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

The shared role of amyloid-ß (Aß) 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 Aß 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 Aß clearance, creating conditions for a self-reinforcing cycle of increased vascular Aß, reduced perivascular clearance and further CAA and AD progression. Despite the close relationship between vascular and plaque Aß 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-Aß immunotherapy are another probable intersection between CAA and AD, representing overload of perivascular clearance pathways and the effects of removing Aß 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.