Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, California, USA.
Neurogenetics Program, Department of Neurology, University of California, Los Angeles, California, USA.
Alzheimers Dement. 2023 Aug;19(8):3448-3457. doi: 10.1002/alz.12989. Epub 2023 Feb 18.
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.
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).
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.
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.
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).
我们检测了编码参与海马体可塑性和记忆的突触前蛋白的 SNAP-25 基因变异与认知和阿尔茨海默病（AD）神经影像学结果在临床正常成年人中的性别相关性。
对参与者进行了 SNAP-25 rs1051312（T>C；SNAP-25 表达：C 等位基因>T/T）的基因分型。在发现队列（N=311）中，我们检测了 SNAP-25 变体与认知、Aβ-PET 阳性和颞叶体积的性别交互作用。认知模型在独立队列（N=82）中得到了复制。
在发现队列中，C 等位基因携带者在女性中表现出更好的言语记忆和语言能力、更低的 Aβ-PET 阳性率和更大的颞叶体积，而在男性中则没有。较大的颞叶体积与 C 携带者女性的言语记忆更好相关。女性特异性 C 等位基因言语记忆优势在复制队列中得到了证实。
在女性中，SNAP-25 基因的遗传变异与抵抗淀粉样斑块形成有关，并且可能通过加固颞叶结构来支持言语记忆。
SNAP-25 rs1051312（T>C）的 C 等位基因导致基础 SNAP-25 表达升高。C 等位基因携带者在临床正常女性中表现出更好的言语记忆，而在男性中则没有。女性 C 携带者的颞叶体积较大，这预测了言语记忆。女性 C 携带者也表现出最低的淀粉样β-PET 阳性率。SNAP-25 基因可能影响女性对阿尔茨海默病（AD）的特异性抵抗。
