Cerebral amyloid angiopathy and Alzheimer disease - one peptide, two pathways

Abstract

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.

Figure 1 |

Co-existing amyloid-β in neuritic plaques and vessel walls. Anti-amyloid-β immunostaining (clone 6F/3D, Agilent, 1:200) of a postmortem section of the occipital lobe from a 67-year-old man (left) reveals co-existing neuritic plaques (right, top) and cerebral amyloid angiopathy (CAA; right, bottom) in leptomeningeal and cortical vessels.

Figure 2 |

Impairment of perivascular drainage in cerebral amyloid angiopathy and Alzheimer disease. Healthy perivascular amyloid-β (Aβ) clearance occurs along the walls of arteries and relies on intact vessels and normal vasoactivity (top). Interference of perivascular clearance by cerebral amyloid angiopathy (CAA) could establish a self-reinforcing cycle of Aβ deposition, loss of vascular smooth muscle cells and vasoactivity, and further reduction in clearance (bottom). This self-reinforcing mechanism would exacerbate both Alzheimer disease pathology by reducing Aβ clearance and CAA-related vascular lesions, such as haemorrhages, and tissue injury.

Figure 3 |

Mechanisms of amyloid-related imaging abnormalities. a | In the normal physiological state, amyloid-β (Aβ) is cleared from the brain in part via perivascular pathways. b | In Alzheimer disease, accumulation of Aβ in brain parenchyma and vessels results in disrupted vascular integrity and impaired clearance. c | Anti-Aβ immunotherapy mobilizes parenchymal Aβ, which moves into already impaired perivascular drainage pathways, and initiates an immune response to vessels. These effects worsen cerebral amyloid angiopathy and render vessels transiently leaky to proteinaceous fluid and blood products, leading to amyloid-related imaging abnormalities (ARIA; ARIA-E and ARIA-H, respectively). d | Limited evidence suggests that with repeated immunization and continued clearance of vascular Aβ, the structural integrity of vessels and the efficiency of perivascular clearance can improve and the risk of ARIA consequently decreases.