Abstract
People with Down syndrome (DS) are predisposed to Alzheimer's disease (AD). The amyloid hypothesis informs studies of AD. InAD-DS, but not sporadic AD, increasedAPPcopy number is necessary, defining theAPPgene dose hypothesis. Whichamyloid precursor protein (APP)products contributeneeds to be determined. Brain levels of full-length protein (fl-hAPP), C-terminal fragments (hCTFs), and amyloid beta (Aβ) peptides were measured in DS, AD-DS, non-demented controls (ND), and sporadic AD cases. TheAPPgene-dose hypothesis was evaluated in the Dp16 model. DS and AD-DS differed from ND and AD for allAPPproducts. In AD-DS,Aβ42 and Aβ40 levels exceededAD.APPproducts were increased in the Dp16 model; increasedAPPgene dose was necessary for loss of vulnerable neurons, tau pathology, and activation of astrocytes and microglia. Increases inAPPproducts other than Aβ distinguished AD-DS from AD. Deciphering AD-DS pathogenesis necessitates deciphering whichAPPproducts contribute and how.
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