School of Medicine, Escuela Superior Politécnica de Chimborazo, Riobamba, Ecuador.
Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands.
Genes Brain Behav. 2020 Jul;19(6):e12656. doi: 10.1111/gbb.12656. Epub 2020 May 8.
It remains unclear whether the genetic risk for late-onset Alzheimer disease (AD) is linked to premorbid individual differences in general cognitive ability and brain structure. The objective of the present study was to determine whether the genetic risk of late-onset AD is related to premorbid individual differences in intelligence quotient (IQ) and characteristics of the cerebral white-matter in children. The study sample included children of the Generation R Study from Rotterdam, The Netherlands. IQ was measured using a well-validated Dutch nonverbal IQ test (n = 1908) at ages 5 to 9 years. White-matter microstructure was assessed by measuring fractional anisotropy (FA) of white-matter tracts using diffusion tensor imaging (DTI) (n = 919) at ages 9 to 12 years. Genetic risk was quantified using three biologically defined genetic risk scores (GRSs) hypothesized to be related to the pathophysiology of late-onset AD: immune response, cholesterol/lipid metabolism and endocytosis. Higher genetic risk for late-onset AD that included genes associated with immune responsivity had a negative influence on cognition and cerebral white-matter microstructure. For each unit increase in the immune response GRS, IQ decreased by 0.259 SD (95% CI [-0.500, -0.017]). For each unit increase in the immune response GRS, global FA decreased by 0.373 SD (95% CI [-0.721, -0.026]). Neither cholesterol/lipid metabolism nor endocytosis GRSs were associated with IQ or cerebral white-matter microstructure. Our findings suggest that elevated genetic risk for late-onset AD may in part be manifest during childhood neurodevelopment through alterations in immune responsivity.
目前尚不清楚晚发性阿尔茨海默病（AD）的遗传风险是否与发病前个体认知能力和大脑结构的差异有关。本研究的目的是确定晚发性 AD 的遗传风险是否与儿童发病前的智商（IQ）和大脑白质特征的个体差异有关。研究样本包括荷兰鹿特丹的 Generation R 研究的儿童。使用经过良好验证的荷兰非语言智商测试（n = 1908）在 5 至 9 岁时测量 IQ。使用弥散张量成像（DTI）在 9 至 12 岁时测量白质微观结构，通过测量白质束的分数各向异性（FA）来评估白质微观结构（n = 919）。使用三种假设与晚发性 AD 病理生理学相关的生物学定义的遗传风险评分（GRS）量化遗传风险：免疫反应、胆固醇/脂质代谢和内吞作用。与免疫反应相关的晚发性 AD 相关基因的遗传风险增加对认知和大脑白质微观结构有负面影响。免疫反应 GRS 每增加一个单位，智商就会降低 0.259 个标准差（95%CI[-0.500，-0.017]）。免疫反应 GRS 每增加一个单位，全脑 FA 就会降低 0.373 个标准差（95%CI[-0.721，-0.026]）。胆固醇/脂质代谢或内吞作用 GRS 均与 IQ 或大脑白质微观结构无关。我们的研究结果表明，晚发性 AD 的遗传风险增加可能部分通过免疫反应的改变在儿童神经发育过程中表现出来。
