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Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders
Open accessAbstract
The blood–brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration. This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy. The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described. The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed. Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting the BBB are presented.
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“Simultaneously, widespread leakage and deposition of blood-derived proteins such as fibrinogen, thrombin, and albumin are observed [49, 55].”
From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [55]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“As AD progresses to its late stages, the effectiveness of nanoparticle-based therapies often diminishes due to the increased disruption of the BBB [148].”
From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [162]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Conversely, stimulating intracellular degradation without restoring BBB efflux may be insufficient to reduce vascular and parenchymal A β accumulation [ 58 ].”
From Restores Aβ Clearance by Overcoming PCSK9–LRP1 Dysregulation and TRIB3‐Mediated Autophagy Blockade in Alzheimer's Disease (2026) · cites this paper as [58]
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In the citing paper
“However, the TJ proteins are reported to be affected under multiple pathological conditions or by approaches causing transient disruption, compromising the integrity of BBB and increasing influx of substances via the paracellular pathway [121, 122].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [122]
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In the citing paper
“Astrocytic processes surround most of the vascular surface, regulating the blood–brain barrier (BBB) permeability [6, 7, 8, 9]—by modulating tight junction proteins such as claudin‐5 [10], or endothelial proteins such vimentin, which is associated with the stability of cerebral vasculature [11]—and integrate neuronal activity with blood flow [1, 2, 3, 4, 5, 12, 13, 14, 15, 16, 17, 18, 19, 20].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: APOE3 Christchurch homozygote glioprotection (2023) · cites this paper as [9]
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“Together with microglia, astrocytes constitute the principal defensive system of the CNS [37], responding to numerous damage‐related stimuli [6, 7, 8, 9] including amyloid β peptides (Aβ) and glutamate overload, in a process known as astrocyte reactivity [15, 37, 38, 39, 40].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: APOE3 Christchurch homozygote glioprotection (2023) · cites this paper as [9]
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In the citing paper
“Hence, astrocyte reactivity has frequently been associated with neuroinflammation, unfavorable glial scar formation [7, 8, 9, 37, 38, 43, 48, 49], glutamate dyshomeostasis [43, 50, 51], altered coverage of synapses and blood vessels, and BBB breakout [38, 42, 43, 45, 46, 47].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: APOE3 Christchurch homozygote glioprotection (2023) · cites this paper as [9]
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“Furthermore, a breakdown of the blood brain barrier has been shown in neurodegenerative diseases [81, 82].”
The cited source says what the claim attributes to it.
In the citing paper
“With advancing neurodegenerative disease, BBB integrity becomes compromised [63].”
From Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease (2025) · cites this paper as [63]
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In the citing paper
“Loss of claudins is associated with BBB breakdown in human neurodegenerative disorders (155, 569) and acute CNS diseases (692), as well as in animal models of these diseases (420), as discussed below.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [569]
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In the citing paper
“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 [569]
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In the citing paper
“As previously reviewed, FDG-PET reflects mainly the transport activity of GLUT1 BBB transporter (420, 569).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [569]
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In the citing paper
“These focal vascular changes limit CNS distribution of neurotherapeutics in disease-affected regions by disrupting diffusional transport across brain ECS and/or by blocking normal ISF flow dynamics (519, 569).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [569]
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In the citing paper
“Besides FDG-PET and verapamil-PET that have been used to test functions of BBB GLUT1 transporter and activity of ABCB1 (P-gp) efflux transporter in AD and PD (420, 569), respectively”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [569]
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In the citing paper
“to be effective, drug administration to the brain requires a functionally and structurally healthy BBB since its pathological breakdown, which precedes and sustains neurodegeneration, implies perturbations in the endothelial bulk flow transcytosis and in the expression of transporter systems. Consequently, blood-borne medications, including antibodies, proteins, peptides, and small molecules, bec”
From The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer’s Disease: A Possible Target for the Disease Treatment (2024) · cites this paper as [30]
The cited source says what the claim attributes to it.
In the citing paper
“Blood–brain barrier breakdown has been demonstrated to occur in AD in the general population [63], but whether the blood–brain barrier is disrupted in DS or DSAD is currently unknown.”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [63]
The cited source says what the claim attributes to it.
In the citing paper
“Malfunction of the BBB in neurodegenerative diseases contributes to neuronal damage, synaptic dysfunction and loss of neuronal connectivity [48].”
From Differential RNA packaging into small extracellular vesicles by neurons and astrocytes (2021) · cites this paper as [48]
In the citing paper
“BBB disruption is well characterized in other neurodegenerative diseases, including PD, ALS, FTD, and HD.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [660]
In the citing paper
“Decreased cerebral blood flow, coupled with increased Aβ levels induced by BBB deterioration can also aggravate tau pathology [628, 629].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [629]
In the citing paper
“Both patients with AD and AD animal models exhibit neurovascular system impairment including abnormalities in the number, diameter, and density of blood vessels, which lead to decreased brain perfusion and blood–brain barrier disruption (10, 39, 40).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [39]
In the citing paper
“It has been identified that the expressions of the two blood efflux transporters LRP1 and ABCB1 were reduced during AD, whereas the expression of the blood influx transporter RAGE is elevated.21,25”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [21]
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Defining blood-induced microglia functions in neurodegeneration through multiomic profiling
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Blood brain barrier and inflammation in depression
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Background
Metadata
- Authors
- Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V.
- Affiliations
- University of Southern California (US)
- Venue
- Nature Reviews Neurology
- Published
- 2018-01-29
- Volume
- 14
- Issue
- 3
- Pages
- 133-150
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- PMC
- PMC5829048
- OpenAlex
- W2786608785
- Semantic Scholar
- 4d92c092b2819e1ed90219e4dbb45c7fe3d87806
- Cited by
- 3,076
- References
- 257
- Citations by year
- 2026: 419 · 2025: 455 · 2024: 467 · 2023: 402 · 2022: 378 · 2021: 377 · 2020: 313 · 2019: 183 · 2018: 78
- FWCI
- 22.61
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG023084, R01AG039452, F31AG044997, P50AG005142, RF1AG039452, P01AG052350)
- National Institute of Neurological Disorders and Stroke (R01NS100459, R01NS090904, R01NS034467)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Keywords
- blood-brain barrier disruption, neurodegeneration, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-associated dementia, chronic traumatic encephalopathy, neuroinflammation, synaptic dysfunction, postmortem brain
- MeSH terms
- Blood-Brain Barrier, Humans, Neurodegenerative Diseases
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