Genomic insights into the etiology of Alzheimer's disease: a review

Abstract

Christiane Reitz1–3 1Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, 2Gertrude H Sergievsky Center, 3Department of Neurology, Columbia University, New York, NY, USA Abstract: Over the past decade, studies capitalizing on high-throughput genome technologies have significantly advanced the knowledge on the genetic underpinnings of Alzheimer's disease (AD) by identifying a wide set of pathophysiological mechanisms implicated in the disease in addition to amyloid precursor protein (APP) metabolism. These include: innate immune response and inflammation, lipid metabolism, endocytosis, cell migration, tau pathology, hippocampal synaptic function and axonal transport, regulation of gene expression and posttranslational modification of proteins, and microglial and myeloid cell function. The cumulative population attributable fraction associated with known genetic variants amounts now to ~80%. High-throughput sequencing studies have started to map specific causative variants in these genes and have provided invaluable evidence for an involvement of rare variants in AD, overturning the “common disease–common variant” hypothesis. The ongoing and future large-scale translational studies and next generation whole genome or whole exome sequencing efforts hold the promise of mapping the specific causative variants in these genes; of identifying additional risk variants, including rare and structural variants; and of identifying novel targets for genetic testing, prevention, and treatment. Keywords: genetics, gene, variation, polymorphism, genome-wide association study, sequencing