Alzheimer’s disease risk alleles of PICALM gene may accelerate cognitive (memory and attention) performance in middle‐aged healthy APOE‐ε4 carriers

Abstract Background The APOE (allele ε4) and PICALM (SNPs rs541458: allele T; and rs3851179: allele G) genes were recognized as risk factors for late‐onset Alzheimer’s disease (AD). However, effects of these risk genes on the cognitive functions of healthy individuals are still not determined and their possible interactions have never been studied. We investigated the preclinical influence of both genes on brain cognitive functions in a healthy middle‐aged population. Method Seventy three healthy adults (50‐63 y/o) completed computer tasks measuring attention, cognitive control and memory. MSIT task included an easy‐control condition and an attentionally demanding condition with combined cognitive conflicts. Sternberg’s task included an easy condition (there is a need to memorize 4 letters strings) and a hard‐one (with 8 letters strings). APOE (rs429358/rs7412) and PICALM (rs3851179 and rs541458) alleles were determined using a traditional Sanger sequencing protocol. The data was divided according to the genetic tests results (control group: absence of ε4 and less‐risky PICALM alleles; the double risk group: ε4‐carriers, and homozygous carriers of high‐risk PICALM alleles; single risk group: ε4‐carriers and less‐risky PICALM alleles). ANOVA was used to determine the effects of genetic variants on task performance (reaction time (RT) and accuracy for easy/hard MSIT and Sternberg conditions). Result Results revealed that while the groups did not differ in accuracy or RTs for easy conditions, they did differ significantly on hard conditions (p<0.05). The single‐risk group showed longer RTs than the control group in both tasks. The effect was preserved when performing the analysis of covariance (ANCOVA) with the age as a covariate. Conclusion AD risk genes, APOE and PICALM , can affect cognitive abilities even in healthy individuals. APOE ‐ε4‐carriers needed longer time to process difficult stimuli but surprisingly an addition of PICALM risk alleles seemed to reverse this tendency. Further studies are needed to unambiguously determine the effects of the PICALM and its interactions with other risk genes (including APOE ) in modulating the cognitive abilities of still healthy individuals. [Supported by National Science Centre, Poland, no. 2018/31/N/HS6/03551.]