application) Cerebral amyloid angiopathy (CAA) is a major cause of primary intracerebral hemorrhage in the elderly and a disease of growing importance in the aging population. CAA also represents an intriguing model system for exploring the pathogenesis of Alzheimer's disease (AD). The research proposal at the core of this training program is a multidisciplinary epidemiologic study aimed at understanding the molecular pathogenesis of CAA. Several potential molecular risk factors, including the apolipoprotein E e4 allele, cerebrospinal fluid B-amyloid peptide, and serum cholesterol, will be assessed for their effects on the presence and progression of CAA. A major goal of this research program is to lay the groundwork for future interventional drug trials in CAA. Towards this end, the technique of gradient-echo MRI will be evaluated as a possible clinical marker for extent of disease. In addition, a preliminary pharmacologic study will be performed to determine whether activation of a specific signaling pathway might decrease production of B-amyloid peptide in patients with CAA. These research projects will be performed in collaboration with and under the supervision of Drs. John Growdon and Bradley Hyman, two distinguished investigators who have applied similar batteries of approaches to the understanding of AD. The quality of training will be further enhanced by the candidate's use of the diversity of clinical and scientific expertise available in the Harvard Medical School community. The proposed training program will include advanced epidemiologic and statistical coursework at the Harvard School of Public Health. Building on the candidate's strong background in molecular research and substantial early progress in clinical studies, the proposed training will assure the candidate's development into a fully independent clinical investigator.
