Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.
Medical college, Qingdao University, Qingdao, China.
J Alzheimers Dis. 2023;96(4):1651-1661. doi: 10.3233/JAD-230516.
APOE ɛ4 and PICALM are established genes associated with risk of late-onset Alzheimer's disease (AD). Previous study indicated interaction of PICALM with APOE ɛ4 in AD patients.
To explore whether PICALM variation could moderate the influences of APOE ɛ4 on AD pathology biomarkers and cognition in pre-dementia stage.
A total of 1,034 non-demented participants (mean age 74 years, 56% females, 40% APOE ɛ4 carriers) were genotyped for PICALM rs3851179 and APOE ɛ4 at baseline and were followed for influences on changes of cognition and cerebrospinal fluid (CSF) AD markers in six years. The interaction effects were examined via regression models adjusting for age, gender, education, and cognitive diagnosis.
The interaction term of rs3851179×APOE ɛ4 accounted for a significant amount of variance in baseline general cognition (p = 0.039) and memory function (p = 0.002). The relationships of APOE ɛ4 with trajectory of CSF Aβ42 (p = 0.007), CSF P-tau181 (p = 0.003), CSF T-tau (p = 0.001), and memory function (p = 0.017) were also moderated by rs3851179 variation.
APOE ɛ4 carriers experienced slower clinical and pathological progression when they had more protective A alleles of PICALM rs3851179. These findings firstly revealed the gene-gene interactive effects of PICALM with APOE ɛ4 in pre-dementia stage.
APOEɛ4 和 PICALM 是与迟发性阿尔茨海默病（AD）风险相关的既定基因。先前的研究表明 PICALM 与 AD 患者中的 APOEɛ4 存在相互作用。
探索 PICALM 变异是否可以调节 APOEɛ4 对痴呆前阶段 AD 病理生物标志物和认知的影响。
共有 1034 名非痴呆参与者（平均年龄 74 岁，56%为女性，40%为 APOEɛ4 携带者）在基线时进行了 PICALM rs3851179 和 APOEɛ4 的基因分型，并在 6 年内观察认知和脑脊液（CSF）AD 标志物变化的影响。通过调整年龄、性别、教育和认知诊断的回归模型来检验交互作用效应。
rs3851179×APOEɛ4 的交互项占基线一般认知（p=0.039）和记忆功能（p=0.002）的显著方差。APOEɛ4 与 CSF Aβ42（p=0.007）、CSF P-tau181（p=0.003）、CSF T-tau（p=0.001）和记忆功能（p=0.017）轨迹的关系也受到 rs3851179 变异的调节。
APOEɛ4 携带者携带更多保护性 PICALM rs3851179 的 A 等位基因时，经历更慢的临床和病理进展。这些发现首次揭示了痴呆前阶段 PICALM 与 APOEɛ4 的基因-基因相互作用。
