Brain‐derived neurotrophic factor genes are associated with neuropsychiatric symptom progression in dementia. The Cache county dementia progression study

Abstract

AbstractBackgroundPolymorphisms in genes coding for the neurotrophin, brain‐derived neurotrophic factor (BDNF) or its receptors, have been associated with Alzheimer’s disease and related disorders (ADRD), with sex‐dependent effects. Associations with neuropsychiatric symptom (NPS) progression after dementia onset has been largely unexplored. In a population‐based cohort, we examined the relationships between BDNF gene single‐nucleotide polymorphisms (SNPs) and NPS progression after dementia onset.Method880 participants [61.3% female; mean (SD) age = 82.0 (71) years] with dementia [68.2% AD; 13.5% Vascular Dementia (VaD); 18.3% other dementia (OD)] were assessed on the Neuropsychiatric Inventory (NPI) every six‐to‐18 months. Mean(SD) baseline dementia duration was 2.9(2.7) years. The following SNPs were examined as predictors of NPI scores over time in linear mixed‐effects models: rs6265 (BDNF G196A/Val66Met), rs56164415 (BDNF C270T), rs2289656 (NTRK2 receptor TrkB), and rs2072446 (NGFR p75NTR). Covariates included age of dementia onset, education, apolipoprotein E genotype, and dementia type and duration at baseline.ResultSex‐dependent effects were found for two SNPs. Compared to those with major alleles, males with the rs56164415 minor allele exhibited a lower initial Apathy score, that increased over time (C/t*sex*time2:b = ‐0.063, SE = 0.029, p = .033); by contrast, females showed no differences by SNP alleles. Females homozygous for the rs2289656 minor allele exhibited a rapid increase in Anxiety that decreased over time (t/t*sex*time2: b = ‐0.145, SE = 0.054, p = .0073). For both sexes, presence of minor alleles for BDNF polymorphisms rs6265 (G/a*time2: b = ‐0.017, SE = 0.004, p < .001; a/a*time2: b = ‐0.035, SE = 0.013, p = .006) and rs56164415 (C/t*time2: b = 0.019, SE = 0.005, p < .001) was associated with increased NPI Agitation/Aggression well after baseline. Rs6265 minor allele homozygotes (a/a*time2: b = ‐0.049, SE = 0.013, p < .001) and rs2072446 minor allele carriers (Ct/tt*time2: b = ‐0.012, SE = 0.005, p = .025) exhibited initial increases in Delusions, which diminished approximately 5 years thereafter.ConclusionSpecific BDNF genotypes were associated with NPS presentation after dementia onset, with some sex‐dependent effects. Future research on enhancing BDNF signaling may present possible targets for intervention.