Associations between ALOX5 and ALOX5AP Genetic Polymorphisms and Cognitive Performance in Patients with Alzheimer’s Dementia and Mild Cognitive Impairment

Abstract Background Leukotriene activity may contribute to cognitive deficits in Alzheimer’s disease (AD). Leukotrienes are synthesized by 5‐lipoxygenase (5‐LOX) and its activating protein (FLAP), encoded by ALOX5 and ALOX5AP , respectively. This cross‐sectional study investigated the associations of ALOX5 and ALOX5AP single nucleotide polymorphisms (SNPs) with cognitive performance in patients with AD or mild cognitive impairment (MCI). Method ALOX5 SNP rs2029253 and ALOX5AP SNPs rs10507391, rs12429692, rs4147064, rs9551963, rs9579646 were selected based on previous associations to ischemic stroke. Participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) diagnosed with AD or MCI at baseline were separated by genotype for each SNP. Rey Auditory Verbal Learning Test (RAVLT), Mini Mental State Exam (MMSE), and Trail Making Part B (TRAB) tests were selected to measure memory, overall cognitive status, and executive function, respectively. Associations between SNPs and white matter hyperintensities (WMH) were also explored. Additive, dominant, and recessive models were tested for each SNP and outcome pair. Linear regressions were used to assess associations between genotypes and outcomes controlling for age, sex, and education. Result rs12429692 TT homozygotes (MAF = 25.3%) had lower RAVLT learning (i.e. Trial 5 minus Trial 1) scores (F 1,508 = 7.19, p = 0.008, n = 513, recessive model). rs4147064 TC heterozygotes (MAF = 46.5%) had higher MMSE scores than TT homozygotes (F 2,508 = 3.34, p = 0.036, n = 514, additive model). rs9551963 CC homozygotes (MAF = 49.1%) had higher TRAB times (F 1,481 = 6.06 , p = 0.014, n = 486, recessive model). Split by sex, rs12429692 was associated with TRAB times in males (F 1,277 = 5.52 , p = 0.020, n = 281, dominant model) and rs9551963 was associated with RAVLT % forgetting scores in females (F 1,212 = 4.98 , p = 0.027, n = 216, recessive model). The rs12429692 A/T SNP (MAF = 25.4%) trended towards an association with WMH (F 1,507 = 3.33 , p = 0.069, n = 512, recessive model). Conclusion Three ALOX5AP SNPs were associated with aspects of cognitive performance. This preliminary clinical evidence suggests a possible effect of leukotriene synthesis on cognition in patients with AD or MCI.