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

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 pathol - ogy, hippocampal synaptic function and axonal transport, regulation of gene expression and posttranslational modification of proteins, and microglial and myeloid cell function. The cumu - lative 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.