Assessing the effect of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on mRNA transcript levels, Alzheimer’s disease (AD) risk and cognitive performance (P2.163)

OBJECTIVE: To analyze the impact of the BDNF Val66Met variant on transcript levels, AD risk and cognitive function. BACKGROUND: Published meta-analyses show association of Val66Met with increased AD risk and cognitive decline. DESIGN/METHODS: The Val66Met variant was genotyped using a validated Taqman assay. Logistic or linear regression analyses with covariates were implemented in PLINK to test the correlation of the Val66Met genotypes with AD status in our Caucasian case-control series (2951 ADs, 4564 controls), and with gene expression levels from our published brain eGWAS (~200 AD and ~200 non-AD), as well as with baseline cognitive performance as measured by Logical Memory Delayed Recall score (MRLMD) from Mayo Clinic Study of Aging participants, respectively. RESULTS: We observed a suggestive trend of decreased cerebellar BDNF mRNA levels in the combined set of AD and non-ADs, and in non-ADs alone. There was no consistent trend in temporal cortex. We also observed a suggestive trend towards decreased AD risk (OR = 0.92, p = 0.098) in carriers. This trend is reversed in APOE- e4 homozygotes, matching previously published data (OR =1.54, p = 0.13; 372 cases vs . 62 controls). Diagnosis of AD occurs at a suggestively lower age in Val66Met carriers (β = -0.39, p = 0.21), a finding that reaches nominal significance in APOE -e4 homozygotes (β = -2.16, p = 0.01). We were unable to detect an association between Val66Met status and MRLMD, regardless of APOE genotype. CONCLUSIONS: Our results suggest that within the cerebellum, decreased BDNF mRNA transcript may be mediated through the Val66Met mutation. Effects of the polymorphism on AD risk appear to be dependent on APOE -e4 genotype, but age of AD onset appears to be earlier in carriers of the minor allele. We did not detect an association between Val66Met status and cognitive performance as measured by MRLMD. Disclosure: Dr. Burgess has nothing to disclose. Dr. Carrasquillo has nothing to disclose. Dr. Zou has nothing to disclose. Dr. Chai has nothing to disclose. Dr. Younkin has nothing to disclose. Dr. Allen has nothing to disclose. Dr. Serie has nothing to disclose. Dr. Crook has nothing to disclose. Dr. Pankratz has nothing to disclose. Dr. Nair has nothing to disclose. Dr. Middha has nothing to disclose. Dr. Maharjan has nothing to disclose. Dr. Nguyen has nothing to disclose. Dr. Malphrus has nothing to disclose. Dr. Lincoln has nothing to disclose. Dr. Bisceglio has nothing to disclose. Dr. Asmann has nothing to disclose. Dr. Pedraza has nothing to disclose. Dr. Roberts has nothing to disclose. Dr. Lucas has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Ivnik has nothing to disclose. Dr. Machulda has nothing to disclose. Dr. Graff-Radford has received personal compensation for activities with Codman and Cytox as a scientific advisory board member or a consultant. Dr. Graff-Radford has received royalty payments for UpToDate. Dr. Petersen has received personal compensation for activities with Pfizer Inc. and Janssen Alzheimer9s Immunotherapy. Dr. Dickson has nothing to disclose. Dr. Younkin has nothing to disclose. Dr. Taner has nothing to disclose.