Alternative Approaches in Gene Discovery and Characterization in Alzheimer's Disease

Abstract

Uncovering the genetic risk and protective factors for complex diseases is of fundamental importance for advancing therapeutic and biomarker discoveries. This endeavor is particularly challenging for neuropsychiatric diseases where diagnoses predominantly rely on the clinical presentation, which may be heterogeneous, possibly due to the heterogeneity of the underlying genetic susceptibility factors and environmental exposures. Although genome-wide association studies of various neuropsychiatric diseases have recently identified susceptibility loci, there likely remain additional genetic risk factors that underlie the liability to these conditions. Furthermore, identification and characterization of the causal risk variant(s) in each of these novel susceptibility loci constitute a formidable task, particularly in the absence of any prior knowledge about their function or mechanism of action. Biologically relevant, quantitative phenotypes, i.e., endophenotypes, provide a powerful alternative to the more traditional, binary disease phenotypes in the discovery and characterization of susceptibility genes for neuropsychiatric conditions. In this review, we focus on Alzheimer's disease (AD) as a model neuropsychiatric disease and provide a synopsis of the recent literature on the use of endophenotypes in AD genetics. We highlight gene expression, neuropathology and cognitive endophenotypes in AD, with examples demonstrating the utility of these alternative approaches in the discovery of novel susceptibility genes and pathways. In addition, we discuss how these avenues generate testable hypothesis about the pathophysiology of genetic factors that have far-reaching implications for therapies.

Keywords: Alzheimer’s disease; Cognition; Endophenotype; Gene expression; Genetics; Neuropathology.

Fig. 1

Definition (a) and utility (b) of endophenotypes. The graded arrow represents the continuum of AD with darker colors symbolizing greater clinical expression of disease. The brackets and text above them depict the different uses of endophenotypes at various disease stages (Color figure online)

Fig. 2

Simplified model for the pathophysiology of AD and its endophenotypes: the flow of major pathogenic mechanisms from top to bottom represent the proposed consequence of events. The interactions between the various pathomechanisms are omitted for simplicity. The dotted arrows and boxes symbolize the pathogenic events that presumably precede the endophenotypes, and the endophenotypes, respectively. The examples of genes that are associated with the endophenotypes are taken from the text. While there are clearly many other plausible endophenotypes in this cascade, only those that are the focus of this review are shown