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CONTEXT: 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. DESIGN: A cross-sectional study using genetics, high-resolution magnetic resonance imaging, diffusion tensor imaging, and cognitive testing in healthy individuals spanning the adult lifespan. SETTING: University hospital. PARTICIPANTS: A total of 69 healthy volunteers ranging from 19 to 82 years of age. MAIN OUTCOME MEASURES: 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.

Original publication




Journal article


Arch Gen Psychiatry

Publication Date





198 - 206


Adult, Age Factors, Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Apolipoprotein E4, Brain, Brain-Derived Neurotrophic Factor, Cerebral Cortex, Cross-Sectional Studies, Diffusion Magnetic Resonance Imaging, Female, Genetic Carrier Screening, Genetic Predisposition to Disease, Genotype, Humans, Image Processing, Computer-Assisted, Imaging, Three-Dimensional, Male, Mental Recall, Middle Aged, Nerve Net, Neuropsychological Tests, Phenotype, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Risk Factors, Young Adult