The International Genomics of Alzheimer’s Project (IGAP), after scanning the DNA of over 74,000 patients and controls from 15 countries, has found 11 new regions of the genome involved in late-onset Alzheimer’s disease. Besides doubling the number of genes now implicated in Alzheimers’s, IGAP has confirmed the involvement of a number of the disease’s biological pathways, while discovering entirely new ones. Especially interesting are new details on the role of inflammatory processes, and revelations about risk factors pertaining to hippocampal synaptic function, the cytoskeleton, and axonal transport, as well as myeloid and microglial cell functions.
IGAP was started 2011 by four of the largest Alzheimer’s research consortia—the Alzheimer's Disease Genetics Consortium (ADGC), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), the European Alzheimer Disease Initiative (EADI), and the Genetic and Environmental Research in Alzheimer Disease (GERAD) consortium. IGAP published its results in Nature Genetics on October 27, in a paper entitled “Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.”
This paper describes how IGAP’s investigators conducted a two-stage, genome-wide association study (GWAS): “In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on four previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls.” This work’s unprecedented scope enabled IGAP’s investigators to identify more genes than had been identified in the previous 20 years.
Until 2009, only one gene variant, Apolipoprotein E-e4 (APOE-e4), had been identified as a known risk factor. Since then, prior to IGAP’s discoveries, the list of known gene risk factors had grown to include other players—PICALM, CLU, CR1, BIN1, MS4A, CD2AP, EPHA1, ABCA7, SORL1, and TREM2. Now, with IGAP’s contribution, the list of genetic risk factors has grown to include HLA-DRB5/DRB1, PTK2B, SLC24A4-0RING3, DSG2, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, and CASS4. In addition, the IGAP identified 13 loci with “suggestive evidence of association.”
One of the more significant new associations was found in the HLA-DRB5/DRB1 region, one of the most complex parts of the genome, which plays a role in the immune system and inflammatory response. It has also been associated with multiple sclerosis and Parkinson's disease, suggesting that the diseases where abnormal proteins accumulate in the brain may have a common mechanism involved, and possibly have a common drug target.
“We know that healthy cells are very good at clearing out debris, thanks in part to the immune response system, but in these neurodegenerative diseases where the brain has an inflammatory response to bad proteins and starts forming plaques and tangle clumps, perhaps the immune response can get out of hand and do damage,” said Gerard Schellenberg, Ph.D., a professor at the University of Pennsylvania School of Medicine and director of the ADGC. “Through this powerful international group as well as our own U.S. collaborations, we'll expand the dataset even further to look for rare variants and continue our analysis to find more opportunities to better understand the disease and find viable therapeutic targets. Large-scale sequencing will certainly play a part in the next phase of our genetics studies.”
Building on the IGAP results, Alzheimer’s researchers will continue to explore the role played by genes, including considerations of how:
- SORL1 and CASS4 influence amyloid (and how CASS4 and FERMT2 affect tau, another protein hallmark of Alzheimer's disease).
- HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, and TREM2 influence inflammation
- SORL1 affects lipid transport and endocytosis.
- MEF2C and PTK2B influence synaptic function in the hippocampus.
- CASS4, CELF1, NME8, and INPP5 affect brain cell function.
Anticipating such work, Sudha Seshadri, M.D., a professor at the Boston University School of Medicine and leader of CHARGE, offered this comment: “We need to better understand how exactly these genes work in health and disease, and to perhaps make drugs from these genes and molecules. We will continue to mine these results for new insights, even as we include more patients and use new technologies like whole-genome sequencing to find more new pathways and genes.”