Blood-brain barrier dysfunction and Alzheimer’s disease: associations, pathogenic mechanisms, and therapeutic potential
Open accessAbstract
Alzheimer’s disease (AD) is a common neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ), hyperphosphorylation of tau, and neuroinflammation in the brain. The blood–brain barrier (BBB) limits solutes from circulating blood from entering the brain, which is essential for neuronal functioning. Focusing on BBB function is important for the early detection of AD and in-depth study of AD pathogenic mechanisms. However, the mechanism of BBB alteration in AD is still unclear, which hinders further research on therapeutics that target the BBB to delay the progression of AD. The exact timing of the vascular abnormalities in AD and the complex cause-and-effect relationships remain uncertain. Thus, it is necessary to summarize and emphasize this process. First, in this review, the current evidence for BBB dysfunction in AD is summarized. Then, the interrelationships and pathogenic mechanisms between BBB dysfunction and the risk factors for AD, such as Aβ, tau, neuroinflammation, apolipoprotein E (ApoE) genotype and aging, were analyzed. Finally, we discuss the current status and future directions of therapeutic AD strategies targeting the BBB. We hope that these summaries or reviews will allow readers to better understand the relationship between the BBB and AD.
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Alzheimer's disease-related blood-brain barrier alterations initiate a vicious cycle: blood-brain barrier breakdown disrupts brain activity, triggering progressive synaptic and neuronal dysfunction, which further compromises the barrier.
“These mechanisms are often perceived as a “vicious cycle”: these alterations initiate BBB breakdown that disrupts the brain’s normal activity, triggering progressive synaptic and neuronal dysfunction, which in turn further compromises the barrier [40].”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [40]
In “BBB dysfunction correlates with AD pathology” (page unavailable), the paper describes feedback loops in which BBB damage contributes to neurodegeneration while Aβ pathology or inflammation further damages the barrier. It does not establish the claimed sequence in which progressive synaptic and neuronal dysfunction itself further compromises the BBB; the passages identify Aβ deposits and inflammatory processes as the drivers of further barrier damage. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn early Alzheimer's disease, pericyte damage may precede Aβ deposition.
“Characteristic pathological features observed in the early phase of AD include, among others, pericyte damage—which may even precede Aβ deposition [47].”
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 [47]
The 'Evidence of BBB dysfunction in animal research' section reports reduced pericyte numbers in an AD mouse model. The 'Aging: a primary risk factor for BBB' section says BBB permeability changes precede cerebrospinal-fluid Aβ abnormalities, but it does not establish that pericyte damage precedes Aβ deposition. Page numbers are unavailable in our copy. (LLM, conf=0.79)
Experimental — accuracy not yet measuredBlood-brain barrier dysfunction impedes the clearance of oligomeric tau proteins and promotes tau diffusion.
“The barrier’s dysfunction impedes the clearance of oligomeric tau proteins and promotes tau diffusion.”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [40]
Neurofibrillary tangles exacerbate blood-brain barrier damage.
“NFTs exacerbate BBB damage.”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [40]
Blood-brain barrier breakdown is categorized by a cascade of structural and functional alterations impairing its function in preventing the entry of foreign substances into the central nervous system, compromising neuron integrity and triggering neurodegeneration.
“BBB breakdown is categorized by a cascade of structural and functional alterations impairing its function in preventing the entry of foreign substances into the CNS, therefore compromising neurons’ integrity and triggering neurodegeneration [40].”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [40]
Dysregulation of receptors responsible for beta-amyloid homeostasis leads to beta-amyloid aggregation in vessel walls (amyloid angiopathy), impairing blood-brain barrier function and worsening vascular pathology.
“The dysregulation of receptors responsible for Aβ homeostasis leads to Aβ aggregation in the vessel walls (amyloid angiopathy), impairing the BBB function and worsening vascular pathology.”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [40]
In response to inflammation, central nervous system glial cells produce proinflammatory cytokines that compromise the barrier's integrity, preventing its repair and exacerbating inflammation.
“Additionally, as a response to inflammation, CNS glial cells produce proinflammatory cytokines that compromise the barrier’s integrity, preventing its repair and, consequently, exacerbating inflammation.”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [40]
Evidence from postmortem brain tissue analysis, neuroimaging technology, cerebrospinal fluid content, and animal research strongly supports a connection between blood-brain barrier dysfunction and Alzheimer's disease.
“The evidence found by postmortem brain tissue analysis, neuroimaging technology, CSF content, and animal research strongly supports a connection between BBB dysfunction and AD [40].”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [40]
Cognitive dysfunction in Alzheimer's disease predates the mild cognitive impairment phase by several years.
“This cognitive dysfunction was even discovered to predate by several years the mild cognitive impairment (MCI) phase, where the first symptoms start to arise.”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [40]
The Introduction says that blood–brain barrier disruption, not cognitive dysfunction, precedes symptoms of cognitive impairment by several years. The aging-BBB section describes greater barrier disruption during MCI, but does not establish that cognitive dysfunction predates MCI. Searches for cognitive dysfunction preceding MCI and for the timing of first symptoms found no passage supporting that timeline. (LLM, conf=0.74)
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“These mechanisms are often perceived as a “vicious cycle”: these alterations initiate BBB breakdown that disrupts the brain’s normal activity, triggering progressive synaptic and neuronal dysfunction, which in turn further compromises the barrier [40].”
InfluentialPrimary Cilia and Cardiovascular Risk Factors in Alzheimer's Disease
Sunderman, C. L., Forero, K. V., Alorjani, Q., Buqaileh, R., Gallagher, G. M., Ventresca, S. M., Messer, W. S., & AbouAlaiwi, W. A. (2025) · Brain Sciences · doi:10.3390/brainsci15091004 · Cited by 1 · see citing works
“Pericytes make up part of the basement membrane and regulate vascular permeability [103].”
- Authors
- Chen, Y., He, Y., Han, J., Wei, W., & Chen, F.
- Affiliations
- Shenzhen Sixth People's Hospital (CN)
- Guangdong Medical College (CN)
- Corresponding author
- Wei, Wenyan
- Chen, Feng
- Venue
- Frontiers in Aging Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2023-11-13
- Volume
- 15
- Pages
- 1258640-1258640
- ISSN
- 1663-4365 (ISSN-L)
- PMC
- PMC10679748
- OpenAlex
- W4388646390
- Cited by
- 116
- References
- 24
- Citations by year
- 2026: 49 · 2025: 51 · 2024: 16
- FWCI
- 3.02
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Aging Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (82301611)
- China Postdoctoral Science Foundation (2022M710848)
- Natural Science Foundation of Guangdong Province
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- Alzheimer's disease, blood-brain barrier dysfunction, amyloid-beta, tau hyperphosphorylation, neuroinflammation, APOE genotype, aging, vascular anomalies, AD pathogenesis
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