Research Papers: Gerotarget (Focus on Aging):

Dose-dependent genotype effects of BDNF Val66Met polymorphism on default mode network in early stage Alzheimer’s disease

Pin-Hsuan Lin, Shih-Jen Tsai, Chi-Wei Huang, Liu Mu-En, Shih-Wei Hsu, Chen-Chang Lee, Nai-Ching Chen, Ya-Ting Chang, Min-Yu Lan and Chiung-Chih Chang _

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Oncotarget. 2016; 7:54200-54214. https://doi.org/10.18632/oncotarget.11027

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Pin-Hsuan Lin1, Shih-Jen Tsai2,3, Chi-Wei Huang1,5, Liu Mu-En3, Shih-Wei Hsu4, Chen-Chang Lee4, Nai-Ching Chen1,5, Ya-Ting Chang1,5, Min-Yu Lan5 and Chiung-Chih Chang5

1 Department of Health and Beauty, Shu-Zen College of Medicine and Management, Kaohsiung, Taiwan

2 Psychiatric Department of Taipei Veterans General Hospital, Taipei, Taiwan

3 Psychiatric Division, School of Medicine, National Yang-Ming University, Taipei, Taiwan

4 Department of Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan

5 Department of Neurology, Cognition and Aging Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan

Correspondence to:

Chiung-Chih Chang, email:

Keywords: Alzheimer’s disease, genetic dosage effect, anatomical structural covariance, default mode network, brain-derived neurotrophic factor, Gerotarget

Received: June 10, 2016 Accepted: July 22, 2016 Published: August 02, 2016


In humans, brain-derived neurotrophic factor (BDNF) has been shown to play a pivotal role in neurocognition, and its gene contains a functional polymorphism (Val66Met) that may explain individual differences in brain volume and memory-related activity.

In this study, we enrolled 186 Alzheimer’s disease (AD) patients who underwent 3D T1 magnetic resonance imaging, and explored the gray matter (GM) structural covariance networks (SCN). The patients were divided into three groups according to their genotype: Met/Met (n = 45), Val/Met (n = 86) and Val/Val (n = 55). Seed-based analysis was performed focusing on four SCN networks. Neurobehavioral scores served as the major outcome factor.

Only peak cluster volumes of default mode medial temporal lobe network showed significant genotype interactions, of which the interconnected peak clusters showed dose-dependent genotype effects. There were also significant correlations between the cognitive test scores and interconnected-cluster volumes, especially in the orbitofrontal cortex.

These findings support the hypothesis that BDNF rs6265 polymorphisms modulate entorhinal cortex-interconnected clusters and the valine allele was associated with stronger structural covariance patterns that determined the cognitive outcomes.

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