HoldsUp

FoundMyFitness · 2023-02-28 · Rhonda Patrick (host), Axel Montagne

Axel Montagne, PhD, on Solving Alzheimer’s and Dementia with Blood-Brain Barrier Repair

74 research-tied claims examined: 5 contradicted 5 overstated 7 context 50 supported 7 unverified

50

Supported by research

0:06:37Axel Montagnesupportedmoderate

During normal aging, the hippocampus within the medial temporal lobe exhibits increased blood-brain barrier leakiness compared to younger controls.

"we see special brain regions that start to leak with normal aging, and these regions, it's a bit—that's the region of the hippocampus that we call medial temporal lobe... That region somehow, we still don't know why at that time, is leakier than normal in people that are older versus controls young" (said at 0:06:37)

Human neuroimaging studies using high-resolution dynamic contrast-enhanced MRI demonstrate that normal aging is associated with blood-brain barrier (BBB) breakdown that begins in the hippocampus within the medial temporal lobe. Montagne et al. (2015) showed that regional BBB permeability in the hippocampus (specifically in the CA1 and dentate gyrus subregions) increases in older individuals compared to younger controls, representing an early vascular event during human brain aging.

0:08:10Axel Montagnesupportedmoderate

Baseline blood-brain barrier breakdown measured by MRI or biofluid biomarkers predicts the rate of future cognitive decline.

"And we know, so in this paper that you mentioned, we can predict future cognitive decline. So the people having more leakiness at baseline when we scan them or when we measure in their plasma or CSF cerebrospinal fluid the level of vascular problems in the brain, we know that they are going to decline faster than the people that have low levels of these biomarkers." (said at 0:08:10)

Prospective longitudinal studies demonstrate that higher baseline blood-brain barrier (BBB) permeability (measured via dynamic contrast-enhanced MRI) and elevated biofluid biomarkers of capillary mural cell/pericyte damage (such as CSF soluble PDGFRβ) are significantly associated with faster rates of future cognitive decline, independent of classic Alzheimer's disease pathology (amyloid-β and tau).

0:08:42Axel Montagnesupportedmoderate

The brain regions demonstrating blood-brain barrier leakiness are anatomically distinct and independent from areas where amyloid plaques and tau tangles accumulate early on.

"what we found is the leaky areas that we see in the brain have nothing to do with the areas where we start seeing the buildup of amyloid plaques and tau tangles. So it seems to be two different, two independent paths, I would say." (said at 0:08:42)

Dynamic contrast-enhanced MRI (DCE-MRI) and biomarker studies investigating blood-brain barrier (BBB) integrity in humans have demonstrated that early BBB leakage—localized primarily to the hippocampus and medial temporal lobe—occurs independently of classical Alzheimer's disease pathology. Regional BBB breakdown does not correlate with or depend on amyloid-β or tau biomarker changes measured by positron emission tomography (PET) or cerebrospinal fluid, supporting the conclusion that early vascular leakage and classical Alzheimer's proteinopathy represent independent pathological pathways.

0:09:13Axel Montagnesupportedhigh

Cerebral amyloid angiopathy (CAA) disrupts cerebral blood vessels.

"when people start to have amyloid plaques, they tend to have what we call cerebral amyloid angiopathy, CAA, which also will disrupt vessels." (said at 0:09:13)

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid-beta peptides within the walls of leptomeningeal and cortical blood vessels. Extensive neuropathological and clinical evidence demonstrates that CAA structurally and functionally disrupts cerebral blood vessels, leading to smooth muscle cell degeneration, loss of vessel wall integrity, blood-brain barrier dysfunction, and an increased risk of cerebral microbleeds and intracerebral hemorrhage.

0:11:43Axel Montagnesupportedmoderate

Vascular dysfunction can be detected 10 or more years prior to cognitive decline in cognitively normal carriers of APOE4.

"So we know that the people carrying this particular gene have more chance to develop Alzheimer's disease than other people, and these people have much more vascular problems in the brain, and they are still cognitively normal. So we can detect, as you said, we can detect perhaps—I don't want to speculate, but we know roughly that at least we can detect 10 years, if not more, prior to cognitive decline, we can detect those vascular problems." (said at 0:11:43)

Research demonstrates that cerebrovascular dysfunction, specifically blood-brain barrier (BBB) breakdown, is detectable in cognitively normal carriers of the APOE4 allele and predicts future cognitive decline. Advanced neuroimaging (dynamic contrast-enhanced MRI) and cerebrospinal fluid biomarkers (such as soluble PDGFRβ) show significant hippocampal and medial temporal lobe capillary breakdown in cognitively unimpaired APOE4 individuals years before clinical symptoms emerge, independently of amyloid-β or tau pathology.

  • supports: APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. (Nature 2020) · cited 1301x in the literature
    "Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography... High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers" (abstract, results, passage verified)
    pubmedfull study (doi)
0:18:29Axel Montagnesupportedmoderate

Normal aging is associated with an estimated 10 to 20 percent loss of pericytes around the brain microvasculature.

"we know from mouse studies and human studies, postmortem brain tissue analysis, we can see that when we stain, when we look at those pericytes around the microvasculature, there is roughly a 10 to 20 percent loss of these cells just with normal aging." (said at 0:18:29)

Postmortem tissue and neuroimaging studies in humans and rodents confirm that normal aging is accompanied by mild microvascular pericyte loss and injury (typically reported in the 10% to 20% range during normal aging, compared to more substantial 30% to 60% pericyte loss seen in pathological states like Alzheimer's disease), which correlates with age-dependent blood-brain barrier permeability in brain regions such as the hippocampus.

  • supports: Blood-brain barrier breakdown in the aging human hippocampus. (Neuron 2015) · cited 2136x in the literature
    "The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment." (abstract, results, passage verified)
    pubmedfull study (doi)
0:18:57Axel Montagnesupportedlow

The human hippocampus has fewer pericytes at baseline compared to the cortex.

"Let's say, if I talk again about the hippocampus, there are reports showing that there's fewer pericytes in the hippocampus than the cortex of the human brain at baseline." (said at 0:18:57)

Post-mortem human neuropathology studies examining vascular mural cells have quantified pericyte metrics across brain regions in neurologically intact human controls, reporting lower baseline pericyte numbers and vascular coverage in the hippocampus relative to cortical areas. For instance, Sengillo et al. (2013) quantified capillary pericyte numbers and coverage in human postmortem hippocampal and cortical tissue, providing baseline control values alongside comparisons in Alzheimer's disease pathology.

0:20:15Axel Montagnesupportedmoderate

Brain pericytes express contractile proteins that allow them to constrict and dilate cerebral blood vessels.

"The second major property of a pericyte is that they do have contractile proteins, meaning that those cells are able to constrict vessels and dilate vessels." (said at 0:20:15)

Brain pericytes express contractile machinery—including alpha-smooth muscle actin (α-SMA) and non-muscle/smooth muscle myosin isoforms—enabling them to actively contract and relax to modulate capillary diameter and regulate cerebral microvascular blood flow.

0:21:58Axel Montagnesupportedmoderate

During aging, cerebral endothelial cells upregulate cell adhesion molecules that recruit immune cells from the blood into the brain.

"there is cell adhesion molecules that start to be expressed at the endothelium, which is normally not there or in very minimal quantity, and we start having significant amounts of these cell adhesion molecules throughout the whole body. And the brain is very sensitive to that because these cell adhesion molecules, what they do is they collect the immune cells from the blood, sorry, to bring them into the brain." (said at 0:21:58)

Published experimental and translational research confirms that aging induces the upregulation of cell adhesion molecules (such as VCAM-1 and ICAM-1) on cerebral endothelial cells. In the healthy young brain, these molecules are expressed at low basal levels, but aged systemic factors and inflammatory signaling upregulate them at the blood-brain barrier, facilitating the adhesion and infiltration/transmigration of circulating peripheral immune cells (such as CD8+ T cells) into the central nervous system.

0:25:41Axel Montagnesupportedlow

The expression of the MFSD2A transporter at cerebral blood vessels decreases with aging and dementia.

"And there is recent studies that show that as we age and with dementia, MFSD2A, so the receptor for omega-3, is reduced at the blood vessels." (said at 0:25:41)

Preclinical studies demonstrate that MFSD2A (a primary transporter for DHA across the blood-brain barrier) protein expression declines in the brain microvasculature during aging and in animal models of Alzheimer's disease. In mice, aging leads to significant down-regulation of MFSD2A in brain microvessels and impaired brain docosahexaenoic acid uptake (PMID: 36795730). Similarly, animal models of Alzheimer's disease (5xFAD) show reduced MFSD2A expression in retinal/CNS vascular tissue (PMID: 37762391), and human clinical cohorts show decreased circulating blood levels of MFSD2A correlating with disease severity in Alzheimer's disease (PMID: 31861865). Evidence remains primarily preclinical and observational.

0:25:53Axel Montagnesupportedlow

Hotspots of MFSD2A transporter reduction on cerebral blood vessels colocalize with areas of pericyte loss.

"And there is also a link that where there is a reduction in this MFSD2A on blood vessels, that's where we see pericyte loss... we can see that these hotspots of MFSD2A loss are also hotspots of pericyte loss" (said at 0:25:53)

Published neurovascular research shows that brain pericytes regulate endothelial MFSD2A expression and membrane localization, and that loss or reduced coverage of pericytes is associated with regional downregulation or loss of MFSD2A in central nervous system microvessels. For example, co-culture models and mutant mouse models with reduced pericyte coverage or loss exhibit corresponding reductions in endothelial MFSD2A expression and functional BBB transcytosis suppression.

0:29:34Axel Montagnesupportedhigh

Cerebral small vessel disease is the second most common form of dementia behind Alzheimer's disease.

"with dementia, Alzheimer's disease is one, but the second major form of dementia is cerebral small vessel disease." (said at 0:29:34)

Vascular dementia (or vascular cognitive impairment and dementia, VCID), of which cerebral small vessel disease is the most prevalent underlying vascular pathology, is widely established as the second most common form of dementia after Alzheimer's disease, accounting for approximately 15% to 20% of all dementia cases.

0:09:47Axel Montagnesupportedmoderate

Vascular dysfunction promotes the formation of amyloid plaques in the brain.

"And we know that having vascular dysfunction will promote also the formation of amyloid plaques in the brain." (said at 0:09:47)

Vascular and neurovascular unit dysfunction impairs the clearance of amyloid-beta (Aβ) across the blood-brain barrier (BBB) and perivascular routes (e.g., through downregulation of transport receptors like LRP1 and pericyte degeneration), promoting the accumulation and aggregation of Aβ into parenchymal amyloid plaques and cerebral vascular amyloid deposits. This mechanism is central to the established two-hit vascular hypothesis of Alzheimer's disease.

0:30:24Axel Montagnesupportedmoderate

Alzheimer's disease and small vessel disease both exhibit microbleeds on brain MRI caused by blood-brain barrier breakdown allowing red blood cells into the brain.

"If you look at two brains, Alzheimer's and small vessel disease, you're going to see a lot of similarities, meaning that you're going to see what we call microbleeds. We were talking about blood-brain barrier breakdown, so if there is a significant breakdown of the vessels, you can start having red blood cells going to your brain that are detectable using MRI." (said at 0:30:24)

Cerebral microbleeds (CMBs) are well-established radiological features observed on susceptibility-weighted or T2*-weighted MRI in both cerebral small vessel disease and Alzheimer's disease (often in conjunction with cerebral amyloid angiopathy). Pathophysiologically, CMBs arise from blood-brain barrier dysfunction and microvascular disruption, which permit the extravasation of erythrocytes (red blood cells) into the adjacent brain parenchyma, where iron/hemosiderin accumulation creates the magnetic susceptibility signal detected on MRI.

0:30:59Axel Montagnesupportedhigh

Small vessel disease causes lacunar infarcts that can be detected on MRI and lead to progressive cognitive decline.

"Also, small vessel disease, compared to Alzheimer's disease, they tend to have small strokes, like what we call lacunes. So they have small spots, small lesions that we can detect in the brain, which chronically and over time, you will have a deterioration of your cognitive functions." (said at 0:30:59)

The speaker's statement accurately reflects established neuroimaging and clinical criteria for cerebral small vessel disease (SVD). SVD characteristically causes small subcortical strokes (lacunar infarcts and lacunes) that are readily identified on brain MRI as fluid-filled cavities or small focal lesions. Accumulation of these lesions and associated microvascular damage contributes directly to progressive vascular cognitive impairment and cognitive decline over time.

0:31:49Axel Montagnesupportedmoderate

White matter hyperintensities are associated with blood-brain barrier leakage, pericyte detachment, and leakage of blood toxins that damage myelin sheaths and axons.

"How these white matter diseases are from the blood vessels, it's still ongoing research, but we know that these areas do have leaky vessels, possibly pericyte detachment, leakage of blood toxins into the brain, which will damage the myelin sheaths and all the axons and the white matter fibers that make your cognition run properly." (said at 0:31:49)

The speaker states that white matter diseases (such as white matter hyperintensities) originate from neurovascular dysfunction involving leaky blood vessels, pericyte degeneration/detachment, and blood-brain barrier breakdown that allows blood components into brain tissue, ultimately damaging myelin sheaths and axons. This accurately reflects current neurovascular models of cerebral small vessel disease and white matter hyperintensities (WMH). Published literature documents that gliovascular unit disruption—characterized by pericyte loss/dysfunction, blood-brain barrier breach, tissue edema, myelin loss, and axonal abnormalities—underlies white matter hyperintensities and associated cognitive decline.

0:33:20Axel Montagnesupportedmoderate

Patients with small vessel disease have high levels of soluble cell adhesion molecules shed from brain endothelial cells detectable in biofluids.

"When they get shedded, they are released into the blood, right? And we can measure them. And we know that people that do have small vessel disease, they have very high levels of soluble forms of these cell adhesion molecules that we can detect in biofluids." (said at 0:33:20)

Multiple observational and clinical studies demonstrate that patients with cerebral small vessel disease (cSVD), including subcortical vascular encephalopathy and white matter hyperintensities, have significantly elevated circulating levels of soluble cell adhesion molecules (such as sICAM-1, sVCAM-1, and sE-selectin) shed during endothelial activation and dysfunction.

0:33:52Axel Montagnesupportedmoderate

Soluble PDGF receptor beta is shed from pericytes into plasma and CSF and serves as a measurable biomarker of pericyte dysfunction in small vessel disease.

"And we can measure one—I don't know if you mentioned that today, but the soluble form of a very complicated name, PDGF receptor beta, so platelet-derived growth factor receptor beta. That's a receptor on the pericytes, and that's the same thing: it can be shedded and released into the plasma and into the CSF, and that can be measured." (said at 0:33:52)

Platelet-derived growth factor receptor-beta (PDGFRβ) is expressed on brain pericytes, and its soluble extracellular domain (sPDGFRβ) is shed during pericyte injury or activation and released into both cerebrospinal fluid (CSF) and blood plasma. Clinical and translational studies demonstrate that sPDGFRβ can be quantified in human CSF and plasma samples, serving as a biomarker of neurovascular pericyte injury and blood-brain barrier dysfunction.

0:35:57Axel Montagnesupportedhigh

CADASIL involves NOTCH3 protein aggregates in pericytes and vascular smooth muscle cells, leading to severe white matter disease and cognitive decline beginning around age 30 to 40.

"And it involves aggregates, and for CADASIL it's NOTCH3 proteins that aggregate in pericytes and vascular smooth muscle cells, which makes vessels dysfunctional very quickly. And those people develop white matter disease at the age of 30, 40 years old, and they go towards cognitive deterioration very rapidly." (said at 0:35:57)

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is caused by mutations in the NOTCH3 gene, which encodes a receptor predominantly expressed in vascular mural cells (pericytes and vascular smooth muscle cells). The disease is pathologically characterized by the accumulation and aggregation of mutant NOTCH3 extracellular domain and granular osmiophilic material (GOM) surrounding these cells, driving mural cell degeneration, vessel dysfunction, and blood-brain barrier impairment. Clinically and radiographically, this leads to early white matter hyperintensities and lesions (commonly appearing between age 30 and 40) that progress to recurrent subcortical ischemic strokes, mood disorders, and cognitive decline progressing to vascular dementia.

  • supports: Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy wit… (Annals of neurology 2015) · cited 177x in the literature
    "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common inherited small-vessel disease, is associated with vascular aggregation of mutant Notch3 protein, dysfunction of cerebral vessels, and dementia. Pericytes, perivascular cells involved in microvascular function, express Notch3... With increasing age, mutated Notch3 aggregated around pericytes and smooth muscle cells." (abstract, passage verified)
    pubmedfull study (doi)
  • supports: The pericyte: A critical cell in the pathogenesis of CADASIL. (Cerebral circulation - cognition and behavior 2021) · cited 25x in the literature
    "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease presenting with migraine, mood and cognitive disorders, focal neurological deficits, recurrent ischemic attacks, lacunar infarcts and brain white matter changes. As they age, CADASIL patients invariably develop cognitive impairment and subcortical dementia. CADASIL is caused by missense mutations in the NOTCH3 gene resulting in a profound cerebral vasculopathy affecting primarily arterial vascular smooth muscle cells, which target the microcirculation and perfusion. Based on a thorough review of morphological lesions in arteries, veins, and capillaries in CADASIL, we surmise that arteriolar and capillary pericyte damage or deficiency appears a key feature in the pathogenesis of the disease." (abstract, passage verified)
    pubmedfull study (doi)
  • supports: Signaling pathways and molecular mechanisms involved in the onset and progression of cereb… (The journal of headache and pain 2025) · cited 6x in the literature
    "CADASIL has diverse clinical features such as migraine with aura, dementia, and recurrent strokes, and is caused by a pathogenic mutation in the NOTCH3 gene which encodes a transmembrane receptor found in smooth muscle cells of small arteries and pericytes of brain capillaries. Pathogenic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, leading to the abnormal accumulation of granular osmiophilic material in the vessels of affected individuals." (abstract, passage verified)
    pubmedfull study (doi)
0:36:27Axel Montagnesupportedhigh

CARASIL is a genetic form of small vessel disease caused by HTRA1 mutations that exhibits white matter disease, microbleeds, lacunes, and blood-brain barrier dysfunction.

"And CARASIL, about the same thing, it's HTRA1, sorry, protein that is involved. But there is also the genetic form that has exactly the same features: white matter disease, microbleeds, lacunes, and blood-brain barrier issues." (said at 0:36:27)

CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) is an established monogenic form of cerebral small vessel disease caused by mutations in the HTRA1 (high-temperature requirement A serine peptidase 1) gene. The hallmark neuroimaging and pathological features of CARASIL include extensive white matter hyperintensities (leukoencephalopathy), lacunar infarcts, cerebral microbleeds, and loss of blood-brain barrier integrity due to vascular matrix degradation and wall thickening.

0:37:56Axel Montagnesupportedmoderate

A substantial proportion of patients diagnosed with small vessel disease exhibit cerebral amyloid angiopathy or amyloid plaques upon postmortem brain tissue analysis.

"To give you an example, we have the UK Biobank here where we have brain tissue samples where we can really look at the features of these different things. And a good proportion of small vessel disease-diagnosed patients, they do have some sort of CAA—that's what we talked about earlier, cerebral amyloid angiopathy—and some of them have amyloid plaques." (said at 0:37:56)

Postmortem neuropathological studies confirm that cerebral small vessel disease (SVD), cerebral amyloid angiopathy (CAA), and Alzheimer's disease-related amyloid-beta plaque pathology frequently co-occur. Neuropathologically, sporadic SVD is predominantly categorized into arteriolosclerosis and CAA, and individuals with small vessel disease frequently present with concurrent CAA or parenchymal amyloid plaques at autopsy.

0:40:16Axel Montagnesupportedhigh

GLUT1 is the primary glucose transporter at the blood-brain barrier and is significantly reduced in postmortem brain vessels of Alzheimer's patients.

"the main transporter of glucose at the blood-brain barrier to make sure glucose comes to the brain is GLUT1. So that's a receptor, GLUT1, that has been found to be reduced in Alzheimer's disease. So people have looked at postmortem brain tissue banks, looking at the microvasculature and the bigger vessels, and they found that Alzheimer's patients, they have much less GLUT1 at the blood-brain barrier" (said at 0:40:16)

The claim is supported by human postmortem brain studies and systematic review evidence. Glucose transporter-1 (GLUT1) is the primary facilitative glucose transporter expressed at the blood-brain barrier. Multiple postmortem tissue studies of Alzheimer's disease patients, examining cerebral microvessels and parietal cortex vasculature, demonstrate significant reductions in GLUT1 expression compared to non-demented controls.

0:41:37Axel Montagnesupportedhigh

Patients with Alzheimer's disease show significantly reduced FDG signal on PET imaging compared to healthy controls.

"So we know that when we inject that tracer—it's fluorodeoxyglucose tracer—into a patient, if you have Alzheimer's, compared to control, you will have much less FDG signal." (said at 0:41:37)

Extensive meta-analytic evidence confirms that patients with Alzheimer's disease exhibit significant cerebral glucose hypometabolism—demonstrated by substantially reduced fluorodeoxyglucose (FDG) tracer uptake and signal on PET imaging—compared to healthy controls, particularly in the temporoparietal regions, posterior cingulate, and precuneus.

0:43:00Rhonda Patrick (host)supportedvery low

Animal studies show that omega-3 fatty acid deficiency causes a reduction in brain GLUT1 transporters and triggers blood-brain barrier breakdown.

"I remember reading a couple of studies years ago where animal studies showed omega-3 deficiency caused a reduction in GLUT1 transporters in the brain. Again, of course omega-3 deficiency also breaks down the blood-brain barrier." (said at 0:43:00)

Rodent models demonstrate that dietary deficiency in omega-3 polyunsaturated fatty acids leads to a significant decrease in glucose transporter 1 (GLUT1) protein expression in brain microvessels and endothelial cells of the blood-brain barrier (decreases of approximately 23% to 25%), reducing basal glucose transport and utilization. Because this evidence is derived entirely from animal models and in vitro rodent endothelial cells, the certainty of evidence for human clinical effects is very low.

0:47:13Axel Montagnesupportedmoderate

Proteomic analysis of human plasma identified over 30 blood-brain barrier-related proteins elevated during normal aging, with soluble VCAM-1 identified as the top candidate.

"And what he found, I think the most striking finding was with normal aging, he found I think 30-plus proteins in the plasma that were elevated with normal aging that were related to blood-brain barrier. And if you look down, I think the top five candidates were proteins of the endothelial cells. Obviously, the number one that stood out as the number one protein that is elevated with normal aging was soluble VCAM-1." (said at 0:47:13)

Proteomic and molecular analyses of plasma and brain endothelial cells from aging humans and mice (notably from Tony Wyss-Coray's group at Stanford) identified prominent elevations in blood-brain barrier- and endothelial-related proteins with normal aging, with soluble VCAM-1 (vascular cell adhesion molecule 1) identified as a top elevated candidate that mediates age-related neurovascular and cognitive decline.

0:49:41Axel Montagnesupportedmoderate

Fibrinogen extravasates and deposits in brain parenchyma in Alzheimer's disease and small vessel disease due to blood-brain barrier breakdown.

"if you compare a control brain, someone cognitively normal with no issues whatsoever, and an Alzheimer's brain or a small vessel disease brain, you start seeing what we call this extravascular deposition of fibrinogen... so it has been found in Alzheimer's disease. We also found that in animals that either do have Alzheimer's disease or have some sort of blood-brain barrier issues." (said at 0:49:41)

Post-mortem human brain studies and experimental animal models confirm that blood-brain barrier (BBB) breakdown leads to the extravasation and parenchymal deposition of fibrinogen in Alzheimer's disease and forms of cerebral small vessel disease. In human Alzheimer's disease brains and transgenic rodent models, extravasated fibrinogen is deposited at sites of vascular permeability, co-localizing with amyloid-beta deposits and reactive microglia. In small vessel disease paradigms, fibrinogen extravasation is also observed, particularly in white matter lesions surrounding enlarged perivascular spaces and lacunar infarcts, although general age-related BBB changes can also lead to baseline plasma protein leakage.

0:52:24Axel Montagnesupportedvery low

Systemically lowering fibrinogen in mouse models of blood-brain barrier dysfunction reduced brain fibrinogen leakage and partially restored cerebral blood flow and barrier integrity.

"Interestingly, in animals we were able to reduce fibrinogen levels systemically in the blood... we were able to demonstrate that there is less—obviously, it makes sense—less fibrinogen going in to the brain to cause damage, and also, interestingly, by reducing fibrinogen we were able to partially restore vascular functions in terms of blood flow and also integrity of the barrier." (said at 0:52:24)

Animal research in mouse models of blood-brain barrier (BBB) breakdown and vascular dysfunction indicates that systemic genetic or pharmacological depletion of fibrinogen reduces brain fibrinogen deposition and attenuates vascular pathology, microcirculatory deficits, and white matter injury. Because this claim is based exclusively on preclinical rodent models, the GRADE certainty is very low. [WARNING: a cited paper has been RETRACTED]

0:53:55Axel Montagnesupportedvery low

Fibrinogen binds to CD11b receptors on microglia, triggering an inflammatory reaction in the brain.

"And the last thing on fibrinogen is just remember now fibrinogen can activate the brain-resident immune cells that are microglia cells through CD11b. So that's a specific receptor. So when fibrinogen gets in, it can bind to microglia, so it will induce an overreaction, over-inflammation of the brain" (said at 0:53:55)

Extensive mechanistic and animal research demonstrates that extravasated fibrinogen binds to the Mac-1 (CD11b/CD18) integrin receptor expressed on brain-resident microglia. This interaction stimulates intracellular signaling (including Akt and Rho pathways), triggering microglial activation, reactive oxygen species generation, and neuroinflammation. Disruption of this specific fibrinogen–CD11b binding motif genetically or pharmacologically suppresses microglial activation and neuroinflammatory pathology in models of multiple sclerosis and Alzheimer's disease. Because this mechanism has been established primarily in cellular and animal disease models, GRADE certainty is very low.

0:55:57Rhonda Patrick (host)supportedmoderate

Exposure to high levels of air particulate matter increases plasma fibrinogen levels, whereas high omega-3 intake blunts this increase.

"when people are exposed to high amounts of it, it causes their fibrinogen to go up, right? It's again an inflammatory marker as well. But people that were taking in high amounts of omega-3, it blunted the increase in fibrinogen in plasma." (said at 0:55:57)

The claim accurately reflects findings from human observational research examining how blood omega-3 fatty acid levels modify the hematological and inflammatory response to particulate matter (PM) air pollution. In an observational study of cardiac patients (Rich et al., 2018), short-term increases in PM2.5 exposure were significantly associated with increases in serum fibrinogen among individuals with low to medium blood levels of omega-3 fatty acids (3.1% increase per 5.6 μg/m3 increase in PM2.5), whereas this increase was substantially blunted (0.9% increase, non-significant) among patients with high blood levels of marine-derived omega-3 fatty acids (EPA and DHA).

  • supports: Do elevated blood levels of omega-3 fatty acids modify effects of particulate air pollutan… (Air quality, atmosphere, & health 2018) · cited 8x in the literature
    "Each 5.6 μg/m 3 increase in PM 2.5 concentration in the previous hour was associated with a 3.1% increase in fibrinogen (95% CI = 1.5%, 4.7%) in those subjects with LOWMED total ω-3 fatty acid levels, but only a 0.9% increase (95% CI = - 1.5%, 3.2%) in patients with HIGH total ω-3 fatty acid levels. This same pattern was observed with fish oil-derived docosahexaenoic and eicosapentaenoic acids but not alpha-linolenic (from plant oil or seeds)... Thus, increased blood levels of fish-based ω-3 fatty acids attenuated increases in fibrinogen associated with short-term increases in ambient PM." (abstract, results, passage verified)
    pubmedfull study (doi)
0:54:25Axel Montagnesupportedlow

Researcher Katerina Akassoglou developed a therapeutic antibody that blocks the interaction between fibrinogen and microglia to prevent neuroinflammation.

"there is a fantastic researcher, Katerina Akassoglou. She is at Gladstone Institutes, UCSF, where I think she developed an antibody that blocks the interaction between fibrinogen and microglia to avoid that overexpression of inflammation or overactivation of microglia cells" (said at 0:54:25)

Preclinical studies led by Dr. Katerina Akassoglou at Gladstone Institutes / UCSF developed monoclonal antibody 5B8 (and its humanized derivative THN391), which specifically binds the cryptic inflammatory epitope (γ377–395) of fibrin. This blocks fibrin from binding to Mac-1/CD11b receptors on microglia and macrophages, suppressing microglial activation, oxidative stress, and neuroinflammation in animal models of multiple sclerosis and Alzheimer's disease without interfering with normal blood clotting.

  • supports: Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. (Nature immunology 2018) · cited 218x in the literature
    "Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ 377-395 , to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration." (abstract, results, passage verified)
    pubmedfull study (doi)
  • supports: Development of a humanized anti-fibrin monoclonal antibody for the treatment of neuroinfla… (Journal of neuroinflammation 2025) · cited 4x in the literature
    "At sites of vascular damage, conversion of the blood coagulation protein fibrinogen to fibrin exposes a cryptic inflammatory epitope, γ377–395, which can bind CD11b/CD18 and CD11c/CD18 complement receptors on microglia, macrophages, and dendritic cells. Genetic targeting of the fibrin γ377–395 epitope or its pharmacologic inhibition with the mouse monoclonal antibody 5B8 protects from inflammation and neurodegeneration in AD and MS mouse models. Here, we present the development of THN391, a first-in-class humanized antibody, to neutralize fibrin toxicity without adverse anticoagulant effects for the treatment of neurodegenerative, retinal, and inflammatory diseases." (abstract, results, passage verified)
    pubmedfull study (doi)
0:57:59Axel Montagnesupportedmoderate

Epidemiological studies demonstrate that living in large cities with air pollution increases the risk of developing dementia.

"And there is multiple studies, as you know, showing that if you if you live in the city, big city, you have more chance to develop some sort of dementia." (said at 0:57:59)

Large-scale epidemiological studies and systematic reviews consistently demonstrate that long-term exposure to urban outdoor air pollutants—such as fine particulate matter (PM2.5), nitrogen dioxide (NO2), and black carbon—is associated with an increased risk of incident dementia. A comprehensive 2025 systematic review and meta-analysis published in The Lancet Planetary Health evaluated 32 studies encompassing millions of participants, finding significant associations between incident dementia and long-term exposure to PM2.5 (pooled HR 1.08 per 5 μg/m3 increase), NO2 (pooled HR 1.03 per 10 μg/m3 increase), and black carbon (pooled HR 1.13 per 1 μg/m3 increase). Earlier and subsequent meta-analyses confirm these findings across international cohorts.

1:01:07Rhonda Patrick (host)supportedmoderate

Omega-3 supplementation has been shown in research to help blunt the adverse effects of air pollution.

"as well as omega-3 has been shown—I know I keep going back to that, but it's been shown to help blunt some of the air pollution. I know the research shows it, you know, so." (said at 1:01:07)

Clinical trials and prospective studies demonstrate that omega-3 polyunsaturated fatty acid (fish oil) supplementation can mitigate or blunt several adverse physiological responses to air pollutants (such as ozone and fine particulate matter, PM2.5). Randomized controlled trials show fish oil significantly blunts acute pollutant-induced decrements in lung function (FEV1 and FEV1/FVC) as well as adverse vascular, inflammatory, and heart-rate variability responses, though sample sizes in individual intervention trials remain relatively small.

1:02:39Axel Montagnesupportedmoderate

Individuals carrying at least one APOE4 allele exhibit increased blood-brain barrier leakage in the medial temporal lobe detectable via dynamic contrast-enhanced MRI.

"the people carrying at least one allele of APOE4, they tend to have more leakage in the medial temporal lobe that we can see with MRI and biomarkers." (said at 1:02:39)

A landmark 2020 study by Montagne et al. published in Nature demonstrated that human individuals carrying at least one APOE4 allele (ε3/ε4 or ε4/ε4) exhibit increased blood-brain barrier (BBB) breakdown in the hippocampus and medial temporal lobe compared to non-carriers (ε3/ε3), detectable via dynamic contrast-enhanced MRI. This BBB leakage was observed even in cognitively unimpaired APOE4 carriers and was further confirmed through cerebrospinal fluid biomarkers of pericyte injury (such as soluble PDGFRβ).

  • supports: APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. (Nature 2020) · cited 1301x in the literature
    "Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography" (abstract, results, passage verified)
    pubmedfull study (doi)
1:03:10Axel Montagnesupportedhigh

Astrocytes are the primary source of APOE production in the brain.

"so APOE, you have to know that the major source of APOE are astrocytes." (said at 1:03:10)

The speaker's statement that astrocytes are the major source of apolipoprotein E (APOE) in the brain is well supported by scientific literature. In the central nervous system under normal physiological conditions, APOE is primarily synthesized and secreted by astrocytes to transport cholesterol and phospholipids to neurons, with secondary contributions from microglia and injured neurons under neuroinflammatory or pathological conditions.

1:03:41Axel Montagnesupportedvery low

APOE4 has lower binding affinity for the LRP1 receptor on pericytes than APOE3, triggering an NF-κB and cyclophilin A signaling cascade that drives MMP-9 expression.

"You have less chance to bind to LRP1, which will induce a cascade within the pericytes that involves NF-κB—it's a bit complicated—cyclophilin A, which then will lead to expression of MMP-9 from pericytes and endothelial cells. So basically, if you have the APOE4 gene, you will induce much more that cascade than people having the APOE3, because it doesn't bind to the LRP1 on pericytes, so it doesn't trigger the cascade of expressing cyclophilin A, which will release MMP-9." (said at 1:03:41)

Preclinical evidence in transgenic mice and human post-mortem brain tissue indicates that APOE3 suppresses a proinflammatory cyclophilin A (CypA)–NF-κB–MMP-9 cascade in pericytes by binding to the LRP1 receptor. In contrast, APOE4 fails to suppress this pathway via LRP1, leading to activation of the CypA–NF-κB–MMP-9 pathway in pericytes and endothelial cells and subsequent blood-brain barrier breakdown. Because this mechanism is derived from animal models and post-mortem tissue studies, the certainty of evidence is very low.

1:04:12Axel Montagnesupportedmoderate

MMP-9 breaks down endothelial tight junctions and degrades the vascular basement membrane, causing blood-brain barrier leakage.

"Number one is disrupting the tight junctions between the endothelial cells... And the other thing is there's a basement membrane—we haven't talked about this—there is a basement membrane wrapping around the vessels and wrapping around the pericytes, and MMP-9 is also eating up this basement membrane." (said at 1:04:12)

Published experimental and mechanistic studies demonstrate that matrix metalloproteinase-9 (MMP-9) degrades both endothelial tight junction proteins and extracellular matrix components of the vascular basement membrane, leading to blood-brain barrier (BBB) breakdown and increased permeability in models of stroke and neurovascular injury.

1:06:15Axel Montagnesupportedmoderate

MMP-9 and cyclophilin A levels in the cerebrospinal fluid are elevated approximately 3- to 4-fold in APOE4 carriers compared to APOE3 carriers.

"both MMP-9 and cyclophilin A levels were elevated in cerebrospinal fluid of people carrying the APOE4 gene. So we were talking about three- to fourfold, if I remember correctly, compared to people carrying the APOE3 gene." (said at 1:06:15)

A landmark clinical cohort study published in Nature (Montagne et al., 2020) demonstrated that APOE4 carriers (ε3/ε4 or ε4/ε4) exhibit blood-brain barrier (BBB) breakdown and pericyte injury compared to non-carriers (ε3/ε3). This BBB dysfunction was associated with elevated cerebrospinal fluid (CSF) levels and activity of the BBB-degrading cyclophilin A (CypA)-matrix metalloproteinase-9 (MMP-9) pathway, showing approximately 3- to 4-fold higher CSF concentrations/activity in APOE4 carriers compared to APOE3 controls.

1:06:46Axel Montagnesupportedlow

Cultured human iPSC-derived pericytes from APOE4 donors produce more cyclophilin A and MMP-9 at baseline than pericytes from APOE3 donors.

"we were able to also see that the pericytes, just at baseline looking at that, they produce much more cyclophilin A and MMP-9 than the pericytes that do have APOE3." (said at 1:06:46)

Published human postmortem and cellular studies demonstrate that pericytes expressing APOE4 exhibit elevated baseline activation and production of the cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) pathway compared with APOE3 pericytes. This elevated CypA-MMP-9 pathway activation in APOE4 pericytes contributes to accelerated pericyte degeneration and blood-brain barrier breakdown.

1:07:48Axel Montagnesupportedvery low

Administering the cyclophilin A inhibitor Debio 025 daily for one month to humanized APOE4 mice partially restored vascular tight junctions, pericyte coverage, and improved neuronal function and cognition.

"And we gave every day for one month to the APOE4 mice, we gave an inhibitor of cyclophilin A that is called Debio 025... we were able to partially and significantly restore vascular function. So just by blocking cyclophilin A, we were able to restore tight junctions, we were able to restore the pericyte coverage of the vasculature, and ultimately those mice had less neuronal damage and less cognitive problems." (said at 1:07:48)

Preclinical studies in APOE4 transgenic and knock-in mouse models demonstrate that human APOE4 activates a cyclophilin A (CypA)-NF-κB-MMP9 pathway in pericytes, leading to pericyte loss, degradation of tight junction proteins, blood-brain barrier breakdown, neuronal injury, and behavioral deficits. Pharmacological inhibition or genetic suppression of cyclophilin A (including with non-immunosuppressive inhibitors such as Debio 025/alisporivir) significantly restores tight junctions, pericyte coverage, and vascular integrity, attenuating neuronal loss and cognitive/behavioral impairments in these mouse models. Because the findings are established in animal models, the certainty of evidence for human clinical translation is very low.

1:09:20Axel Montagnesupportedhigh

Debio 025 is the same drug as alisporivir.

"HOST: Is that drug, a couple questions regarding it, is it the same as alisporivir, I think? GUEST1: Yes, it is. Yes." (said at 1:09:20)

Debio 025 is the developmental code name for alisporivir, an orally active, non-immunosuppressive cyclosporine analogue and cyclophilin inhibitor developed for antiviral and other therapeutic indications.

1:16:54Rhonda Patrick (host)supportedhigh

Almost 50% of US adults have hypertension, and 20% of young adults aged 18 to 39 have hypertension.

"almost 50% of US adults have hypertension, and 20% of young adults do, aged 18 to 39." (said at 1:16:54)

Nationally representative surveillance data from the National Health and Nutrition Examination Survey (NHANES) define hypertension under the 2017 ACC/AHA guideline (systolic blood pressure ≥130 mm Hg, diastolic blood pressure ≥80 mm Hg, or current antihypertensive medication use). According to CDC and NHANES reports, the overall prevalence of hypertension among US adults is approximately 47.7% to 49.5% (nearly 50%), and the prevalence among young adults aged 18 to 39 years is approximately 21% to 23% (roughly 1 in 5).

1:18:33Axel Montagnesupportedmoderate

Hypertension is associated with blood-brain barrier leakage, pericyte loss, and increased microbleeds in the basal ganglia.

"and there's like the basal ganglia and those deep structures that suffer quite a lot from hypertension, where we see also there's always an association: when people have hypertension, they tend to have more microbleeds also in this area of basal ganglia. So yes, it does impact the brain. And we know there are a few studies that show that hypertension also triggers blood-brain barrier leakage and pericyte loss." (said at 1:18:33)

Hypertension is a primary cause of arteriolosclerotic cerebral small vessel disease, which characteristically produces microbleeds in deep subcortical brain structures such as the basal ganglia, thalamus, and brainstem. Preclinical and mechanistic studies demonstrate that chronic hypertension promotes endothelial injury, loss of pericytes, and disruption of the blood-brain barrier.

1:19:36Axel Montagnesupportedmoderate

Studies show that administering antihypertensive medications has a positive impact on cognition.

"And there are some studies showing that giving antihypertensive drugs has a positive impact on cognition as well." (said at 1:19:36)

Multiple clinical trials and large meta-analyses demonstrate that treating hypertension with antihypertensive medications preserves cognitive function and reduces the risk of cognitive impairment. In the SPRINT MIND randomized controlled trial, intensive blood pressure control significantly reduced the incidence of mild cognitive impairment (HR 0.81, 95% CI 0.69–0.95) and the composite of mild cognitive impairment or probable dementia. A 2021 Cochrane systematic review of randomized trials also found a modest benefit on global cognitive function (Mini-Mental State Examination scores) in patients receiving antihypertensive therapy compared to placebo. Additionally, a large 2023 individual participant data meta-analysis of longitudinal cohort studies confirmed that individuals with treated hypertension had a 26% lower risk of dementia compared to those with untreated hypertension.

1:23:41Rhonda Patrick (host)supportedlow

Observational studies show sauna use 4 to 7 times per week is associated with an approximately 60% lower risk of dementia and Alzheimer's disease, and 2 to 3 times per week with a 20% lower risk.

"there are studies showing that, you know, dose-dependently, sauna use is associated with like a 60% lower dementia risk and Alzheimer's disease risk if you're using the sauna four to seven times a week. If you use it, you know, two to three times a week, there's like a 20% lower risk after adjusting for other factors as well." (said at 1:23:41)

The speaker's statement accurately summarizes the results of the Kuopio Ischaemic Heart Disease (KIHD) prospective cohort study published by Laukkanen and colleagues (2017). In this prospective study of 2,315 middle-aged Finnish men followed for a median of 20.7 years, men reporting 4 to 7 sauna sessions per week had a 66% lower risk of dementia (hazard ratio [HR] 0.34, 95% CI 0.16-0.71) and a 65% lower risk of Alzheimer's disease (HR 0.35, 95% CI 0.14-0.90) compared to those using the sauna once per week, after multivariable adjustment. For 2 to 3 sessions per week, the adjusted risk reduction was approximately 20% to 22% (HR for dementia 0.78, 95% CI 0.57-1.06; HR for Alzheimer's disease 0.80, 95% CI 0.53-1.20). Because this evidence comes from observational data in a cohort limited to middle-aged Finnish men, the certainty of evidence is low.

  • supports: Sauna bathing is inversely associated with dementia and Alzheimer's disease in middle-aged… (Age and ageing 2017) · cited 135x in the literature
    "In analysis adjusted for age, alcohol consumption, body mass index, systolic blood pressure, smoking status, Type 2 diabetes, previous myocardial infarction, resting heart rate and serum low-density lipoprotein cholesterol, compared with men with only 1 sauna bathing session per week, the HR for dementia was 0.78 (95% CI: 0.57-1.06) for 2-3 sauna bathing sessions per week and 0.34 (95% CI: 0.16-0.71) for 4-7 sauna bathing sessions per week. The corresponding HRs for Alzheimer's disease were 0.80 (95% CI: 0.53-1.20) and 0.35 (95% CI: 0.14-0.90)." (abstract, results, passage verified)
    pubmedfull study (doi)
1:24:12Rhonda Patrick (host)supportedmoderate

Intervention studies show sauna use produces physiological effects on blood pressure and heart rate variability comparable to moderate aerobic exercise.

"But we do know sauna—like there's intervention studies, I mean, it's comparable to moderate aerobic exercise in terms of the effects on blood pressure, heart rate variability, and stuff." (said at 1:24:12)

Intervention studies comparing sauna bathing with moderate-intensity aerobic exercise (or exercise combinations) indicate that sauna exposure elicits acute cardiovascular and hemodynamic responses—including reductions in blood pressure and changes in autonomic/cardiorespiratory markers such as heart rate variability—that are comparable to those seen with moderate aerobic exercise.

1:26:16Axel Montagnesupportedmoderate

Alcohol consumption increases blood cytokine levels, promoting vascular inflammation.

"just the alcohol itself impacts blood-brain barrier functions just by increasing the level of cytokines in the blood, which will increase the inflammation of the blood vessels." (said at 1:26:16)

Published mechanistic reviews and preclinical studies support the claim that alcohol consumption promotes systemic and neurovascular inflammation, including the elevation of circulating pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) and subsequent breakdown and dysfunction of the blood-brain barrier (BBB).

1:29:52Axel Montagnesupportedhigh

Individuals with obesity have higher circulating levels of pro-inflammatory cytokines and chemokines.

"I found studies that show that obesity, of course, these people tend to have higher levels of pro-inflammatory markers, cytokines, chemokines in the blood, and things like that, which will have an impact on barrier function." (said at 1:29:52)

A large body of clinical and experimental literature confirms that obesity is characterized by a state of chronic low-grade systemic inflammation, with increased circulating levels of pro-inflammatory cytokines (such as IL-6, IL-1β, IL-18, and TNF-α) and chemokines (such as MCP-1/CCL2 and CXC chemokines) largely driven by hypertrophic adipose tissue and infiltrating immune cells.

1:07:48Axel Montagnesupportedvery low

Humanized APOE4 mice exhibit reduced cerebral blood flow, increased blood-brain barrier leakage, and cognitive deficits in novel object recognition and location tasks compared to APOE3 mice.

"We used the humanized APOE4 mice... they have reduced blood flow in the brain, they have a leakier blood-brain barrier, they have some behavioral problems also in terms of cognition, what we call novel object recognition, novel object location, those memory issues." (said at 1:07:48)

Preclinical studies and systematic meta-analyses in humanized (targeted replacement / knock-in) APOE4 mice confirm that, compared to APOE3 controls, APOE4 mice exhibit reduced cerebral blood flow, breakdown/leakage of the blood-brain barrier (via activation of the cyclophilin A-NF-κB-MMP9 pathway in pericytes), and cognitive/memory deficits in behavioral paradigms such as novel object recognition and Morris water maze tasks. Because this evidence is derived from animal models, the GRADE certainty is rated as very low.

1:31:44Rhonda Patrick (host)supportedmoderate

Elevated homocysteine is associated with brain dysfunction and dementia.

"because I did see, you know, like it's also associated with brain dysfunction and dementia" (said at 1:31:44)

Elevated blood homocysteine (hyperhomocysteinemia) is consistently associated with cognitive impairment, brain dysfunction, and dementia across observational and prospective cohort studies. A 2019 dose-response meta-analysis of 28 prospective cohort studies (28,257 participants) showed that every 5 µmol/L increase in blood homocysteine is linearly associated with a 15% increase in the risk of Alzheimer's disease (RR 1.15, 95% CI: 1.04–1.26). An international consensus panel also concluded that elevated plasma total homocysteine is an established risk factor for cognitive decline and dementia.

1:34:28Axel Montagnesupportedmoderate

Soluble platelet-derived growth factor receptor-beta biomarker validation is ongoing in US clinical cohorts of hundreds to thousands of participants to confirm its elevation with aging and the APOE4 allele.

"So it's ongoing in clinical trials in the US. So I guess it has been done in hundreds of patients, participants, so now they try to build up, go to thousands. So, you know, you need some validation step with a bigger cohort and make sure that this is truly elevated, let's say, with APOE4, with aging, in a much larger cohort of patients." (said at 1:34:28)

Published cohort studies confirm the ongoing clinical validation and investigation of soluble platelet-derived growth factor receptor-beta (sPDGFRβ) in cerebrospinal fluid as a biomarker of pericyte injury and blood-brain barrier dysfunction across aging and APOE4 carrier status. Initial studies in smaller cohorts (e.g., Montagne et al., Nature 2020) demonstrated that elevated CSF sPDGFRβ predicts cognitive decline and reflects pericyte degeneration in APOE4 carriers, while larger cohorts encompassing hundreds of participants (such as the Swedish BioFINDER-2 cohort with 771 participants; Neurology 2023) have further examined and confirmed its relationship with aging and blood-brain barrier integrity, noting ongoing expansion and validation in large multicenter clinical cohorts.

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.