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

Abstract

AbstractIntroductionWe 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, Aβ‐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 Aβ‐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.Highlights The 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).