Towards holistic theory and therapeutics of Alzheimer's disease: The AD-DROP ontology.

Abstract

The community of clinicians and researchers working on Alzheimer's disease (AD) is an amalgam of distinct communities with different means and ends to treat cognitive decline in the elderly. In spite of this diversity, since the 1990s, biomedical research has been mostly guided by the reductionistic amyloid cascade hypothesis (ACH). Dominant ACH-based approaches have not yet managed to deliver viable therapies Herrup's (2015) "case for rejecting the ACH" suggests that the community could benefit from studying other disease-relevant processes (DRPs) for AD, and might "choose them all." However, this strategy puts all DRPs on the same footing, and we will continue the work of Herrup by offering a hierarchical theoretical scheme of DRPs for AD. We shall not make or evaluate claims about particular DRPs. Firstly, we define the primary properties of DRPs (specificity, pathogenic intensity, and frequency in AD) and propose specificity as an important sorting criterion for DRPs studied in AD research (Figure 1) before performing a specificity analysis for two DRPs. Our analyses of tau protein dysfunction and autophagy (Figures 2 & 3) reveal how a DRP's role in AD differs according to its specificity, and allow us to define causes, risk factors, and markers of AD (Table 1). We discuss how our theoretical framework should be completed with quantitative knowledge of pathogenic intensity and frequency in AD patients. We therefore finish by proposing a disease ontology, a disease relevance ontology by process (AD-DROP), arguing that our hypothetical framework could improve much-needed communication around priority setting in the diverse AD research community.