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IU-led research team identifies genetic variant linked to better memory performance

  • Nov. 11, 2014

INDIANAPOLIS -- People with a newly identified genetic variant perform better on certain types of memory tests, a discovery that may point the way to new treatments for the memory impairments caused by Alzheimer's disease or other age-associated conditions.

In what the international research team is calling the largest study to date of human memory, an analysis of genomic data and memory test results from more than 14,000 older adults identified a location in the genome that was associated with better memory performance. The researchers noted that the gene has not been associated with cognition in the past.

The research team, led by IU School of Medicine post-doctoral researcher and medical student Vijay K. Ramanan, Ph.D., and Andrew J. Saykin, Psy.D., director of the Indiana Alzheimer Disease Center and the IU Center for Neuroimaging, reported its results today in the journal Molecular Psychiatry.

The genome-wide study found that better performance on tests of episodic memory was associated with a change in the DNA on chromosome 2 -- a G instead of the more common A nucleotide in a gene known as FASTKD2. The genetic variant -- known as a single nucleotide polymorphism, or SNP -- was also associated with a larger hippocampus and more dense gray matter in the brain on magnetic resonance imaging scans. The hippocampus is a brain structure involved in storing and retrieving memory. The inability to recall a recent current event, a newspaper article or what one had for dinner is one of the earliest symptoms of Alzheimer's disease and is also related to hippocampal atrophy.

The FASTKD2 gene is responsible for the production of a protein involved in apoptosis, a process of programmed cell death. The researchers also examined cerebrospinal fluid samples from 82 participants and found lower levels of proteins associated with cell death in the participants with the memory-protective G variant.

More research will be needed to determine whether drugs targeting the FASTKD2 gene could be used to protect against memory loss and related issues in Alzheimer's disease, Dr. Saykin said.

"There is likely no single 'memory gene'; we expect that memory is driven by a combination of multiple genes along with environment and lifestyle," Dr. Saykin said. "Although the influence of FASTKD2 was modest, there are parallels to research in diabetes, cancer and hypertension that uncovered genetic variants with similar effects that turned out to be targets for drugs that are now commonly used."

Other researchers contributing to the work were Kwangsik Nho, Ph.D., Li Shen, Ph.D., Shannon L. Risacher, Ph.D., Sungeun Kim, Ph.D., Brenna C. McDonald, Psy.D., Martin R. Farlow, M.D., Tatiana M. Foroud, Ph.D., and Sujuan Gao, Ph.D., of the IU School of Medicine; on behalf of the AddNeuroMed Consortium: Hilkka Soininen, M.D., Ph.D. University of Eastern Finland; Iwona Kłoszewska, M.D., Ph.D., Medical University of Lodz, Poland; Patrizia Mecocci, M.D., Ph.D., University of Perugia, Italy; Magda Tsolaki, M.D., Ph.D., Aristotle University, Greece; Bruno Vellas, M.D., Ph.D., University of Toulouse, France and Simon Lovestone, Ph.D., MRCPsych, University of Oxford, U.K.; Paul S. Aisen, M.D., University of California, San Diego; Ronald C. Petersen, M.D., and Clifford R. Jack, Jr., M.D., Mayo Clinic Minnesota; Leslie M. Shaw, Ph.D., and John Q. Trojanowski, Ph.D., University of Pennsylvania School of Medicine; Michael W. Weiner, M.D., University of California, San Francisco; Robert C. Green, M.D., M.P.H., and Philip L. De Jager, M.D., Ph.D., Harvard Medical School; Arthur W. Toga, Ph.D., University of Southern California; Lei Yu, Ph.D., and David A. Bennett, M.D., Rush University Medical Center, Chicago.

Data sources included the Health and Retirement Study, which is sponsored by the National Institute on Aging (grants U01AG009740, RC2AG036495, and RC4AG039029) and is conducted by the University of Michigan.

Data collection and sharing for the project was funded by the Alzheimer's Disease Neuroimaging Initiative, (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Additional ADNI support comes from the NIH grants P30AG010129, K01AG030514, and U24AG21886. Funding for whole genome sequencing in ADNI participants was provided by the Alzheimer’s Association and the Brin Wojcicki Foundation. The Indiana Memory and Aging Study is supported by the Indiana CTSI (NIH grants U54 RR025761, RR027710-01, and RR020128). AddNeuroMed was funded through the EU FP6 Programme. Data management and the specific analyses reported here were supported by NIH R01AG19771, P30AG10133, R01LM011360, and R00LM011384, as well as NSF IIS-1117335.

Andrew J. Saykin, Psy.D.

Andrew J. Saykin, Psy.D.

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