Blood-brain barrier leakage in Alzheimer’s disease: From discovery to clinical relevance
Open accessAbstract
Alzheimer's disease (AD) is the most common form of dementia. AD brain pathology starts decades before the onset of clinical symptoms. One early pathological hallmark is blood-brain barrier dysfunction characterized by barrier leakage and associated with cognitive decline. In this review, we summarize the existing literature on the extent and clinical relevance of barrier leakage in AD. First, we focus on AD animal models and their susceptibility to barrier leakage based on age and genetic background. Second, we re-examine barrier dysfunction in clinical and postmortem studies, summarize changes that lead to barrier leakage in patients and highlight the clinical relevance of barrier leakage in AD. Third, we summarize signaling mechanisms that link barrier leakage to neurodegeneration and cognitive decline in AD. Finally, we discuss clinical relevance and potential therapeutic strategies and provide future perspectives on investigating barrier leakage in AD. Identifying mechanistic steps underlying barrier leakage has the potential to unravel new targets that can be used to develop novel therapeutic strategies to repair barrier leakage and slow cognitive decline in AD and AD-related dementias.
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In AD, dysregulation of tight junction proteins, increased matrix metalloproteinase signaling, and degeneration and loss of pericytes may contribute to BBB leakage, leading to accumulation of blood-derived neurotoxic proteins in the brain, causing neuroinflammation and oxidative stress.
“Some evidence suggests that in AD, dysregulation of tight junction proteins, increased matrix metalloproteinase signaling, and degeneration and loss of pericytes may all contribute to BBB leakage, leading to the accumulation of numerous blood-derived neurotoxic proteins in the brain, causing neuroinflammation and oxidative stress.356,360–362”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [356]
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Experimental — accuracy not yet measuredThe differences observed in this study are likely to reflect changes specific to CAA, rather than general features of cognitive impairment.
“In previous research, Alzheimer disease and cerebral small vessel disease have also been related to BBB leakage,12,33 which means that the differences observed in this study are likely to reflect changes specific to CAA, rather than the general features of cognitive impairment.”
From In Vivo Imaging of Blood-Brain Barrier Leakage Using a Contrast Agent in Patients With Cerebral Amyloid Angiopathy: An Exploratory Study (2025) · cites this paper as [33]
In advanced Alzheimer's disease, transporter impairment worsens, notably with decreased P-glycoprotein activity.
“Furthermore, transporter impairment worsens, notably with decreased P-glycoprotein activity [49, 54].”
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 [54]
The supplied passages and searches of the paper’s full text for P-glycoprotein, P-gp, ABCB1, and worsening transporter function did not yield a passage reporting decreased P-glycoprotein activity as Alzheimer’s disease advances. The Introduction discusses worsening cognitive symptoms, but does not connect disease stage to transporter activity. No page number was available for these passages. (LLM, conf=0.73)
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References 614 · Cited by 127
Research works printed but not linked: 7
- Alzheimer’s Disease Fact Sheet. In. (Vol. 2021): National Institute of Aging.
- Dementia Fact Sheet. In. (Vol. 2021): World Health Organization.
- Effects of Alzheimer’s disease drugs. In. (Vol. 2021). Alzheimer’s Society.
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- Authors
- Nehra, G., Bauer, B., & Hartz, A. M. S.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Hartz, Anika M.S.
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 2022-06
- Volume
- 234
- Pages
- 108119
- ISSN
- 0163-7258 (ISSN-L)
- PMC
- PMC9107516
- OpenAlex
- W4210271919
- Cited by
- 127
- References
- 614
- Citations by year
- 2026: 31 · 2025: 36 · 2024: 19 · 2023: 34 · 2022: 6 · 2021: 1
- FWCI
- 2.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Pharmacology & Therapeutics (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (2R01AG039621)
- National Institute on Aging
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, blood-brain barrier disruption, blood-brain barrier dysfunction, animal models of Alzheimer's disease, postmortem neuropathology, cognitive decline, neurodegeneration, signaling mechanisms, treatment options
- MeSH terms
- Alzheimer Disease, Animals, Biological Transport, Blood-Brain Barrier, Disease Models, Animal, Humans, Cognitive Dysfunction
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