Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, WI, USA.
J Alzheimers Dis. 2023;94(4):1587-1605. doi: 10.3233/JAD-230097.
Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan.
In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways.
PRS and p-PRSs with and without APOE were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample.
We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-β, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded.
In addition to APOE, the p-PRSs can predict age-dependent changes in amyloid-β, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-β and tau, long before the onset of clinical symptoms.
与临床前认知能力下降和生物标志物变化相关的迟发性阿尔茨海默病（LOAD）的遗传评分。与总体多基因风险评分（PRS）相比，预测特定生物标志物或认知成分的特定途径PRS（p-PRS）可能更适合在寿命早期预测 LOAD 病理学。
在这项研究中，我们利用了威斯康星州阿尔茨海默病预防登记处的纵向数据，并探索了在六个生物学途径的各个年龄点上认知和生物标志物的变化模式。
分别根据最近的全基因组关联研究荟萃分析中与 LOAD 相关的显著 SNP 构建了 PRS 和 p-PRS，并与 APOE 单独进行比较。我们使用线性混合效应模型来评估 PRS/p-PRS 与 1175 名个体认知轨迹之间的关联。我们还将该模型应用于脑脊液生物标志物的结果子集。在独立样本中进行了复制分析。
我们发现 p-PRS 和总体 PRS 可以预测认知和生物标志物的临床前变化。PRS/p-PRS 对认知、淀粉样蛋白-β和 tau 结果变化率的影响取决于年龄，并且当 APOE 包含在这些风险评分中时，与排除 APOE 时相比，它们在寿命早期出现。
除了 APOE 之外，p-PRS 还可以预测淀粉样蛋白-β、tau 和认知的年龄依赖性变化。一旦得到验证，它们可以用于识别具有淀粉样蛋白-β和 tau 积累遗传风险升高的个体，远早于临床症状出现之前。
