Characterizing the Role of Brain Derived Neurotrophic Factor Genetic Variation in Alzheimer’s Disease Neurodegeneration

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.