Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada.
Department of Psychology, University of Alberta, Edmonton, Canada.
J Alzheimers Dis. 2018;62(2):887-900. doi: 10.3233/JAD-170909.
Trajectories of complex neurocognitive phenotypes in preclinical aging may be produced differentially through selective and interactive combinations of genetic risk.
We organize three possible combinations into a "network" of genetic risk indices derived from polymorphisms associated with normal and impaired cognitive aging, as well as Alzheimer's disease (AD). Specifically, we assemble and examine three genetic clusters relevant to non-demented cognitive trajectories: 1) Apolipoprotein E (APOE), 2) a Cognitive Aging Genetic Risk Score (CA-GRS; Catechol-O-methyltransferase + Brain-derived neurotrophic factor), and 3) an AD-Genetic Risk Score (AD-GRS; Clusterin + Complement receptor 1 + Phosphatidylinositol-binding clathrin assembly protein).
We use an accelerated longitudinal design (n = 634; age range = 55-95 years) to test whether AD-GRS (low versus high) moderates the effect of increasing CA-GRS risk on executive function (EF) performance and change as stratified by APOE status (ɛ4+ versus ɛ4-).
APOEɛ4 carriers with high AD-GRS had poorer EF performance at the centering age (75 years) and steeper 9-year decline with increasing CA-GRS but this association was not present in APOEɛ4 carriers with low AD-GRS.
APOEɛ4 carriers with high AD-GRS are at elevated risk of cognitive decline when they also possess higher CA-GRS risk. Genetic risk from both common cognitive aging and AD-related indices may interact in intensification networks to differentially predict (1) level and trajectories of EF decline and (2) potential selective vulnerability for transitions into impairment and dementia.
在临床前衰老中，复杂神经认知表型的轨迹可能通过遗传风险的选择性和交互组合产生差异。
我们将三种可能的组合组织成一个源自与正常和受损认知衰老以及阿尔茨海默病（AD）相关的多态性的遗传风险指数的“网络”。具体来说，我们组装并检查了三个与非痴呆认知轨迹相关的遗传簇：1）载脂蛋白 E（APOE），2）认知衰老遗传风险评分（CA-GRS；儿茶酚-O-甲基转移酶+脑源性神经营养因子），以及 3）AD-遗传风险评分（AD-GRS；载脂蛋白 H+补体受体 1+磷脂结合网格蛋白组装蛋白）。
我们使用加速纵向设计（n=634；年龄范围=55-95 岁）来测试 AD-GRS（低与高）是否调节 CA-GRS 风险增加对执行功能（EF）表现和变化的影响，这些变化按 APOE 状态（ɛ4+与 ɛ4-）分层。
具有高 AD-GRS 的 APOEɛ4 携带者在中心化年龄（75 岁）时具有较差的 EF 表现，并且随着 CA-GRS 的增加，9 年的下降幅度更大，但在具有低 AD-GRS 的 APOEɛ4 携带者中不存在这种关联。
当 APOEɛ4 携带者具有高 AD-GRS 并且还具有更高的 CA-GRS 风险时，他们患认知衰退的风险更高。来自常见认知衰老和 AD 相关指标的遗传风险可能通过相互作用的强化网络，以不同的方式预测（1）EF 下降的水平和轨迹，以及（2）潜在的选择性脆弱性，用于向损伤和痴呆过渡。
