Characterizing the role of brain derived neurotrophic factor genetic variation in Alzheimer's disease neurodegeneration.

Robyn A Honea,Jeffrey M Burns,Alison M Goate,Rodrigo D Perea,Andrew J Saykin,Carlos Cruchaga,Daniel R Weinberger,Stephen D Ginsberg

doi:10.1371/journal.pone.0076001

Abstract

There is accumulating evidence that neurotrophins, like brain-derived neurotrophic factor (BDNF), may impact aging and Alzheimer’s Disease. However, traditional genetic association studies have not found a clear relationship between BDNF and AD. Our goal was to test whether BDNF single nucleotide polymorphisms (SNPs) impact Alzheimer’s Disease-related brain imaging and cognitive markers of disease. We completed an imaging genetics study on 645 Alzheimer’s Disease Neuroimaging Initiative participants (ND=175, MCI=316, AD=154) who had cognitive, brain imaging, and genetics data at baseline and a subset of those with brain imaging data at two years. Samples were genotyped using the Illumina Human610-Quad BeadChip. 13 SNPs in BDNF were identified in the dataset following quality control measures (rs6265(Val66Met), rs12273363, rs11030094, rs925946, rs1050187, rs2203877, rs11030104, rs11030108, rs10835211, rs7934165, rs908867, rs1491850, rs1157459). We analyzed a subgroup of 8 SNPs that were in low linkage disequilibrium with each other. Automated brain morphometric measures were available through ADNI investigators, and we analyzed baseline cognitive scores, hippocampal and whole brain volumes, and rates of hippocampal and whole brain atrophy and rates of change in the ADAS-Cog over one and two years. Three out of eight BDNF SNPs analyzed were significantly associated with measures of cognitive decline (rs1157659, rs11030094, rs11030108). No SNPs were significantly associated with baseline brain volume measures, however six SNPs were significantly associated with hippocampal and/or whole brain atrophy over two years (rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850). We also found an interaction between the BDNF Val66Met SNP and age with whole brain volume. Our imaging-genetics analysis in a large dataset suggests that while BDNF genetic variation is not specifically associated with a diagnosis of AD, it appears to play a role in AD-related brain neurodegeneration.

Highlights

Alzheimer’s Disease (AD) is a neurodegenerative disorder that results in the increased production of amyloid-B peptide and Tau protein hyperphosphorylation, as well as the degeneration and death of neurons
ND subjects had the highest number of associations with imaging endophenotypes, genetic variation in rs6265 (p = .027) and rs10501087 (p = .048) was associated with percent of right hippocampal atrophy over two years, and variation in rs1157659 was associated with left hippocampal atrophy (p = .025)
Our imaging-genetics analysis in a large dataset suggests that brain-derived neurotrophic factor (BDNF) genetic variation may play a role in AD-related cognitive deficits as well as brain neurodegeneration

Summary

Introduction

Alzheimer’s Disease (AD) is a neurodegenerative disorder that results in the increased production of amyloid-B peptide and Tau protein hyperphosphorylation, as well as the degeneration and death of neurons. To further characterize complex genes associated with AD, a growing number of studies are using an intermediate phenotype approach, which utilizes biomarkers, such as structural brain imaging of hippocampal atrophy, as endpoints in genetic analyses of risk. Imaging genetics studies, which may be more sensitive traditional gene-association studies, have recently identified a role for the BDNF Val66Met SNP in hippocampal volume loss [12], memory impairments [13], reduced medial temporal lobe activity [14] and modified experience-dependent plasticity in the motor cortex [15] in healthy humans. Some studies have shown that variation in this Val66Met polymorphism may increase risk for Alzheimer’s Disease and impact cognitive performance [17,18]. Other functional SNPs in BDNF have been identified that may impact human brain function [23], demonstrating the importance of investigating multiple BDNF SNPs using an AD phenotype approach to clarify BDNF’s role in brain neurodegeneration

Objectives

Methods

Results

Conclusion