title: BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease.
abstract: 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-β-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-β in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) ε4 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 Val66homozygotes, 48 Met66carriers). Among preclinical mutation carriers, Met66carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val66homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β42levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val66homozygotes and Met66carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met66carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer's disease.
authors: 1 The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia yen.lim@florey.edu.au.
authors: Yen Ying
authors: YY
authors: Lim
authors: 2 Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
authors: Jason
authors: J
authors: Hassenstab
authors: 3 Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA.
authors: Carlos
authors: C
authors: Cruchaga
authors: 4 Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Alison
authors: A
authors: Goate
authors: 2 Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
authors: Anne M
authors: AM
authors: Fagan
authors: 5 Department of Radiology, Washington University in St. Louis, St. Louis, MO, USA.
authors: Tammie L S
authors: TL
authors: Benzinger
authors: 1 The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia 6 Cogstate Ltd., Melbourne, Victoria, Australia.
authors: Paul
authors: P
authors: Maruff
authors: 7 Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors: Peter J
authors: PJ
authors: Snyder
authors: 1 The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia.
authors: Colin L
authors: CL
authors: Masters
authors: 8 Ageing and Memory Center, Instituto de Investigaciones Neurologicas "Raúl Carrea" (FLENI), Buenos Aires, Argentina.
authors: Ricardo
authors: R
authors: Allegri
authors: 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.
authors: Jasmeer
authors: J
authors: Chhatwal
authors: 11 Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Martin R
authors: MR
authors: Farlow
authors: 12 Department of Neurology, Mayo Clinic Jacksonville, FL, USA.
authors: Neill R
authors: NR
authors: Graff-Radford
authors: 13 German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany 14 Section for Dementia Research, Department of Cellular Neurology, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.
authors: Christoph
authors: C
authors: Laske
authors: 15 Department of Neurology, University of Munich, Munich, Germany.
authors: Johannes
authors: J
authors: Levin
authors: 2 Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
authors: Eric
authors: E
authors: McDade
authors: 16 Memory and Aging Center, Keck School of Medicine of the University of Southern California, CA, USA.
authors: John M
authors: JM
authors: Ringman
authors: 17 Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK.
authors: Martin
authors: M
authors: Rossor
authors: 7 Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors: Stephen
authors: S
authors: Salloway
authors: 18 Neuroscience Research Australia, Sydney, NSW, Australia 19 School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
authors: Peter R
authors: PR
authors: Schofield
authors: 2 Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
authors: David M
authors: DM
authors: Holtzman
authors: 2 Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
authors: John C
authors: JC
authors: Morris
authors: 2 Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
authors: Randall J
authors: RJ
authors: Bateman
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000502:physiology*; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000000981:diagnostic imaging / Q000235:genetics*; D008715:Methionine / Q000235:genetics*; D008875:Middle Aged; D014633:Valine / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016875:tau Proteins; C579455:BDNF protein, human; D008715:Methionine; D014633:Valine
keywords: Alzheimer’s disease; amyloid-β; dementia; genetics; tau