Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses

Key Points Alzheimer's disease (AD) is a highly heritable disorder, the genetic underpinnings of which remain incompletely understood despite intense research over the past 30 years. Over 1,000 individual genetic-association studies have been published in the field of AD; these studies are exhaustively annotated and systematically meta-analysed in a continuously updated online database called AlzGene. Genome-wide association (GWA) studies, which have the potential to pinpoint new pathogenetic pathways by simultaneously testing thousands of genetic markers in a largely hypothesis-free fashion, are becoming increasingly available for AD. Over 20 genetic loci currently show evidence for a significant role in modifying risk for AD in the AlzGene meta-analyses. One-third of these were originally described in GWA studies. The potential functional and pathogenetic implications of some of the most interesting of these genes (angiotensin I converting enzyme ( ACE ); cholesterol 25-hydroxylase ( CH25H ); cholinergic receptor, nicotinic, β2 ( CHRNB2 ); cystatin C ( CST3 ); GRB2-associated binding protein 2 ( GAB2 ); lamin A/C ( LMNA ); microtubule-associated protein tau ( MAPT ); prion protein ( PRNP ); sortilin-related receptor, L(DLR class) A repeats-containing ( SORL1 ) and transferrin ( TF )) can now be summarized. Studies of the genetic causes of Alzheimer's disease have yielded a bewildering array of candidate genes. Bertram and Tanzi describe the results of ongoing systematic meta-analyses of these studies and discuss how some of the risk factors identified might contribute to disease pathology. The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein ( APP ) and the presenilins ( PSEN1 and PSEN2 )), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E ( APOE )). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk fac