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 - citing their own research

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.

0:11:43supportedmoderatetheir 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.

0:51:21contradictedvery lowtheir own paperAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

Extravasated fibrinogen in the brain is neurotoxic and is internalized by oligodendrocytes, causing them to die via autophagy and promoting white matter disease.

"And we found that it's neurotoxic, so toxic to neurons. It's also toxic to oligodendrocytes... So they take it up, so they internalize fibrinogen, and they die by what we call autophagy, so it's almost like a suicide cell death, and which leads to white matter disease." (said at 0:51:21)

The claim refers to findings originally reported in a 2018 study (Montagne et al., Nature Medicine), which described pericyte degeneration leading to extravasated fibrinogen accumulation, autophagy-dependent cell death in oligodendrocytes, and white matter dysfunction in mouse models (PMID 29400711). However, this study was formally retracted in 2024 (PMID 38580816), invalidating its data and conclusions regarding fibrinogen-induced oligodendrocyte autophagy and white matter pathology.

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]

0:58:15contradictedvery lowtheir own paperAxel Montagne, PhD, on Solving Alzheimer’s and Dementia with

Exposing mice to Los Angeles highway airborne particulate matter caused blood-brain barrier breakdown and pericyte degeneration within days.

"I'm part of two studies that we've published four to five years ago maybe where we expose the mice to airborne particles from Los Angeles. We were taking from the highway the particles and giving it to the mouse to see what's the impact of the pollution on vascular function... we found a high peak of vascular—it's a longitudinal disease, but very rapidly, a few days after giving the particles to the mouse, we were seeing blood-brain barrier breakdown and pericyte degeneration very quickly" (said at 0:58:15)

Published experimental research investigating the effects of Los Angeles traffic-derived nanoparticulate matter (nPM) in mice found that exposure to nPM alone did not alter blood-brain barrier integrity or regional cerebral blood flow. Instead, nPM exposure only exacerbated blood-brain barrier permeability and vascular pathology in the presence of pre-existing cerebral hypoperfusion induced by bilateral carotid artery stenosis.

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).

1:06:15supportedmoderatetheir 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.

1:34:28supportedmoderatetheir 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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