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. Amyloid-β deposition underlies the pathogenesis of cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD), but the disease pathways differ. Here, Greenberg et al. consider the interactions between CAA and AD, the factors that determine which disease pathway transpires, and the implications for therapeutic development. Amyloid-β (Aβ) in the brain interstitial fluid can be cleared via perivascular drainage pathways or deposited as neuritic plaques in the brain parenchyma or as cerebral amyloid angiopathy (CAA) along vessel walls. Vascular dysfunction caused by CAA reduces perivascular Aβ clearance in animal models, creating a vicious cycle of vascular and parenchymal Aβ accumulation. Factors that favour vascular Aβ deposition over parenchymal deposition include termination of Aβ at or before position 41, missense mutations within the Aβ coding region, and some co-deposited proteins, such as fibrinogen. Amyloid-related imaging abnormalities observed in trials of anti-Aβ immunotherapy might result from mobilization of plaque Aβ into the perivascular drainage system or from antibody targeting of vascular Aβ deposits. Development of methods for imaging perivascular drainage in humans would be a key step towards identifying treatments for enhancing Aβ clearance and reducing vascular and parenchymal deposition.