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.

BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention

“…15,20,21 However, in one of these studies, the authors reported relationships between greater BDNF expression in the dorsolateral prefrontal cortex and slower cognitive decline. 21 Another group did not find associations with the polymorphism but noted that greater serum BDNF levels resulted in reduced dementia and AD incidence.…”

“…20 Finally, a third report did not find associations with the Val66Met polymorphism but did with other BDNF SNPs, specifically rs1157659, rs11030094, and rs11030108. 15 These discrepancies underscore the need for further understanding of the intricacies in the relationship between BDNF polymorphisms, BDNF expression, and cognitive function.…”

“…Carriage of 1 or 2 Met alleles is associated with lower BDNF production, 14 decreased hippocampal volume, 15 and cognitive decline. [16][17][18][19] However, null 20,21 and opposite findings 22,23 have been documented, making the relationship between BDNF and cognition in aging populations unclear.…”

Adult neurogenesis and neurodegenerative diseases: A systems biology perspective

“…BDNF polymorphism Val66Met modulates integration of neurons in vivo and regulates episodic memory and hippocampal physiological activation in humans [Egan et al, 2003; McDole et al, 2015]. Moreover, genetic variation in BDNF associated with hippocampal atrophy and cognitive decline have been identified using neuroimaging-genetics methods [Honea et al, 2013]. Pro-inflammatory cytokine IL-6 plays an important role in the formation of new neurons and glial cells from neural progenitor cells during adult neurogenesis, and IL-6 variations have been associated with AD, multiple sclerosis, and severe traumatic brain injury [Schmidt et al, 2003; He et al, 2010; Dalla Libera et al, 2011; Erta et al, 2012].…”

Cortisol and BDNF levels in depression within schizophrenia structure: approach to treating

“…Нейротрофический фак-тор мозга (BDNF) играет очень важную роль как в раз-витии, так и пластичности мозга. В настоящее время уровень BDNF рассматривают в качестве одного из базовых маркеров нейродегенерации [18,13], что ставит вопрос о возможном влиянии депрессии на течение шизофренического процесса. Изучение это-го вопроса не только имеет теоретическое значение, но и представляется важным с позиции обоснования подходов к терапии данной категории пациентов.…”