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-bediscovered 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% increase in Aβ40 or Aβ42 peptides, which subsequently aggregate to form the neuritic plaque in the AD patient’s brain. 1-4 The increased Aβ synthesis and aggregation constitute a toxic gain-of-function (gain of aggregation) that is characteristic of autosomal dominant genetic disease. These points form the genetic basis for the amyloid hypothesis.

Amyloid hypothesis. The primary role of altered amyloidogenesis in the causation of AD has been supported convincingly by data of Selkoe, 5-13 Glenner and Wong, 14 Goldgaber et al., 15 Tanzi et al., 16 Masters et al., 17 Kowal et al., 18 and Geula et al., 19 among others. The amyloid hypothesis has achieved more than a critical mass of scientific data so it is now appropriately a central construct of AD pathogenesis. An increased synthesis of Aβ from APP in the early-onset forms of AD due to APP and PS1 and PS2 mutations is a central point in support of the amyloid hypothesis, which states that abnormal amyloidogenesis or amyloid clearance are primarily causal of the pathogenesis of AD. Other molecular pathologies are of secondary importance. A more cautious view would be to say that amyloid deposition is necessary but not sufficient to cause the dementia of AD. Other factors also play a role. Additional support for the amyloid hypothesis include: AD brains contain increased numbers of Aβ plaques over time; Aβ deposition precedes clinical symptoms of AD; sporadic AD patients have decreased clearance of Aβ through the CSF; sporadic patients have increased aggregation or decreased turnover of Aβ; other systemic amyloidoses are treated by decreasing the concentration of the amyloidogenic protein; Aβ is increased in plasma of persons older than 65 years who later develop AD compared to age-matched controls; Down syndrome …