Alzheimer disease (AD) is currently the leading cause of dementia worldwide with no disease modifying therapy available. Despite the burden of disease, there is still no consensus on the underlying pathophysiology leading to sporadic AD. The previously held amyloid-beta (Aβ) hypothesis is giving way to a multifactorial model that involves various pathologic components, including Aβ and tau. In this paradigm, other components including inflammatory processes (i.e. microglia), structural components (blood brain barrier), and the amyloid precursor protein (APP) play significant roles in disease. We present here a review on the emerging role of APP in AD, independent of Aβ, including its significance in normal physiology and disease. We briefly describe the various isoforms of APP, its processing pathways, and how this contributes to function. Furthermore, we present our own observations and discussion on APP pathology in AD human tissue. Finally, we combine this knowledge of APP to suggest an interaction with tau that could be applied to AD and other tauopathies such as chronic traumatic encephalopathy. This emerging view of APP places it as an independent-mediator of AD pathology with implications for future research and treatment avenues.

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