Department of Neurology, Mayo Clinic-Minnesota, Rochester, MN, USA.
Department of Quantitative Health Sciences, Mayo Clinic-Florida, Jacksonville, FL, USA.
J Alzheimers Dis. 2022;88(4):1615-1625. doi: 10.3233/JAD-220164.
Brain accumulation of amyloid-β is a hallmark event in Alzheimer's disease (AD) whose underlying mechanisms are incompletely understood. Case-control genome-wide association studies have implicated numerous genetic variants in risk of clinically diagnosed AD dementia.
To test for associations between case-control AD risk variants and amyloid PET burden in older adults, and to assess whether a polygenic measure encompassing these factors would account for a large proportion of the unexplained variance in amyloid PET levels in the wider population.
We analyzed data from the Mayo Clinic Study of Aging (MCSA) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Global cortical amyloid PET burden was the primary outcome. The 38 gene variants from Wightman et al. (2021) were analyzed as predictors, with PRSice-2 used to assess the collective phenotypic variance explained.
Known AD risk variants in APOE, PICALM, CR1, and CLU were associated with amyloid PET levels. In aggregate, the AD risk variants were strongly associated with amyloid PET levels in the MCSA (p = 1.51×10-50) and ADNI (p = 3.21×10-64). However, in both cohorts the non-APOE variants uniquely contributed only modestly (MCSA = 2.1%, ADNI = 4.4%) to explaining variation in amyloid PET levels.
Additional case-control AD risk variants added only modestly to APOE in accounting for individual variation in amyloid PET burden, results which were consistent across independent cohorts with distinct recruitment strategies and subject characteristics. Our findings suggest that advancing precision medicine for dementia may require integration of strategies complementing case-control approaches, including biomarker-specific genetic associations, gene-by-environment interactions, and markers of disease progression and heterogeneity.
脑内淀粉样蛋白-β的积累是阿尔茨海默病（AD）的一个标志性事件，其潜在机制尚不完全清楚。病例对照全基因组关联研究表明，许多遗传变异与临床诊断为 AD 痴呆的风险有关。
检测病例对照 AD 风险变异与老年人群中淀粉样蛋白 PET 负荷之间的关联，并评估是否可以用包含这些因素的多基因指标来解释更广泛人群中淀粉样蛋白 PET 水平未被解释的大部分变异性。
我们分析了梅奥诊所衰老研究（MCSA）和阿尔茨海默病神经影像学倡议（ADNI）的数据。 全局皮质淀粉样蛋白 PET 负荷是主要结果。 分析了 Wightman 等人的 38 个基因变异作为预测因子，并用 PRSice-2 来评估综合表型变异的解释程度。
APOE、PICALM、CR1 和 CLU 中的已知 AD 风险变异与淀粉样蛋白 PET 水平相关。 总体而言，AD 风险变异与 MCSA（p = 1.51×10-50）和 ADNI（p = 3.21×10-64）中的淀粉样蛋白 PET 水平呈强烈相关。 然而，在两个队列中，非 APOE 变异体仅能适度地（MCSA = 2.1%，ADNI = 4.4%）解释淀粉样蛋白 PET 水平的变异性。
在解释淀粉样蛋白 PET 负荷的个体差异方面，除了 APOE 外，额外的病例对照 AD 风险变异仅略有增加，这一结果在具有不同招募策略和受试者特征的独立队列中是一致的。 我们的研究结果表明，为痴呆症推进精准医学可能需要整合补充病例对照方法的策略，包括生物标志物特异性遗传关联、基因-环境相互作用以及疾病进展和异质性的标志物。
