Two types of familial cerebral amyloid angiopathy or hereditary cerebral hemorrhage with amyloidosis (HCHWA) has been described: the Icelandic type (HCHWA-I), and the Dutch type (HCHWA-D). Both are autosomal-dominant forms of amyloidosis restricted to the small vasculature of the brain and clinically characterized by recurrent strokes leading to an early death. In spite of their clinico- pathological similarities, the amyloid fibrils are structurally different. In the case of HCHWA-I, the amyloid protein is a degradation product of a variant of Cystatin C, a normal serum protein and an inhibitor of cysteine proteases. Since it is not known whether the amyloid protein is the expression of a genetic aberration or due to polymorphism, we propose to isolate the normal and variant Cystatin C genes. Furthermore, attempts will be made to develop a restriction map analysis for early diagnosis. On the other hand the amyloid protein in HCHWA-D type has been shown very recently to be related to Alzheimer's disease beta-protein and preliminary observations indicate that similar amyloid subunits are present in sporadic cerebral amyloid angiopathy and asymptomatic elderly people. It is our hypothesis that some aberrant post- translational modification and/or genetic variants of amyloid precursor proteins can cause gross structural modifications. As a consequence they may be only partially degraded, resulting in abnormally cleaved peptides. These peptides may undergo self assembly and/or enzymatic cross-linking to form insoluble amyloid fibrils. The processing of the beta-protein precursor in different cell types may account for the heterogeneous pattern of clinical manifestations and amyloid deposition in this group of disorders that we designate "beta-protein deposition disease". We propose (a) the isolation and complete characterization of the amyloid protein obtained from HCHWA-D, sporadic cerebral amyloid angiopathy and asymptomatic elderly persons, (b) to study their relationship to Alzheimer's disease beta-protein and to their different clinico-pathological manifestations, (c) the isolation of beta-protein precursor(s) from several sources by using polyclonal antibodies to homologous synthetic peptides, and (d) to study processing by searching for specific brain enzymes responsible for the limited and selected degradation of the beta- protein precursor and fibril formation.