The APOE ε4/ε4 Genotype Potentiates Vascular Fibrin(Ogen) Deposition in Amyloid-Laden Vessels in the Brains of Alzheimer's Disease Patients
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Evidence indicates a critical role for cerebrovascular dysfunction in Alzheimer's disease (AD) pathophysiology. We have shown that fibrin(ogen), the principal blood-clotting protein, is deposited in the AD neurovasculature and interacts with beta-amyloid (Ab), resulting in increased formation of blood clots. As apolipoprotein E (ApoE), a lipid-transporting protein with three human isoforms (E2, E3, and E4), also binds to Aβ, we hypothesized that ApoE and fibrin(ogen) may have a combined effect on the vascular pathophysiology in AD. We assessed whether APOE genotype differentially influences vascular fibrin(ogen) deposition in postmortem brain tissue using immunohistochemistry. An increased deposition of fibrin(ogen) was observed in AD cases compared with non-demented controls, and there was a strong correlation between cerebral amyloid angiopathy (CAA) severity and fibrin(ogen) deposition. Moreover, brains from AD cases homozygous for APOE ε4 showed increased deposition of fibrin(ogen), specifically in CAA- and oligomeric Aβ-positive vessels compared with AD APOE ε2 and ε3 allele carriers, an effect that was not directly linked to CAA severity and cerebrovascular atherosclerosis. These data further support a role for fibrin(ogen) in AD pathophysiology and link the APOE ε4/ε4 genotype with increased thrombosis and/or impaired fibrinolysis in the human AD brain.
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Human APOE4 carriers compared with non-carriers develop accelerated BBB breakdown and pericyte degeneration, early neurovascular dysfunction, impaired cerebrovascular reactivity, and diminished regional BBB uptake of glucose.
“Human APOE4 carriers compared with non-carriers develop accelerated BBB breakdown and pericyte degeneration (229, 230, 267, 516, 691, 702), early neurovascular dysfunction (494, 531, 584), impaired cerebrovascular reactivity (227, 568), and diminished regional BBB uptake of glucose (457, 486).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [267]
These blood-derived proteins are often found colocalized with Aβ and are more pronounced in APOE4 carriers compared with noncarriers.
“These blood-derived proteins are often found colocalized with A 𝛃 (267, 509, 527) and are more pronounced in APOE4 carriers compared with noncarriers (230, 267, 516, 691).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [267]
APOE4 carriers at risk for sporadic AD compared with non-carriers develop BBB breakdown and early cerebrovascular dysfunction.
“For example, APOE4 carriers at risk for sporadic AD compared with non-carriers develop BBB breakdown (229, 230, 267, 516, 691, 702) and early cerebrovascular dysfunction (227, 457, 486, 494, 531, 568, 584)”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [267]
Activation of the CypA-MMP-9 pathway associated with blood-brain barrier breakdown has been shown in human APOE4 carriers by cerebrospinal fluid analysis and post mortem brain tissue analysis.
“Activation of CypA-MMP-9 pathway associated with BBB breakdown has been also shown in human APOE4 carriers by cerebrospinal fluid (CSF) analysis (229) and post mortem brain tissue analysis (230, 267).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [267]
Post mortem studies show vascular capillary leakages of blood-derived proteins in the prefrontal and entorhinal cortex and hippocampus of AD patients including perivascular accumulation of fibrin(ogen), thrombin, albumin, immunoglobulin G, and iron-containing proteins such as hemosiderin.
“Post mortem studies show vascular capillary leakages of blood-derived proteins in the prefrontal and entorhinal cortex and hippocampus of AD patients including perivascular accumulation of fibrin(ogen), thrombin, albumin, immunoglobulin G (IgG), and iron-containing proteins such as hemosiderin (120, 125, 230, 267, 412, 509, 527, 691).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [267]
RBC extravasation and brain infiltration by peripheral macrophages and neutrophils are reported in Alzheimer's disease post mortem studies.
“RBC extravasation (125) and brain infiltration by peripheral macrophages (175, 267) and neutrophils (676) are reported in AD post mortem studies”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [267]
CD68 was higher in Alzheimer's disease than control in the frontal cortex in three studies, though for white matter only in one of the studies.
“CD68 was higher in AD than control in the frontal cortex in three studies,18, 41, 82 though for white matter only in one of the studies.41”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [82]
Microglial activation appears to be affected by APOE genotype, with carriers of the ε4 risk allele exhibiting greater activation in some but not all studies.
“Microglial activation appears to be affected by APOE genotype, with carriers of the ε4 risk allele exhibiting greater activation in some48, 56 but not all studies.82”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [82]
Fibrin is present at increased levels in APOE4 AD patients, correlates with the severity of cerebral amyloid angiopathy, and is detected in amyloid-related imaging abnormalities.
“Fibrin is present at increased levels in APOE4 AD patients, correlates with the severity of cerebral amyloid angiopathy, and is detected in amyloid-related imaging abnormalities.32,43,44”
From Machine learning reveals prominent spontaneous behavioral changes and treatment efficacy in humanized and transgenic Alzheimer's disease models (2024) · cites this paper as [44]
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- Authors
- Hultman, K., Strickland, S., & Norris, E. H.
- Affiliations
- Rockefeller University (US)
- Corresponding author
- Norris, Erin H
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2013-05-08
- Volume
- 33
- Issue
- 8
- Pages
- 1251-1258
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC3734776
- OpenAlex
- W2109884554
- Cited by
- 183
- References
- 7
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 23 · 2023: 21 · 2022: 12 · 2021: 20 · 2020: 17 · 2019: 13 · 2018: 12 · 2017: 11 · 2016: 14 · 2015: 11 · 2014: 3 · 2013: 2
- FWCI
- 6.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P30AG028377)
- National Institute of Neurological Disorders and Stroke (R01NS050537, NS50537)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
- Keywords
- Alzheimer's disease, fibrinogen deposition, cerebral amyloid angiopathy, amyloid-beta, cerebrovascular dysfunction, thrombosis, fibrinolysis, oligomeric amyloid, postmortem brain
- MeSH terms
- CD68 Molecule, Aged, Aged, 80 and over, Alzheimer Disease, Blood Vessels, Brain, Female, Fibrinogen, Genotype, Humans, Immunohistochemistry, Male, Middle Aged, Sex Characteristics, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Cerebral Amyloid Angiopathy, Disease Progression, Atherosclerosis, Apolipoprotein E4, Plaque, Amyloid
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