Genetic architecture of Alzheimer's disease

Abstract

Advances in genetic and genomic technologies over the last thirty years have greatly enhanced our knowledge concerning the genetic architecture of Alzheimer's disease (AD). Several genes including APP, PSEN1, PSEN2, and APOE have been shown to exhibit large effects on disease susceptibility, with the remaining risk loci having much smaller effects on AD risk. Notably, common genetic variants impacting AD are not randomly distributed across the genome. Instead, these variants are enriched within regulatory elements active in human myeloid cells, and to a lesser extent liver cells, implicating these cell and tissue types as critical to disease etiology. Integrative approaches are emerging as highly effective for identifying the specific target genes through which AD risk variants act and will likely yield important insights related to potential therapeutic targets in the coming years. In the future, additional consideration of sex- and ethnicity-specific contributions to risk as well as the contribution of complex gene-gene and gene-environment interactions will likely be necessary to further improve our understanding of AD genetic architecture.

Figure 1:. Genetic loci associated with Alzheimer’s disease (AD).

A literature search was used to identify studies reporting genomic loci associated with either risk for AD or various endophenotypes including cerebrospinal fluid measurements of amyloid and/or tau, amyloid deposition as measured by positon emission tomography (PET) or postmortem studies, and brain glucose metabolism as measured by fluorodeoxyglucose (FDG)-PET. Genes with sufficient functional evidence to suggest they are the causal gene in their respective loci are annotated on the figure. Unlabeled loci indicate the causal gene in the region is still unknown. Source information for this figure can be found in Supplementary Table 1. Phenogram was constructed at http://visualization.ritchielab.org/phenograms and modified in Adobe Illustrator for clarity.