Blood-brain barrier breakdown in the aging human hippocampus
Open accessAbstract
The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. 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.Video abstract
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Some studies have suggested that during preclinical stages, vascular dysfunction is among the first detectable biomarker changes reported before symptomatic onset and before changes in other standard AD biomarkers, including amyloid deposition and CSF Aβ42, phosphorylated tau, and total tau.
“Some studies have suggested that during preclinical stages, vascular dysfunction is among the first detectable biomarker changes reported before symptomatic onset and before changes in other standard AD biomarkers, including amyloid deposition and CSF A 𝛃 42, phosphorylated tau (pTau), and total tau (285, 421).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [421]
The Introduction and Discussion report hippocampal BBB breakdown in people with no cognitive impairment, consistent with vascular changes before symptoms. The Results (Molecular biomarker CSF analysis) report no change in CSF Aβ42, tau, or pTau despite evidence of BBB breakdown. The paper does not establish that vascular changes precede amyloid deposition or demonstrate a longitudinal order of biomarker changes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIncreasing evidence supports that early cerebrovascular dysfunction contributes to AD pathophysiology and cognitive impairment.
“In addition to the classic hallmark pathology, A 𝛃 plaques, hyperphosphorylated tau neurofibrillary tangles, and neuron loss, increasing evidence supports that early cerebrovascular dysfunction contributes to AD pathophysiology and cognitive impairment (29, 285, 418, 421, 429, 569, 571, 593, 682, 693).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [421]
Patlak analysis allows detection of subtle changes in BBB permeability.
“These studies used Patlak analysis (46, 47, 466), which allows detection of subtle changes in BBB permeability (46, 248, 418, 421).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [421]
Recent neuroimaging studies in individuals with MCI and early AD reveal BBB breakdown in the hippocampus, including its CA1 and dentate gyrus subfields, and several gray and white matter regions, before brain atrophy and dementia.
“Recent neuroimaging studies in individuals with mild cognitive impairment (MCI) and early AD reveal BBB breakdown in the hippocampus, including its CA1 and dentate gyrus subfields (421), and several gray and white matter regions (220-222), respectively, before brain atrophy and dementia.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [421]
Qalb is elevated in individuals with preclinical Alzheimer's disease, mild cognitive impairment, Alzheimer's disease without vascular risk factors, and Alzheimer's disease with vascular risk factors.
“Qalb is elevated in individuals with preclinical AD (229), MCI (421), AD without vascular risk factors (287, 545, 546), and AD with vascular risk factors (67, 68, 74, 629).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [421]
In multiple sclerosis patients, increased blood-brain barrier permeability has been shown by DCE-MRI in the cortex and adjacent white matter, corpus callosum and internal capsule, and thalamic gray matter.
“More recently, an increase in BBB permeability has been shown in MS patients by DCE-MRI in the cortex and adjacent white matter (392), corpus callosum and internal capsule (121-123, 421, 574), as well as thalamic gray matter (123).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [421]
Recent neuroimaging studies allow measurement of regional BBB integrity and quantification of subtle changes in BBB permeability in CNS regions as small as hippocampal CA1, CA3, and dentate gyrus subfields.
“In terms of studying BBB function in humans, recent neuroimaging studies made important advances to allow us to measure regional BBB integrity and quantify subtle changes in BBB permeability in CNS regions as small as hippocampal CA1, CA3, and dentate gyrus subfields, which has not been possible before (421).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [421]
Growing evidence indicates that BBB damage and early cerebrovascular disease increase risk of dementia and age-related disorders such as AD.
“Growing evidence indicates that BBB damage and early cerebrovascular disease increase risk of dementia and age-related disorders such as AD [625–627].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [626]
A key change in the blood-brain barrier with ageing is increased permeability.
“A key change is the increased permeability of the BBB.154”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [154]
Blood-brain barrier dysfunction occurs early in the neurodegenerative disease cascade.
“As blood brain barrier dysfunction occurs early in the underlying neurodegenerative disease cascade (48), the study medications may be more readily absorbed in our target study population relative to neurologically healthy adults.”
From Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial (2022) · cites this paper as [48]
Local cues such as blood-brain barrier compromise or microinfarcts could drive microglial state changes instead of a brain-wide shift.
“local cues like blood brain barrier compromise (Montagne et al., 2015) or microinfarcts (Smith et al., 2012) could drive state changes rather than a brain-wide shift.”
From Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain (2018) · cites this paper as Montagne et al., 2015
In individuals with mild cognitive impairment, increased CSF sPDGFRβ correlates with increased DCE-MRI measures of blood-brain barrier dysfunction.
“In individuals with mild cognitive impairment, increased CSF sPDGFRβ correlates with increased DCE-MRI measures of BBB dysfunction8.”
From Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction (2019) · cites this paper as [8]
sPDGFRβ is primarily a biomarker of brain capillary pericytes.
“supporting that sPDGFRβ is primarily a biomarker of brain capillary pericytes8,18.”
From Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction (2019) · cites this paper as [8]
Loss of pericytes in mice elevates CSF sPDGFRβ.
“Additionally, loss of pericytes in mice elevates CSF sPDGFRβ8.”
From Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction (2019) · cites this paper as [8]
Human brain pericytes, but not smooth muscle cells, shed sPDGFRβ in culture, and shedding increases with hypoxia or injurious stimuli.
“Human brain pericytes, but not SMCs, shed sPDGFRβ in the culture media, which is increased by hypoxia or injurious stimuli8,18.”
From Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction (2019) · cites this paper as [8]
The imaging protocol was designed to identify subtle blood-brain barrier changes in cognitively impaired patients.
“The imaging protocol performed was developed to detect subtle BBB changes in patients with cognitive impairment and is detailed in Montagne et al. 20158.”
From Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction (2019) · cites this paper as Montagne et al. 2015
Patlak linearized regression produced Ktrans maps with high spatial and temporal resolution, enabling simultaneous regional permeability measurements in white and gray matter and accurate values in small structures like hippocampal subdivisions.
“The Patlak linearized regression mathematical analysis was used to generate the BBB permeability Ktrans maps8,49,50 with high spatial and temporal resolutions allowing not only simultaneous measurements of the regional BBB permeability in different white (WM) and gray matter (GM) regions, but also accurate calculations of the Ktrans values in anatomical regions as small as the subdivisions of the”
From Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction (2019) · cites this paper as [8]
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- Authors
- Montagne, A., Barnes, S. R., Sweeney, M. D., Halliday, M. R., Sagare, A. P., Zhao, Z., Toga, A. W., Jacobs, R. E., Liu, C. Y., Amezcua, L., Harrington, M. G., Chui, H. C., Law, M., & Zlokovic, B. V.
- Affiliations
- University of Southern California (US)
- California Institute of Technology (US)
- Huntington Medical Research Institutes (US)
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 85
- Issue
- 2
- Pages
- 296-302
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4350773
- OpenAlex
- W2034275438
- Cited by
- 2,102
- References
- 50
- Citations by year
- 2026: 214 · 2025: 211 · 2024: 208 · 2023: 213 · 2022: 228 · 2021: 227 · 2020: 204 · 2019: 168 · 2018: 133 · 2017: 122 · 2016: 104 · 2015: 68
- FWCI
- 76.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000130)
- National Institute on Aging (R01AG039452, R37AG023084, P50-AG05142, P50AG005142, R37AG23084, RF1AG039452)
- National Institute of Neurological Disorders and Stroke (R37NS034467, R01NS034467, R37NS34467)
- National Institute of Biomedical Imaging and Bioengineering (EB000993, R21EB013456, R01EB000993, P41EB015922)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- blood-brain barrier disruption, hippocampus, brain aging, Alzheimer's disease, mild cognitive impairment, blood-brain barrier permeability, pericytes, CA1, dentate gyrus, dynamic contrast-enhanced MRI, cerebrospinal fluid biomarkers, cognitive impairment
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, Albumins, Blood-Brain Barrier, Brain, Caudate Nucleus, Cerebral Cortex, Female, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Permeability, Serum Albumin, Thalamus, Case-Control Studies, Neostriatum, Dentate Gyrus, Pericytes, Young Adult, CA1 Region, Hippocampal, CA3 Region, Hippocampal, Cognitive Dysfunction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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