Memory impairment is the cardinal early feature of Alzheimer’s disease, a highly prevalent disorder whose causes remain only partially understood. To identify novel genetic predictors, we used an integrative genomics approach to perform the largest study to date of human memory (n=14 781). Using a genome-wide screen, we discovered a novel association of a polymorphism in the pro-apoptotic gene FASTKD2 (fas-activated serine/threonine kinase domains 2; rs7594645-G) with better memory performance and replicated this finding in independent samples. Consistent with a neuroprotective effect, rs7594645-G carriers exhibited increased hippocampal volume and gray matter density and decreased cerebrospinal fluid levels of apoptotic mediators. The MTOR (mechanistic target of rapamycin) gene and pathways related to endocytosis, cholinergic neurotransmission, epidermal growth factor receptor signaling and immune regulation, among others, also displayed association with memory. These findings nominate FASTKD2 as a target for modulating neurodegeneration and suggest potential mechanisms for therapies to combat memory loss in normal cognitive aging and dementia.
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The HRS is sponsored by the National Institute on Aging (grants U01AG009740, RC2AG036495 and RC4AG039029) and is conducted by the University of Michigan. Further information can be found at http://hrsonline.isr.umich.edu/index.php. Data collection and sharing for this project was funded by the ADNI (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 generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; BioClinica; Biogen Idec; Bristol-Myers Squibb Company; Eisai; Elan Pharmaceuticals; Eli Lilly and Company; F. Hoffmann-La Roche and its affiliated company Genentech; GE Healthcare; Innogenetics; IXICO; Janssen Alzheimer Immunotherapy Research & Development; Johnson & Johnson Pharmaceutical Research & Development; Medpace; Merck; Meso Scale Diagnostics; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer; Piramal Imaging; Servier; Synarc; 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, CA, USA. 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. For IMAS, we acknowledge the support of 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.
All authors contributed substantively to this report. VKR, LS and AJS were involved in study conception and design. HS, IK, PM, MT, BV and SL were involved in coordination and data collection and processing for AddNeuroMed. PSA, RCP, CRJ, LMS, JQT, MWW, RCG, AWT and AJS were involved in coordination and data collection and processing for ADNI. BCM, MRF, TMF, SG and AJS were involved in coordination and data collection and processing for IMAS. PLDJ, LY and DAB were involved in coordination and data collection and processing for ROS and MAP. VKR, KN, LS, SLR, SK, TMF, SG and AJS were involved in data organization and planning and execution of statistical analyses. VKR and AJS drafted the report and prepared all figures and tables. All authors were involved in reviewing and editing of the report.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Ramanan, V., Nho, K., Shen, L. et al. FASTKD2 is associated with memory and hippocampal structure in older adults. Mol Psychiatry 20, 1197–1204 (2015). https://doi.org/10.1038/mp.2014.142
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