[Advances in the research on Alzheimer's disease--overview]

The number of patients suffering from dementia in Japan has been estimated to exceed 1,250,000 and is expected to increase rapidly in the near future. It is quickly becoming a serious medical and social issue. Alzheimer's disease (AD) is a leading cause of dementia, and can be classified into two genetic categories: single-gene and polygenic diseases. Familial Alzheimer's disease (FAD) is classified as a single-gene disease, while sporadic AD is classified as a polygenic disease which involves multiple genetic and environmental factors. Using positional cloning, most of the genes which lead to FAD have recently been identified e.g., the amyloid precursor protein (APP) gene on chromosome 21, presenilin I on chromosome 14 and presenilin II on chromosome 1. Recent studies indicate that mutations in these genes can result in either overproduction of A beta or in production of A beta 1-42. Although the accumulation of A beta has been suggested to be the "primary cause" not only in FAD but also in sporadic AD, it remains unclear how neurodegeneration in AD is related to the accumulation of A beta. The discovery of ApoE4 as a major genetic risk factor for AD has created a new step of research on AD as a polygenic disease. Although it is confirmed that the presence of the ApoE4 allele greatly accelerates age at onset of AD, the role of ApoE4 as a risk factor for AD remains to be fully elucidated. Now that major genes involved in the pathogenesis of AD have been identified, future research should be directed toward elucidation of the molecular mechanisms of how these gene products are involved in the pathogenesis of AD on protein as well as cellular levels.