Re-imagining Alzheimer's disease - the diminishing importance of amyloid and a glimpse of what lies ahead.

Many have criticized the amyloid cascade hypothesis of Alzheimer's disease for its inconsistencies and failures to either accurately predict disease symptoms or guide the development of productive therapies. In addition to criticisms, however, we believe that the field would benefit from having alternative narratives and disease models that can either replace or function alongside of an amyloid-centric view of Alzheimer's. This review is an attempt to meet that need. We offer three experimentally verified amyloid-independent mechanisms, each of which plausibly contributes substantially to the aetiology of Alzheimer's disease: loss of DNA integrity, faulty cell cycle regulation, regression of myelination. We outline the ways in which the failure of each can contribute to AD initiation and progression, and review how, acting alone or in combination with each other, they are sufficient for explaining the full range of AD pathologies. Yet, these three alternatives represent only a few of the many non-amyloid mechanisms that can explain AD pathogenesis. Therefore instead of proposing a single 'alternative hypothesis' to the amyloid cascade theory, sporadic AD is pictured as the result of independent yet intersecting age-related pathologies that afflict the ageing human brain. This article is part of the series "Beyond Amyloid". Cover Image for this issue: doi. 10.1111/jnc.13823.