FASTKD2 is associated with memory and hippocampal structure in older adults.
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.
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.|Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, IN, USA.
V K
VK
Ramanan
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
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Nho
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.|Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
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http://orcid.org/0000-0002-5443-0503
L
Shen
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
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Risacher
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
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Kim
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
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BC
McDonald
Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
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MR
Farlow
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.|Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
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Foroud
Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA.
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S
Gao
Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
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H
Soininen
Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland.
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I
Kłoszewska
Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy.
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P
Mecocci
Third Department of Neurology, Aristotle University, Thessaloniki, Greece.
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M
Tsolaki
INSERM U 558, University of Toulouse, Toulouse, France.
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B
Vellas
Department of Psychiatry, University of Oxford, Oxford, UK.
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Lovestone
Department of Neuroscience, University of California-San Diego, San Diego, CA, USA.
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PS
Aisen
Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, USA.
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RC
Petersen
Department of Radiology, Mayo Clinic Minnesota, Rochester, MN, USA.
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CR
Jack
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.|Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
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LM
Shaw
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.|Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
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JQ
Trojanowski
Departments of Radiology, Medicine, and Psychiatry, University of California-San Francisco, San Francisco, CA, USA.|Department of Veterans Affairs Medical Center, San Francisco, CA, USA.
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Weiner
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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RC
Green
Laboratory of Neuro Imaging, Keck School of Medicine, University of Southern California, Los Angeles, CA USA.
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Toga
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, MA, USA.|Department of Neurology, Harvard Medical School, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
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De Jager
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
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L
Yu
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
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DA
Bennett
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.|Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
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Saykin
D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology* / Q000503:physiopathology; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D013329:Structure-Activity Relationship
C532222:FASTKD2 protein, human; D017346:Protein Serine-Threonine Kinases