Cerebral amyloid angiopathy: one single entity?

Cerebral amyloid angiopathy (CAA) is a common brain disorder among the elderly and individuals with Alzheimer's disease, where accumulation of amyloid-ß can lead to intracerebral hemorrhage and dementia. This review discusses recent developments in understanding the pathophysiology and phenotypes of CAA.

CAA has a long preclinical phase starting decades before symptoms emerge. Its pathophysiology follows consecutive stages of amyloid-ß deposition, decreased vascular reactivity, nonhemorrhagic changes, and ultimately hemorrhages. Although impaired perivascular clearance is the leading hypothesis underlying CAA, several lines of evidence suggest that glymphatic dysfunction also plays a significant role in the disease process. Despite its common pathway, the disease course is variable. Some patients develop more microbleeds, while others develop larger hemorrhages, suggesting a differentiation in vascular remodeling. Some patients with CAA develop a symptomatic immune response, and inflammation could be an important contributor to vascular damage in CAA in general. Furthermore, the prion-like transmission of amyloid-β has been identified as a cause of iatrogenic CAA occurring decades after neurosurgical procedures involving cadaveric dura mater.

Emerging evidence of sporadic, hereditary, inflammatory, and iatrogenic CAA suggests a complex interplay between brain clearance, inflammation and vascular remodeling leading to a diverse clinical phenotype.