Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β= 0.146, p = 0.03). In the case of rare variants, TREM2 (β= 0.309, p = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.

译文

许多针对阿尔茨海默氏病 (AD) 的遗传学研究都集中在与AD风险相关的常见遗传变异的鉴定上,而不是该疾病的其他方面,例如发病年龄或痴呆进展速度。有多种方法可以解开这些表型的遗传结构。我们假设进展速度的遗传结构与发生AD痴呆的风险不同。为了验证这一假设,我们使用了来自ADNI和华盛顿大学Knight-ADRC的纵向临床数据,并基于IGAP研究计算了PRS (多基因风险评分),以比较AD风险和痴呆进展的遗传结构。通过每年临床痴呆评分总和 (CDR)-SB的变化来衡量痴呆的进展。在21个AD风险位点中,未发现与痴呆进展率相关。PRS率与痴呆进展率显著相关 (β =   0.146,p   =   0.03)。在罕见变异的情况下,TREM2 (β =   0.309,p   =   0.02) 也与痴呆的进展率相关。与非变异携带者相比,TREM2变异携带者的痴呆发生率23% 快。总之,我们的结果表明,最近发现的AD易感性的常见和罕见变异对AD患者痴呆进展率的影响有限。

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