The largest international study ever conducted on Alzheimer’s disease, the International Genomics Alzheimer’s Project (I-GAP) consortium has identified 11 new regions of the genome involved in the onset of this neurodegenerative disease.
This study gives an overview of the molecular mechanisms underlying the disease, opening up to a better understanding of the pathophysiology of Alzheimer’s disease. These results were published in Nature Genetics.
Since 2009, 10 genes for Alzheimer’s disease have been identified. However, much of the individual susceptibility to develop the disease remains unexplained. So in February 2011, the leaders of the four largest international research consortia on the genetics of Alzheimer’s disease joined forces to accelerate the discovery of new genes. Supported in part by the National Institute on Aging (NIA) and other components of the National Institutes of Health (NIH), in less than three years, the IGAP program identified more genes than had been identified over the previous 20 years. They collected genetic data on 74,076 patients and controls from 15 countries and were able to discover 11 new genes in addition to those already known, and identify 13 other genes, yet to be validated.
These 11 new confirmed genes may open new avenues to understanding the causes of Alzheimer’s disease. For example, one of the most significant associations was found in the region HLA-DRB5/DRB1 major histocompatibility complex. This finding is interesting in several ways. First, it strongly suggests the involvement of the immune system in the disease. In addition, this same region has also been associated with two other neurodegenerative diseases, one known to have an immune mechanism, multiple sclerosis and another not previously thought to have a major immune component, Parkinson’s disease.
Some of the newly associated genes confirm biological pathways known to be involved in AD, including the amyloid (SORL1, CASS4 ) and tau (CASS4 , FERMT2) pathways. The role of the immune response and inflammation (HLA-DRB5/DRB1 , INPP5D , MEF2C ) already implied by previous work (CR1, TREM2) is reinforced, as are the importance of cell migration (PTK2B), lipid transport and endocytosis (SORL1). New hypotheses have also emerged related to hippocampal synaptic function (MEF2C, PTK2B), the cytoskeleton and axonal transport (CELF1, NME8, CASS4) as well as myeloid and microglial cell functions (INPP5D).