The amyloid hypothesis is initially compelling because the gene for the amyloid beta precursor APP is located on chromosome 21, and patients with trisomy 21 - better known as Down syndrome - who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age.[24][25] The traditional formulation of the amyloid hypothesis points to the cytotoxicity of mature aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis and thus inducing apoptosis.[26] This hypothesis is supported by the observation that higher levels of a variant of the beta amyloid protein known to form fibrils faster in vitro correlate with earlier onset and greater cognitive impairment in mouse models[27] and with AD diagnosis in humans.[28] However, mechanisms for the induced calcium influx, or proposals for alternative cytotoxic mechanisms, by mature fibrils are not obvious.