Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer's disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin).We performed a multi-cohort case-control association study of the BDNF,DBH, and SORT1 loci comprising 5,682 controls and 2,454ADpatients from Northern Europe(87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; OR= 1.1-1.2, p = 0.005-0.3), an effect size that was consistent in the Northern European (OR = 1.1-1.2, p = 0.002-0.8) but not the smaller Spanish (OR = 0.8-1.6, p = 0.4-1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SF = 1.3-1.5 p = 0.002-0.02) translated to a greater risk of AD associated with BDNF in women (OR = 1.2-1.3, p = 0.007-0.00008) than men (OR = 0.9-1.0, p = 0.3-0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (OR = 1.1, p = 0.04) the synergistic interaction (SF = 2.2, p = 0.007) betweenBDNF(rs6265) andDBH(rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SF = 2.4, p = 0.04) than men (SF = 2.0, p = 0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women.
Alzheimer’s Research UK and Alzheimer’s Society and is supported by BRACE (Bristol Research into Alzheimer’s and Care of the Elderly) and the Medical Research Council. This research benefitted from funding awarded to the NIHR Great Ormond Street Hospital Biomedical Research Centre. OB, P S-J and ER were supported by grants from, IDIVAL, Instituto de Salud Carlos III (Fondo de Investigación Sanitario) and European Funds for Regional Development (FEDER); PI15/00058, CP13/00091, PI08/0139, PI12/02288, PI16/01652, PI13/01008), JPND (DEMTEST PI11/03028 and the CIBERNED program. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE1 and 2), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012)