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Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways
Open accessAbstract
The shared role of amyloid-β (Aβ) deposition in cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD) is arguably the clearest instance of crosstalk between neurodegenerative and cerebrovascular processes. The pathogenic pathways of CAA and AD intersect at the levels of Aβ generation, its circulation within the interstitial fluid and perivascular drainage pathways and its brain clearance, but diverge in their mechanisms of brain injury and disease presentation. Here, we review the evidence for and the pathogenic implications of interactions between CAA and AD. Both pathologies seem to be driven by impaired Aβ clearance, creating conditions for a self-reinforcing cycle of increased vascular Aβ, reduced perivascular clearance and further CAA and AD progression. Despite the close relationship between vascular and plaque Aβ deposition, several factors favour one or the other, such as the carboxy-terminal site of the peptide and specific co-deposited proteins. Amyloid-related imaging abnormalities that have been seen in trials of anti-Aβ immunotherapy are another probable intersection between CAA and AD, representing overload of perivascular clearance pathways and the effects of removing Aβ from CAA-positive vessels. The intersections between CAA and AD point to a crucial role for improving vascular function in the treatment of both diseases and indicate the next steps necessary for identifying therapies.
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“Additionally, brains from COVID patients also show ischemic and hemorrhagic lesions, as well as microglial activation [79], which can be seen in many AD patients with cerebral amyloid angiopathy [80].”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [80]
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“Recently, vascular deposits of Aβ peptides (amyloid angiopathy) are increasingly recognized as a common pathology in AD cases, supporting that Aβ peptides circulate within the interstitial fluid, including CSF, and blood vessels through perivascular (e.g. lymphatic) drainage pathways during the crosstalk between the brain and the vascular system [77].”
From Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer’s disease (2020) · cites this paper as [77]
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“Recently, vascular deposits of Aβ peptides (amyloid angiopathy) are increasingly recognized as a common pathology in AD cases, supporting that Aβ peptides circulate within the interstitial fluid, including CSF, and blood vessels through perivascular (e.g. lymphatic) drainage pathways during the crosstalk between the brain and the vascular system [77].”
From Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer’s disease (2020) · cites this paper as [77]
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“Inflammation does, however, not seem to be a major component in CAA-related microhemorrhage or microinfarction [38], with the exception of a rare clinical subtype: CAA-related inflammation [6].”
From Cerebrospinal fluid levels of the neurotrophic factor neuroleukin are increased in early Alzheimer’s disease, but not in cerebral amyloid angiopathy (2021) · cites this paper as [6]
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“AQP4 levels are reduced in CAA; since AQP4 plays a vital role in glymphatic Aβ clearance in AD brain parenchyma, this consequently impairs Aβ clearance [606, 608].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [608]
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“AQP4 levels are reduced in CAA; since AQP4 plays a vital role in glymphatic Aβ clearance in AD brain parenchyma, this consequently impairs Aβ clearance [606, 608].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [608]
In the citing paper
“Chronic inflammation‐induced disruption of the BBB is an early biomarker of human cognitive dysfunction and often leads to dementia, 113 and both Aβ deposits and tau pathology aggravate vascular damage. 114 , 115”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [115]
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“There is overwhelming evidence for cerebrovascular alterations in AD pathology and amyloid-β deposition around leptomeningeal vessels is a hall mark of cerebral amyloid angiopathy, occurring in almost all AD patients”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Greenberg et al., 2020
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Metadata
- Authors
- Greenberg, S. M., Bacskai, B. J., Hernandez-Guillamon, M., Pruzin, J., Sperling, R., & van Veluw, S. J.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Greenberg, Steven M.
- Venue
- Nature Reviews Neurology
- Published
- 2019-12-11
- Volume
- 16
- Issue
- 1
- Pages
- 30-42
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- PMC
- PMC7268202
- OpenAlex
- W2995183059
- Cited by
- 947
- References
- 232
- Citations by year
- 2026: 146 · 2025: 198 · 2024: 179 · 2023: 154 · 2022: 113 · 2021: 104 · 2020: 52
- FWCI
- 7.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG026484)
- National Institute of Neurological Disorders and Stroke (RF1NS110054, R01NS096730, U24NS100591)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Keywords
- cerebral amyloid angiopathy, Alzheimer's disease, amyloid-beta, amyloid-beta clearance, amyloid-related imaging abnormalities, anti-amyloid immunotherapy, vascular function
- MeSH terms
- Alzheimer Disease, Brain, Humans, Signal Transduction, Amyloid beta-Peptides, Cerebral Amyloid Angiopathy, Plaque, Amyloid
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