Sex-specific effects of SNAP-25 genotype on verbal memory and Alzheimer's disease biomarkers in clinically normal older adults

IntroductionWe tested sex-dependent associations of variation in the SNAP-25 gene, which encodes a presynaptic protein involved in hippocampal plasticity and memory, on cognitive and Alzheimer's disease (AD) neuroimaging outcomes in clinically normal adults. MethodsParticipants were genotyped for SNAP-25 rs1051312 (T > C; SNAP-25 expression: C-allele > T/T). In a discovery cohort (N = 311), we tested the sex by SNAP-25 variant interaction on cognition, A beta-PET positivity, and temporal lobe volumes. Cognitive models were replicated in an independent cohort (N = 82). ResultsIn the discovery cohort, C-allele carriers exhibited better verbal memory and language, lower A beta-PET positivity rates, and larger temporal volumes than T/T homozygotes among females, but not males. Larger temporal volumes related to better verbal memory only in C-carrier females. The female-specific C-allele verbal memory advantage was evidenced in the replication cohort. ConclusionsIn females, genetic variation in SNAP-25 is associated with resistance to amyloid plaque formation and may support verbal memory through fortification of temporal lobe architecture. HighlightsThe SNAP-25 rs1051312 (T > C) C-allele results in higher basal SNAP-25 expression.C-allele carriers had better verbal memory in clinically normal women, but not men.Female C-carriers had higher temporal lobe volumes, which predicted verbal memory.Female C-carriers also exhibited the lowest rates of amyloid-beta PET positivity.The SNAP-25 gene may influence female-specific resistance to Alzheimer's disease (AD).