Results double the total number of genes involved in AD.

A total of five new genes implicated in Alzheimer disease (AD) have been identified by two research teams reporting in the current online issue of Nature Genetics. Both sets of researchers were involved in the analysis of each other’s data, and point out their combined results have doubled to 10 the total number of genes either newly or previously implicated in AD.

The U.S.-based Alzheimer’s Disease Genetics Consortium (ADGC) implicated variants in MS4A4/MS4A6E, CD2AP, CD33, and EPHA1 with late-onset AD. The other international team, led by scientists at Cardiff University’s MRC Centre for Neuropsychiatric Genetics and Genomics in the U.K., identified a fifth gene variant at ABCA7 along with the same four genes picked up by the ADGC.

The ADGC’s findings result from a three-stage genome-wide association study (GWAS) involving nearly 54,000 participants. The resulting paper is titled “Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease.” The international research team, led by the MRC centre’s Julie Williams, Ph.D., carried out a combined analysis of four GWAS datasets and tested the identified variants for association in independent samples. They report their findings in a paper titled “Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease.”

The ADGC’s study, led by Gerard D. Schellenberg, Ph.D., at the University of Pennsylvania School of Medicine, involved researchers at 44 universities and research institutions in the U.S. The consortium analyzed genetic data from 11,000 AD patients and nearly the same number of elderly controls with no dementia. Three additional institutes contributed confirmatory data from new individuals, taking the total number of people analyzed in the study to over 54,000.

The MRC-led research looked to identify new common susceptibility variants for AD by first undertaking a three-stage associa­tion study based upon predominantly European samples and then by testing these samples for loci showing suggestive evidence for association in the ADGC research.

The overall results from both the new research and previous studies suggest certain types of genes are involved in AD. “What’s exciting is the genes we now know of—the five new ones plus those previously identified—are clustering in patterns,” Dr. Williams notes.

Five of the newly and previously identified AD susceptibility loci in CLU, CR1, ABCA7, CD33, and EPHA1 have putative functions in the immune system, the MRC-led authors write. Those in PICALM, BIN1, CD33, and CD2AP are involved in processes at the cell membrane, includ­ing endocytosis, while APOE, CLU, and ABCA7 are involved in lipid processing.

It’s the genes implicated in endocytosis that are most exciting, Dr. Williams continues. “We now have four genes that implicate this precise process and it offers a very big clue that this process is playing a strong role in the development of Alzheimer disease.”

In 2009 Dr. Williams led what was claimed to be the largest genetic investigation of Alzheimer’s disease ever conducted, involving 16,000 individuals over two years. She maintains the combination of the 2009 work and this latest research will provide valuable new clues about how AD develops. “We are beginning to piece together the pieces of the jigsaw and gain new understanding. We still have a long way to go, but the jigsaw is beginning to come together.”

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