<p>Alzheimer’s disease research is moving into a new era, yet significant questions remain about its underlying biological mechanisms. In this article, we consider how the field might refine the transfer of evidence between research cohorts focused on rare, genetically defined familial forms of dementia, clinical trial cohorts, highly selective of relatively younger people, with single neuropathologies and few co-morbidities, and the overall picture of the dementia syndrome in the whole population. We examine four key areas in which the evidence base must be improved: i) how ‘disease’ definitions apply across these three groups, ii) the precise molecular identification of the protein at the heart of current Alzheimer’s research - amyloid beta protein, iii) the contributions of the full amyloid precursor protein proteolytic system and iv) how this complex proteolytic system relates to wider cellular systems. We describe how a cross-disciplinary approach based on the APP matrix framework, could allow a systematic investigation of new perspectives to inform translational research and precision medicine approaches. Addressing these gaps will give us the biological grounding needed to provide a sound underpinning to innovations in the field.</p>