New Horizons in Studying the Cellular Mechanisms of Alzheimer’s Disease

AbstractFollowing an analysis of the state of investigations and clinical outcomes in the Alzheimer’s research field, I argue that the widely accepted ‘amyloid cascade’ mechanistic explanation of Alzheimer’s disease appears to be fundamentally incomplete. In this context, I propose that a framework termed ‘principled mechanism’ (PM) can help remedy this problem. First, using a series of five ‘tests’, PM systematically compares different components of a given mechanistic explanation against a paradigmatic set of criteria and hints at various ways of making the mechanistic explanation more ‘complete’. I will demonstrate these steps using the amyloid explanation, highlighting its missing or problematic mechanistic elements. Second, PM makes an appeal for the discovery and application of ‘biological principles’ that approximate ceteris paribus generalisations or laws and are operative at the level of a biological cell. Although thermodynamic, evolutionary, ecological and other laws or principles from chemistry and the broader life sciences could inform them, biological principles should be considered ontologically unique. These principles could augment different facets of the mechanistic explanation but also allow further independent nomological explanation of the phenomenon. Whilst this overall strategy can be complementary to certain ‘new mechanist’ approaches, an important distinction of the PM framework is its equal attention to the explanatory utility of biological principles. Lastly, I detail two hypothetical biological principles and show how they could each inform and improve the potentially incomplete mechanistic aspects of the amyloid explanation and how they could provide independent explanations for the cellular features associated with Alzheimer’s disease.