A Pathway-Specific Polygenic Risk Score Is Associated with Tau Pathology and Cognitive Decline
A Pathway-Specific Polygenic Risk Score Is Associated with Tau Pathology and Cognitive Decline
复制标题
通路特异性多基因风险评分与 Tau 病理学和认知能力下降相关
DOI：
10.3233/jad-215163
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发表时间：
2022-01-01
影响因子：
4
通讯作者：
Liu，Bing
中科院分区：
文献类型：
--
作者：
Sun，Yuqing;Wang，Meng;Liu，Bing
背景
Tauopathy是阿尔茨海默病的主要神经病理学标志，与认知障碍有很强的关系。在脑中，tau聚集与tau激酶的调节和tau与微管的结合能力相关。
目的
探索使用特定多基因风险评分（PRS）的可能性，结合涉及tau蛋白激酶和tau蛋白结合途径的遗传影响，作为非痴呆个体中tau病理学和认知能力下降的预测因子。
方法
我们计算了一个特定的路径PRS使用汇总统计从以前的大规模全基因组关联研究痴呆症。我们研究了PRS是否与正电子发射断层扫描（PET）中的tau摄取、tau水平和脑脊液（CSF）中tau水平变化率相关。我们进一步评估了PRS是否与CSF tau水平介导的记忆障碍相关。
结果
较高的PRS与基线时CSF tau水平和tau-PET摄取升高以及CSF tau水平变化率较高相关。此外，PRS与记忆障碍相关，由CSF tau水平升高介导。当排除APOE时，PRS和tau病理学之间的关联是显著的，即使在女性中也是如此。然而，PRS对认知能力下降的影响似乎是由APOE的加入所驱动的。
结论
特定tau相关生物学途径中遗传风险的影响可能使个体更容易受到tau病理学的影响，导致疾病早期临床前阶段的认知功能障碍。
BACKGROUND
Tauopathy is a primary neuropathological hallmark of Alzheimer's disease with a strong relationship to cognitive impairment. In the brain, tau aggregation is associated with the regulation of tau kinases and the binding ability of tau to microtubules.
OBJECTIVE
To explore the potential for using specific polygenic risk scores (PRSs), combining the genetic influences involved in tau-protein kinases and the tau-protein binding pathway, as predictors of tau pathology and cognitive decline in non-demented individuals.
METHODS
We computed a pathway-specific PRS using summary statistics from previous large-scale genome-wide association studies of dementia. We examined whether PRS is related to tau uptake in positron emission tomography (PET), tau levels, and the rate of tau level changes in cerebrospinal fluid (CSF). We further assessed whether PRS is associated with memory impairment mediated by CSF tau levels.
RESULTS
A higher PRS was related to elevated CSF tau levels and tau-PET uptake at baseline, as well as greater rates of change in CSF tau levels. Moreover, PRS was associated with memory impairment, mediated by increased CSF tau levels. The association between PRS and tau pathology was significant when APOE was excluded, even among females. However, the effect of PRS on cognitive decline appeared to be driven by the inclusion of APOE.
CONCLUSION
The influence of genetic risk in a specific tau-related biological pathway may make an individual more susceptible to tau pathology, resulting in cognitive dysfunction in an early preclinical phase of the disease.