Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy

Objective-To clarify the phenotypic heterogeneity in deposition of amyloid beta (A beta) in the parenchyma and in cerebral vessels of the brains of th e patients having presenilin-1 (PSZ) mutations. Mutations in PSI induce inc reased production of A beta 42(43), resulting in an enhanced overall deposi tion of All protein within the cerebral cortex. Methods-Sequence analysis of the PS1 gene of DNA from patients with early o nset Alzheimer's disease, and immunostaining of brain tissues by end specif ic monoclonal antibodies against A beta. Results-Sequence analysis disclosed a novel mutation (N405S) in the PS1 gen e in a Japanese patient with early-onset Alzheimer's disease. Postmortem ex amination of one patient with N405S showed limited cerebral amyloid angiopa thy, whereas postmortem examination of another Japanese patient with Alzhei mer's disease with the E184D mutation disclosed severe cerebral amyloid ang iopathy. The brains of both patients showed widespread neuritic plaques, ne urofibrillary tangles, and neuronal loss. Immunostaining show-ed that A bet a 42 was predominant over A beta 40 in neuritic plaques in both patients, w hereas A beta 40 was found to be predominant over A beta 42 in cerebral amy loid angiopathy in the patient with E184D. However, most cortical vessels o f the patient with N405S were not reactive with either of the antibodies. Conclusion-The N405S mutation of PS1 is a major determinant of cortical A b eta deposition but not cerebral amyloid angiopathy in Alzheimer's disease.