Patients carrying the apolipoprotein E (APOE) epsilon 2 (e2) or epsilon 4 (e4) alleles appear to be at greater risk for CAA-related hemorrhage than those with only the common APOE epsilon 3 (e3) allele. Vascular rupture and bleeding in CAA appears to be a multistep process involving the deposition of amyloid beta-peptide in the vascular wall and subsequent vascular changes such as cracking of the vascular wall. It has been suggested that the e2 and e4 alleles act via separate mechanisms: e4 increased amyloid beta-peptide deposition and e2 causes amyloid-laden vessels to undergo changes such as cracking and necrosis that predispose to rupture.
Mutations in the gene that encodes the amyloid precursor protein (APP) are responsible for some cases of "presenile" CAA.
An interaction between amyloid beta-peptide and tissue-type plasminogen activator also may contribute to the tendency to hemorrhage in CAA. In vitro studies have shown that amyloid beta-peptide analogues markedly stimulate plasminogen activation by tissue-type plasminogen activator. The stimulatory activity is greatest when the analogues form aggregated fibrillar structures similar to those seen in amyloid deposits.
In transgenic mice overexpressing the inflammatory cytokine transforming growth factor (TGF) beta-1 show increased amyloid beta-peptide deposition in cerebral blood vessels. This finding may be applicable to humans as postmortem studies have found that TGF beta-1 mRNA levels correlate strongly with amyloid beta-peptide deposition in damaged blood vessels in patients with CAA.
