Apolipoprotein E (apoE) and apoE-derived proteolytic fragments are present in amyloid deposits in Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA). In this study, we examined which apoE fragments are most strongly associated with amyloid deposits and whether apoE receptor binding domains were present. We found that both apoE2- and apoE4-specific residues were present on plaques and blood vessels in AD and CAA. We quantified Abeta plaque burden and apoE plaque burdens in 5 AD brains. ApoE N-terminal-specific and C-terminal-specific antibodies covered 50% and 74% of Abeta plaque burden, respectively (p < 0.003). Double-labeling demonstrated that the plaque cores contained the entire apoE protein, but that outer regions contained only a C-terminal fragment, suggesting a cleavage in the random coil region of apoE. Presence of N- and C-terminal apoE cleavage fragments in brain extracts was confirmed by immunoblotting. The numbers of plaques identified by the apoE N-terminal-specific antibodies and the apoE C-terminal-specific antibody were equal, but were only approximately 60% of the total Abeta plaque number (p < 0.0001). Analysis of the size distribution of Abeta and apoE deposits demonstrated that most of the Abeta-positive, apoE-negative deposits were the smallest deposits (less than 150 microm2). These data suggest that C-terminal residues of apoE bind to Abeta and that apoE may help aid in the progression of small Abeta deposits to larger deposits. Furthermore, the presence of the apoE receptor binding domain in the center of amyloid deposits could affect surrounding cells via chronic interactions with cell surface apoE receptors.