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

Abstract

Introduction: We 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.

Methods: Participants 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).

Results: In 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.

Conclusions: In 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).

Keywords: Alzheimer's disease; SNAP-25; amyloid-beta; cognition; genetics; neuroimaging; neuropsychology; sex differences; temporal lobe; verbal memory.

FIGURE 1

Female-specific association of SNAP-25 rs1051312 genotype with verbal memory (A) and language (B) in the discovery cohort. Note: For illustrative purposes, verbal memory and language z-scores were regressed against model covariates (age, education, $APOE-\epsilon 4$) and plotted by SNAP-25 genotype and sex. Error bars represent 95% confidence intervals. Cohen’s $d$ estimates reflect C-carrier versus T/T differences. **p < 0.01; *p < 0.05.

FIGURE 2

Rates of $\text{A}\beta -PET$ positivity were lowest in female SNAP-25 rs1051312 C-carriers. Note: Error bars represent 95% confidence intervals. Odds ratios were derived from logistic regression adjusting for age and $APOE-\epsilon 4$. Reference group is C-carriers.

FIGURE 3

AD meta-ROI volumes were larger and selectively associated with verbal memory performances in female SNAP-25 rs1051312 C-carriers. Note: (A) For illustrative purposes, AD meta-ROI volumes were regressed against model covariates (age, education, $APOE-\epsilon 4$, intracranial volume) and standardized prior to plotting. Bars represent mean and 95% confidence intervals and Cohen’s $d$ estimates reflect C-carrier versus T/T differences. *p < 0.05. (B) Sex-dependent associations between SNAP-25 genotype and individual components of the AD meta-ROI. Lines represent Cohen’s $d$ estimates with 95% confidence intervals. (C) Fitted slopes represent the relationship between AD meta-ROI volumes and predicted verbal memory z-scores, adjusted for model covariates (age, education, $APOE-\epsilon 4$, intracranial volume), across sex and SNAP-25 group. AD, Alzheimer’s disease; ROI, region of interest.

FIGURE 4

Sex differences stratified by SNAP-25 (A), and SNAP-25 differences stratified by sex (B), in verbal memory were replicated across cohorts. Note: Point estimates represent Cohen’s $d$ effect sizes and error bars represent 95% confidence intervals. Error bars that do not cross Cohen’s $d\hspace{0.17em}=\hspace{0.17em}0.0$ (dotted line) were statistically significant.