International researchers identify 11 new genes linked to Alzheimer's disease

International groups join forces to find elusive gene variants in largest-ever sample set

An international group of researchers has identified 11 new genes that offer important new insights into the disease pathways involved in Alzheimer's disease. The highly collaborative effort involved scanning the DNA of over 74,000 volunteers-the largest genetic analysis yet conducted in Alzheimer's research-to discover new genetic risk factors linked to late-onset Alzheimer's disease, the most common form of the disorder.

By confirming or suggesting new processes that may influence Alzheimer's disease development-such as inflammation and synaptic function-the findings point to possible targets for the development of drugs aimed directly at prevention or delaying disease progression.

Supported in part by the National Institute on Aging (NIA) and other components of the National Institutes of Health, the International Genomic Alzheimer's Project (IGAP) reported its findings online in Nature Genetics on Oct. 27, 2013. IGAP is comprised of four consortia in the United States and Europe which have been working together since 2011 on genome-wide association studies (GWAS) involving thousands of DNA samples and shared datasets. GWAS are aimed at detecting the subtle gene variants involved in Alzheimer's and defining how the molecular mechanisms influence disease onset and progression.

"Collaboration among researchers is key to discerning the genetic factors contributing to the risk of developing Alzheimer's disease," said Richard J. Hodes, M.D., director of the NIA. "We are tremendously encouraged by the speed and scientific rigor with which IGAP and other genetic consortia are advancing our understanding."

The search for late-onset Alzheimer's risk factor genes had taken considerable time, until the development of GWAS and other techniques. Until 2009, only one gene variant, Apolipoprotein E-e4 (APOE-e4), had been identified as a known risk factor. Since then, prior to today's discovery, the list of known gene risk factors had grown to include other players-PICALM, CLU, CR1, BIN1, MS4A, CD2AP, EPHA1, ABCA7, SORL1 and TREM2.

IGAP's discovery reported today of 11 new genes strengthens evidence about the involvement of certain pathways in the disease, such as the role of the SORL1 gene in the abnormal accumulation of amyloid protein in the brain, , a hallmark of Alzheimer's disease. It also offers new gene risk factors that may influence several cell functions, to include the ability of microglial cells to respond to inflammation.

The researchers identified the new genes by analyzing previously studied and newly collected DNA data from 74,076 older volunteers with Alzheimer's and those free of the disorder from 15 countries. The new genes (HLA-DRB5/HLA0DRB1, PTK2B, SLC24A4-0RING3, DSG2, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2 and CASS4) add to a growing list of gene variants associated with onset and progression of late-onset Alzheimer's. Researchers will continue to explore the roles played by these genes, to include:

• How SORL1 and CASS4 influence amyloid, and how CASS4 and FERMT2 affect tau, another protein hallmark of Alzheimer's disease

• How inflammation is influenced by HLA-DRB5/DRB1, INPP5D, MEF2C, CR1 and TREM2

• How SORL1affects lipid transport and endocytosis (or protein sorting within cells)

• How MEF2C and PTK2B influence synaptic function in the hippocampus, a brain region important to learning and memory

• How CASS4, CELF1, NME8 and INPP5 affect brain cell function

The study also brought to light another 13 variants that merit further analysis.

"Interestingly, we found that several of these newly identified genes are implicated in a number of pathways," said Gerard Schellenberg, Ph.D., University of Pennsylvania School of Medicine, Philadelphia, who directs one of the major IGAP consortia. "Alzheimer's is a complex disorder, and more study is needed to determine the relative role each of these genetic factors may play. I look forward to our continued collaboration to find out more about these-and perhaps other-genes."