Down syndrome and Alzheimer disease: A "multi-hit" hypothesis based on multiple contributing factors resulting in pleotrophic consequences

While dogma and orthodoxy view amyloid-β as the primary mediator of Alzheimertype symptomology and neuropathology in Down syndrome, there are significant reasons to question this. In this commentary, we not only demolish the foundations of this orthodoxy, but rebuild an entirely new mechanism. Our multi-hit system is centered on the key contributions of oxidative stress, hormonal imbalance, and cardiovascular dysfunction that interact to deliver a one-two knockout blow eliciting neuropathological lesions, neuronal death, and ultimately, cognitive decline. This multi-hit hypothesis of Alzheimer-type pathology and degeneration in Down syndrome not only explains the apparent failure of targeted the rapeutics, but will foster the development of novel mechanistic and pharmacological approaches toward future treatment and therapeutic strategies.