Sex Differences in Risk for Alzheimer’s Disease Related to Neurotrophin Gene Polymorphisms: The Cache County Memory Study

Abstract Neurotrophins, including nerve-growth factor (NGF) and brain-derived neurotrophic factor (BDNF), have been implicated in Alzheimer's disease (AD). Associations between AD and neurotrophin signaling genes have been inconsistent, with few studies examining sex differences in risk. We examined four single-nucleotide polymorphisms (SNPs) involved in neurotrophin signaling (rs6265, rs56164415, rs2289656, rs2072446) and risk for AD by sex in a population-based sample of older adults. 3499 individuals without dementia at baseline [Mean (SD) age = 74.64 (6.84)], 58% female] underwent dementia screening and assessment over four triennial waves. Cox Regression was used to examine time to AD or right censoring for each SNP.Female carriers of the minor T allele for rs2072446 and rs56164415 had a 60% (HR = 1.60, 95% CI = 1.02-2.51) and 93% (HR = 1.93, 95% CI = 1.30-2.84) higher hazard for AD, respectively, than male non-carriers of the T allele. Furthermore, male carriers of the T allele of rs2072446 had a 61% lower hazard (HR = 0.39, 95% CI = 0.14-1.06) than male non-carriers at trend-level significance (p = 0.07). The association between certain neurotrophin gene polymorphisms and AD differs by sex and may explain inconsistent findings in the literature.