PMID- 27521573 OWN - NLM STAT- MEDLINE DCOM- 20180410 LR - 20210109 IS - 1460-2156 (Electronic) IS - 0006-8950 (Print) IS - 0006-8950 (Linking) VI - 139 IP - Pt 10 DP - 2016 Oct TI - BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease. PG - 2766-2777 AB - SEE ROGAEVA AND SCHMITT-ULMS DOI101093/AWW201 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-beta-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-beta in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) epsilon4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val(66) homozygotes, 48 Met(66) carriers). Among preclinical mutation carriers, Met(66) carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val(66) homozygotes. Cortical amyloid-beta and cerebrospinal fluid amyloid-beta(42) levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val(66) homozygotes and Met(66) carriers. There was an effect of APOE on amyloid-beta levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-beta on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met(66) carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-beta in autosomal dominant Alzheimer's disease. CI - (c) The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com. FAU - Lim, Yen Ying AU - Lim YY AD - 1 The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia yen.lim@florey.edu.au. FAU - Hassenstab, Jason AU - Hassenstab J AD - 2 Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA. FAU - Cruchaga, Carlos AU - Cruchaga C AD - 3 Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA. FAU - Goate, Alison AU - Goate A AD - 4 Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Fagan, Anne M AU - Fagan AM AD - 2 Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA. FAU - Benzinger, Tammie L S AU - Benzinger TL AD - 5 Department of Radiology, Washington University in St. Louis, St. Louis, MO, USA. FAU - Maruff, Paul AU - Maruff P AD - 1 The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia 6 Cogstate Ltd., Melbourne, Victoria, Australia. FAU - Snyder, Peter J AU - Snyder PJ AD - 7 Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA. FAU - Masters, Colin L AU - Masters CL AD - 1 The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia. FAU - Allegri, Ricardo AU - Allegri R AD - 8 Ageing and Memory Center, Instituto de Investigaciones Neurologicas "Raul Carrea" (FLENI), Buenos Aires, Argentina. FAU - Chhatwal, Jasmeer AU - Chhatwal J AD - 9 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 10 Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Farlow, Martin R AU - Farlow MR AD - 11 Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA. FAU - Graff-Radford, Neill R AU - Graff-Radford NR AD - 12 Department of Neurology, Mayo Clinic Jacksonville, FL, USA. FAU - Laske, Christoph AU - Laske C AD - 13 German Center for Neurodegenerative Diseases (DZNE), Tubingen, Germany 14 Section for Dementia Research, Department of Cellular Neurology, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tubingen, Tubingen, Germany. FAU - Levin, Johannes AU - Levin J AD - 15 Department of Neurology, University of Munich, Munich, Germany. FAU - McDade, Eric AU - McDade E AD - 2 Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA. FAU - Ringman, John M AU - Ringman JM AD - 16 Memory and Aging Center, Keck School of Medicine of the University of Southern California, CA, USA. FAU - Rossor, Martin AU - Rossor M AD - 17 Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK. FAU - Salloway, Stephen AU - Salloway S AD - 7 Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA. FAU - Schofield, Peter R AU - Schofield PR AD - 18 Neuroscience Research Australia, Sydney, NSW, Australia 19 School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia. FAU - Holtzman, David M AU - Holtzman DM AD - 2 Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA. FAU - Morris, John C AU - Morris JC AD - 2 Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA. FAU - Bateman, Randall J AU - Bateman RJ AD - 2 Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA. CN - Dominantly Inherited Alzheimer Network LA - eng GR - P50 AG005142/AG/NIA NIH HHS/United States GR - U24 AG021886/AG/NIA NIH HHS/United States GR - K23 DK094982/DK/NIDDK NIH HHS/United States GR - R01 EB009352/EB/NIBIB NIH HHS/United States GR - MR/L023784/1/MRC_/Medical Research Council/United Kingdom GR - P30 CA091842/CA/NCI NIH HHS/United States GR - UF1 AG032438/AG/NIA NIH HHS/United States GR - UL1 TR000448/TR/NCATS NIH HHS/United States GR - MR/L023784/2/MRC_/Medical Research Council/United Kingdom GR - U19 AG032438/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160812 PL - England TA - Brain JT - Brain : a journal of neurology JID - 0372537 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (tau Proteins) RN - 7171WSG8A2 (BDNF protein, human) RN - AE28F7PNPL (Methionine) RN - HG18B9YRS7 (Valine) SB - IM CIN - 10.1093/aww201 MH - Adult MH - Alzheimer Disease/diagnostic imaging/*genetics MH - Brain-Derived Neurotrophic Factor/*genetics MH - Female MH - Heterozygote MH - Hippocampus/diagnostic imaging/*physiology MH - Humans MH - Male MH - Memory Disorders/diagnostic imaging/*genetics MH - Methionine/*genetics MH - Middle Aged MH - Valine/*genetics MH - tau Proteins/*genetics PMC - PMC5815565 OTO - NOTNLM OT - Alzheimer's disease OT - amyloid-beta OT - dementia OT - genetics OT - tau EDAT- 2016/08/16 06:00 MHDA- 2018/04/11 06:00 PMCR- 2017/10/01 CRDT- 2016/08/14 06:00 PHST- 2016/04/06 00:00 [received] PHST- 2016/06/19 00:00 [accepted] PHST- 2016/08/14 06:00 [entrez] PHST- 2016/08/16 06:00 [pubmed] PHST- 2018/04/11 06:00 [medline] PHST- 2017/10/01 00:00 [pmc-release] AID - aww200 [pii] AID - 10.1093/brain/aww200 [doi] PST - ppublish SO - Brain. 2016 Oct;139(Pt 10):2766-2777. doi: 10.1093/brain/aww200. Epub 2016 Aug 12.