title: The brain-derived neurotrophic factor Val66Met polymorphism and prediction of neural risk for Alzheimer disease.
abstract: BACKGROUND
  The brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may predict the risk of Alzheimer disease (AD). However, genetic association studies of the BDNF gene with AD have produced equivocal results. Imaging-genetics strategies may clarify the manner in which BDNF gene variation predicts the risk of AD via characterization of its effects on at-risk structures or neural networks susceptible in this disorder.
  
  
  OBJECTIVE
  To determine whether the BDNF Val66Met gene variant interacts with age to predict brain and cognitive measures in healthy volunteers across the adult lifespan in an intermediate phenotype pattern related to AD by examining (1) cortical thickness, (2) fractional anisotropy of white matter tracts (ie, white matter integrity), and (3) episodic memory performance.
  
  
  METHODS
  A cross-sectional study using genetics, high-resolution magnetic resonance imaging, diffusion tensor imaging, and cognitive testing in healthy individuals spanning the adult lifespan.
  
  
  METHODS
  University hospital.
  
  
  METHODS
  A total of 69 healthy volunteers ranging from 19 to 82 years of age.
  
  
  METHODS
  The BDNF Val66Met genotype, apolipoprotein E genotype, cortical thickness, microstructural integrity of white matter tracts, and episodic memory performance were evaluated.
  
  
  RESULTS
  The BDNF Val66Met polymorphism interacted with age to predict (1) cortical thickness (prominently at the entorhinal cortex and temporal gyri), (2) fractional anisotropy of white matter tracts (prominently at white matter tracts connecting to the medial temporal lobe), and (3) episodic memory performance. For each of these findings, the pattern was similar: valine/valine individuals in late life were susceptible, and in early adult life, methionine allele carriers demonstrated susceptibility.
  
  
  CONCLUSIONS
  The BDNF gene confers risk in an age-dependent manner on the brain structures and cognitive functions that are consistent with the neural circuitry vulnerable in the earliest stages of AD. Our novel findings provide convergent evidence in vivo for a BDNF genetic mechanism of susceptibility in an intermediate phenotype related to AD.
authors.affiliation: Department of Psychiatry, Geriatric Mental Health Program, Centre for Addiction and Mental Health, 250 College St, Toronto, Ontario, Canada M5T 1R8. aristotle_voineskos@camh.net
authors.forename: Aristotle N
authors.initials: AN
authors.lastname: Voineskos
authors.forename: Jason P
authors.initials: JP
authors.lastname: Lerch
authors.forename: Daniel
authors.initials: D
authors.lastname: Felsky
authors.forename: Sajid
authors.initials: S
authors.lastname: Shaikh
authors.forename: Tarek K
authors.initials: TK
authors.lastname: Rajji
authors.forename: Dielle
authors.initials: D
authors.lastname: Miranda
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Lobaugh
authors.forename: Benoit H
authors.initials: BH
authors.lastname: Mulsant
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Pollock
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D053327:Apolipoprotein E4 / Q000235:genetics; D001921:Brain / Q000473:pathology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002540:Cerebral Cortex / Q000473:pathology; D003430:Cross-Sectional Studies; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D021621:Imaging, Three-Dimensional; D008297:Male; D011939:Mental Recall / Q000502:physiology; D008875:Middle Aged; D009415:Nerve Net / Q000473:pathology; D009483:Neuropsychological Tests; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D055815:Young Adult
chemical_list: D053327:Apolipoprotein E4; D019208:Brain-Derived Neurotrophic Factor