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The amyloid hypothesis informs studies of AD. In\u00a0AD\u2010DS, but not sporadic AD, increased\u00a0<jats:italic>APP<\/jats:italic>\u00a0copy number is necessary, defining the\u00a0<jats:italic>APP<\/jats:italic>\u00a0gene dose hypothesis. Which\u00a0amyloid precursor protein (APP)\u00a0products contribute\u00a0needs to be determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Brain levels of full\u2010length protein (fl\u2010hAPP), C\u2010terminal fragments (hCTFs), and amyloid beta (A\u03b2) peptides were measured in DS, AD\u2010DS, non\u2010demented controls (ND), and sporadic AD cases. The\u00a0<jats:italic>APP<\/jats:italic>\u00a0gene\u2010dose hypothesis was evaluated in the Dp16 model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>DS and AD\u2010DS differed from ND and AD for all\u00a0APP\u00a0products. In AD\u2010DS,\u00a0A\u03b242 and A\u03b240 levels exceeded\u00a0AD.\u00a0APP\u00a0products were increased in the Dp16 model; increased\u00a0<jats:italic>APP<\/jats:italic>\u00a0gene dose was necessary for loss of vulnerable neurons, tau pathology, and activation of astrocytes and microglia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Increases in\u00a0APP\u00a0products other than A\u03b2 distinguished AD\u2010DS from AD. 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