The molecular and genetic basis of AD: The end of the beginning

The Decade of the Brain—the 1990s—was a time of gains in our knowledge of the molecular and genetic basis of Alzheimer’s disease (AD).1-4 The momentum of discovery and depth of molecular information that developed during that time clearly leads one to predict that it is the end of the beginning of deciphering the pathogenesis of AD leading to effective therapy. Most cases of AD are sporadic; however, the molecular and genetic information of specific genes and other risk factors that cause the familial form of AD will shed light on the etiology of the much more abundant sporadic forms. About 10% of familial disease presents as an autosomal dominant mode of transmission. Epidemiologic studies indicate that about 30% of AD patients have a family history of disease in which at least one first-degree relative is affected. It is clear that early onset autosomal dominant AD is a heterogeneous set of disorders caused in separate families by different genetic mutations. Late-onset sporadic disease is the result of yet-to-be-discovered multiple environmental and genetic influences. In support of this view, only one-third of identical twins are concordant for AD, indicating that nongenetic—perhaps environmental—factors are important in the pathogenesis of AD. Mutations in the amyloid precursor protein gene ( APP ) on chromosome 21q, and the presenilin 1 and 2 genes ( PS1 , PS2 ) on chromosomes 14q and 1q, account for approximately one half of early-onset forms of autosomal dominant inherited disease. An additional locus on chromosome 12 has also been described. It is estimated that 50% of dominantly inherited disease remains yet to be mapped and genetically identified. Although the specific functions of the proteins coded by the APP and the PS1 and PS2 genes are only incompletely known, they share a common effect of abnormally processing APP, resulting in a 50% …