HoldsUp

Axel Montagne

UK Dementia Research Institute at the University of Edinburgh Centre for Clinical Brain Sciences

Axel Montagne, PhD, is a Chancellor's Fellow and group leader at the UK Dementia Research Institute at the University of Edinburgh Centre for Clinical Brain Sciences. His research focuses on the role of brain vasculature and blood-brain barrier dysfunction in the early stages of dementia and age-related cognitive decline. His published studies cover topics including glial-vascular interactions, pericytes, transcriptomics of brain vascular cells, cerebral small vessel disease, and neurodegenerative mechanisms in Alzheimer's disease.

62 claims checked on air: 5 context 5 contradicted 3 overstated 43 supported 6 unverified

What they said on air - supported

14 citing their own research

0:06:37supportedmoderatetheir own paperAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:08:10supportedmoderatetheir own paperAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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).

0:08:42supportedmoderatetheir own paperAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:09:13supportedhighAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:09:47supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:11:43supportedmoderatetheir own paperAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:18:29supportedmoderatetheir own paperAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:18:57supportedlowAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:20:15supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:21:58supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:25:41supportedlowAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:25:53supportedlowAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:29:34supportedhighAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:30:24supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:30:59supportedhighAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:31:49supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:33:20supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:33:52supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:35:57supportedhighAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:36:27supportedhighAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:37:56supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:40:16supportedhighAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:41:37supportedhighAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:47:13supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:49:41supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:52:24supportedvery lowtheir own paperAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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]

0:53:55supportedvery lowAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:54:25supportedlowAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

0:57:59supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

1:02:39supportedmoderatetheir own paperAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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).

1:03:10supportedhighAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

1:03:41supportedvery lowAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

1:04:12supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

1:06:15supportedmoderatetheir own paperAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

1:06:46supportedlowtheir own paperAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

1:07:48supportedvery lowtheir own paperAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

1:07:48supportedvery lowtheir own paperAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

1:09:20supportedhighAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

1:18:33supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

1:19:36supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

1:26:16supportedmoderateAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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).

1:29:52supportedhighAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

1:34:28supportedmoderatetheir own paperAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

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.

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