrating a strong, rotenone-induced immune response in the substantia nigra characterized by increased activity in the C1q complement pathway. Because these findings are derived from an animal model, the GRADE certainty is very low.

0:45:44Sarah Marzisupportedvery low

C1q labels synapses, which targets them for phagocytosis and pruning by microglia.

"So it's been shown in a number of different neurodegenerative diseases that microglia can and do phagocytose, eat up synapses, and that's probably not a good thing later in life. And that labeling happens through C1q. So there's some really exciting work on that from Beth Stevens and Soyon Hong that have shown this as the signaling and phagocytosing pathway in synapses." (said at 0:45:44)

The speaker accurately describes landmark preclinical research led by Beth Stevens and Soyon Hong demonstrating that complement protein C1q tags synapses to target them for engulfment and pruning by microglia. In mouse models of development and early Alzheimer's disease, C1q associates with synaptic connections, and blocking C1q, C3, or the microglial receptor CR3 prevents microglial phagocytosis of synapses and limits early synaptic loss. Because this mechanistic evidence comes from preclinical animal models, the certainty level for human neurodegenerative diseases is very low.

0:46:15Sarah Marzisupportedhigh

CD68 is an upregulation marker for reactive, phagocytosing microglia.

"and we in fact see that in the rotenone condition you have activated, phagocytosing microglia that are characterized by the upregulation of a marker called CD68. So this means these are reactive, phagocytosing microglia." (said at 0:46:15)

CD68 (Cluster of Differentiation 68) is a well-established lysosomal protein and standard biological marker used to identify reactive (activated) and phagocytosing microglia and macrophages. Upregulation of CD68 reflects increased lysosomal volume and cellular phagocytic activity in neuroinflammatory conditions.

0:51:39Sarah Marzisupportedvery low

Paraquat's primary mechanism of action is the generation of reactive oxygen species and downstream DNA damage.

"We think actually the primary mechanism of action is more through generation of reactive oxygen species and downstream DNA damage." (said at 0:51:39)

The statement accurately summarizes the established toxicological mechanism of paraquat. Paraquat undergoes continuous cellular redox cycling: it is enzymatically reduced to form a radical cation, which subsequently transfers an electron to molecular oxygen to produce superoxide and other downstream reactive oxygen species (ROS). These elevated ROS levels trigger oxidative stress that oxidizes cellular macromolecules, resulting directly in downstream oxidative DNA damage (such as 8-oxoguanine lesions and double-strand breaks), lipid peroxidation, and cell death. Because evidence for toxicological mechanisms derives primarily from cell culture, animal models, and preclinical biochemical assays, the GRADE certainty is rated very low.

0:55:24Sarah Marzisupportedmoderate

In a 2018 study, widespread histone acetylation changes were found in the entorhinal cortex of Alzheimer's disease brains.

"And so we did um a big study of this um now 7, 8 years ago, 2018... and we showed that there are really widespread changes in this histone modification in the brains of people with Alzheimer's, and specifically in the brain region that is first and most severely affected by the disease." (said at 0:55:24)

A 2018 histone acetylome-wide association study led by Marzi and colleagues (Nature Neuroscience) quantified genome-wide histone H3 lysine 27 acetylation (H3K27ac) in post-mortem entorhinal cortex samples from individuals with Alzheimer's disease and matched controls. The authors identified widespread alterations in histone acetylation associated with Alzheimer's disease neuropathology, finding 4,162 differentially acetylated peaks enriched near genes implicated in amyloid-beta and tau pathology.

0:56:40Sarah Marzisupportedmoderate

Epigenetic profiling of Alzheimer's disease brains reveals widespread epigenetic changes in both microglia and oligodendrocytes.

"what we see is that actually in Alzheimer's disease two cell types have really widespread changes epigenetically, and one is the microglia as we would have expected based on the genetics and based on a lot of our other work. But what surprised us a little bit is actually that even more strikingly, oligodendrocytes show really vast changes in the epigenetics." (said at 0:56:40)

Epigenomic profiling of postmortem human brain tissue across Alzheimer's disease cohorts demonstrates that while genetic risk loci for Alzheimer's disease are heavily enriched within microglia-specific regulatory regions, widespread disease-associated epigenetic alterations (such as differential H3K27 acetylation) predominantly map to oligodendrocytes and microglia.

0:58:36Sarah Marzisupportedhigh

Loss of myelination by oligodendrocytes occurs in Alzheimer's disease.

"Loss of myelination, loss of this insulation is something that is actually seen uh in Alzheimer's disease." (said at 0:58:36)

Loss of myelination and oligodendrocyte dysfunction are well-established pathological features of Alzheimer's disease. Human neuropathology, neuroimaging, and preclinical animal models consistently demonstrate white matter degeneration, myelin breakdown, and impaired remyelination occurring alongside classic amyloid-beta and tau pathology.

1:02:17Sarah Marzisupportedmoderate

Cell-free DNA released from dying brain neurons enters the bloodstream and can be identified as neuron-derived using cell-type-specific epigenetic methylation marks.

"as neurons die in your brain, uh some of their DNA gets released into the intercell—so basically just into the brain, and a lot of it is cleared up, but not all of it, and some of it makes its way into the bloodstream and can be picked up there. And because epigenetics is very cell type-specific, uh if you pick up those specific epigenetic marks that are only found in neurons, you can say, 'Yes, this piece of DNA came from a neuron.'" (said at 1:02:17)

When cells undergo cell death, cell-free DNA (cfDNA) fragments are released into surrounding tissue and can enter the bloodstream. Because DNA methylation profiles are highly cell-type specific, researchers have developed diagnostic assays utilizing neuron-specific differentially methylated regions (DMRs) to identify and quantify neuron-derived cfDNA in blood plasma. Clinical proof-of-concept studies have validated this approach for detecting elevated neuronal cfDNA in blood plasma across neurodegenerative and psychiatric conditions.

1:04:12Sarah Marzisupportedhigh

Neurofilament light is a general marker of neuronal death present in anyone with neurodegenerative disease rather than being specific to a particular disease.

"So that's a good marker for neurons dying in general, but it doesn't tell you what disease is causing the dying of the neurons because it just is um it's it's found in samples of anyone with any neurodegenerative disease." (said at 1:04:12)

The speaker accurately describes neurofilament light chain (NfL) as a general, non-disease-specific marker of neuronal/axonal damage and neurodegeneration rather than a biomarker unique to a single underlying etiology. Published evidence, including a systematic review and meta-analysis of over 10,000 subjects across 35 diagnoses (JAMA Neurology, PMID: 31206160), demonstrates that NfL levels in CSF and plasma are elevated across a broad spectrum of neurological conditions (including Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis, and HIV-associated neurocognitive disorders) compared to healthy controls, reflecting widespread neuroaxonal injury without being pathognomonic for a specific disease.

1:05:55Sarah Marzisupportedmoderate

Epidemiological research shows that exercise and physical activity are protective against Alzheimer's disease risk.

"So epidemiologically we of course know some of the lifestyle factors that might relate to Alzheimer's disease risk. So certainly exercise and activity is something that's quite protective, and I know people are now increasingly studying the effects of exercise on your body, more often on blood and muscle than on the brain." (said at 1:05:55)

Extensive epidemiological research and large-scale meta-analyses of prospective cohort studies consistently demonstrate that higher levels of physical activity and exercise are associated with a significantly lower risk of developing Alzheimer's disease. A 2025 dose-response meta-analysis of 29 prospective studies (over 1.4 million participants) found that high-intensity physical activity reduced Alzheimer's risk by 26% (HR 0.74, 95% CI 0.67–0.83), with an inverse dose-response relationship. Earlier systematic reviews and meta-analyses show similar reductions in risk (ranging from 14% to 35%), which remain robust across long follow-up durations after adjusting for major confounders.

1:07:40Sarah Marzisupportedmoderate

Rotenone is a known environmental cause of Parkinson's disease.

"do known environmental causes of Parkinson's like rotenone, do they cause um patterns that overlap what we see in just sporadic Parkinson's cases where we wouldn't know what they've been exposed to" (said at 1:07:40)

Rotenone is well established in epidemiological and toxicological literature as an environmental risk factor and experimental model for Parkinson's disease. Rotenone inhibits mitochondrial complex I, reproducing the core pathophysiological features of Parkinson's disease—including selective dopaminergic neurodegeneration in the substantia nigra, alpha-synuclein aggregation, and motor deficits. In human epidemiological studies, such as the Agricultural Health Study, occupational exposure to rotenone was significantly associated with a 2.5-fold increased risk of developing Parkinson's disease (OR = 2.5; 95% CI, 1.3–4.7).

1:08:40David Perlmutter (host)supportedmoderate

Trichloroethylene contamination in groundwater at Camp Lejeune is linked to higher rates of Parkinson's disease.

"he's really focused also on trichloroethylene. And its its uh way that it made its way into the groundwater. It explains, you know, the higher rates in—here we have in the States, uh uh Fort Lejeune, uh where exactly very high rates." (said at 1:08:40)

A large population-based cohort study of service members stationed at Camp Lejeune between 1975 and 1985 (where drinking water was heavily contaminated with trichloroethylene and other volatile organic compounds) compared with unexposed personnel at Camp Pendleton found a 70% increased risk of Parkinson's disease (odds ratio 1.70; 95% CI, 1.39–2.07), as well as a significantly increased risk of prodromal Parkinsonian features.

1:00:36David Perlmutter (host)supportedhigh

Valproate acts as a histone deacetylase inhibitor that globally affects histones across the genome.

"So there has been work over the years, before you made it very clear that there's an array of histones that are involved, to consider the use of histone deacetylase inhibitors like valproate to kind of globally affect histones in general." (said at 1:00:36)

The claim is supported by extensive biochemical and epigenetic research. Valproic acid (valproate) is a well-established histone deacetylase (HDAC) inhibitor (class I HDACs preferentially) that causes global histone hyperacetylation and affects chromatin accessibility across the genome.

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.