Changing perspectives on Alzheimer's disease: thinking outside the amyloid box

The past two decades have seen an explosion in funding and research for Alzheimer's disease (AD), which has resulted in a wealth of data exploring the potential underlying processes, particularly with regard to amyloid-β (Aβ). However, to date, therapies based on this knowledge have not been forthcoming. In seeking an explanation for our current pharmacological failures, it has become clear that amyloid is only one part of a multi-factorial disease process incorporating a wealth of deleterious factors. Additionally, there is strong evidence that the initial production of Aβ is part of the evolutionarily conserved stress response, triggered by a host of upstream factors highly altered in aging. Taken together, these observations place Aβ in a drastically different context, with toxicity occurring secondarily to upstream deleterious factors and rendering current therapeutic strategies oversimplified. This re-conceptualization necessitates a paradigm shift in our scientific and social response to AD, placing a greater emphasis on upstream interventions and public health awareness of the measures that can be taken by most individuals to reduce the risk of AD. With the increasing prevalence of AD and the realization that disease-modifying drugs may not be available in the near future, it is the responsibility of science to better communicate the worth of preventative healthcare measures to the public.