First, familial, genetically determined forms of the disease are driven by increased levels of total Aβ, or an increase of the more aggregation-prone Aβ42 peptide relative to Aβ40.5 Second, Down syndrome leads to severe Alzheimer-pathology by middle age in subjects carrying an added copy of chromosome 21 containing the amyloid precursor protein (APP)-gene,6 owing to overexpression of APP and a consequent overproduction of Aβ. This evidence concerns the gene APP and Down syndrome.