Integral to the study design is that once a relationship between a risk factor and cognitive loss is identified, the risk factor must be related to changes in the structural or functional elements that subserve cognition. It is clear from Fig. (3) that there are many risk factors for which the biologic signature has not yet been identified. We are currently investigating the potential for a number of indices to mediate these associations. There are two ongoing epigenome-wide studies of brain tissue and peripheral blood lymphocytes. There are also ongoing RNA expression (microarray and next generation RNA sequencing), proteomic and metabolomic studies searching for novel biologic pathways linking risk factors to clinical disease.
