Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Mol Psychiatry. 2023 Oct;28(10):4451-4462. doi: 10.1038/s41380-023-02170-4. Epub 2023 Sep 5.
The APOE 2/3/4 polymorphism is the greatest genetic risk factor for Alzheimer's disease (AD). This polymorphism is also associated with variation in plasma ApoE level; while APOE4 lowers, APOE2 increases ApoE level. Lower plasma ApoE level has also been suggested to be a risk factor for incident dementia. To our knowledge, no large genome-wide association study (GWAS) has been reported on plasma ApoE level. This study aimed to identify new genetic variants affecting plasma ApoE level as well as to test if baseline ApoE level is associated with cognitive function and incident dementia in a longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study. Baseline plasma ApoE concentration was measured in 3031 participants (95.4% European Americans (EAs)). GWAS analysis was performed on 2580 self-identified EAs where both genotype and plasma ApoE data were available. Lower ApoE concentration was associated with worse cognitive function, but not with incident dementia. As expected, the risk for AD increased from E2/2 through to E4/4 genotypes (P for trend = 4.8E-75). In addition to confirming the expected and opposite associations of APOE2 (P = 4.73E-79) and APOE4 (P = 8.73E-12) with ApoE level, GWAS analysis revealed nine additional independent signals in the APOE region, and together they explained about 22% of the variance in plasma ApoE level. We also identified seven new loci on chromosomes 1, 4, 5, 7, 11, 12 and 20 (P range = 5.49E-08 to 5.36E-10) that explained about 9% of the variance in ApoE level. Plasma ApoE level-associated independent variants, especially in the APOE region, were also associated with AD risk and amyloid deposition in the brain, indicating that genetically determined ApoE level variation may be a risk factor for developing AD. These results improve our understanding of the genetic determinants of plasma ApoE level and their potential value in affecting AD risk.
载脂蛋白 E（APOE）2/3/4 多态性是阿尔茨海默病（AD）最大的遗传风险因素。该多态性也与血浆 ApoE 水平的变化有关；APOE4 降低，APOE2 增加 ApoE 水平。较低的血浆 ApoE 水平也被认为是痴呆发生的危险因素。据我们所知，目前尚无关于血浆 ApoE 水平的大型全基因组关联研究（GWAS）报道。本研究旨在鉴定影响血浆 ApoE 水平的新遗传变异，并在银杏叶评估记忆（GEM）研究的纵向随访队列中测试基线 ApoE 水平与认知功能和痴呆发生的关系。在 3031 名参与者（95.4%为欧洲裔美国人（EAs））中测量了基线时的血浆 ApoE 浓度。在 2580 名自我认定的 EA 中进行了 GWAS 分析，这些人既有基因型又有血浆 ApoE 数据。较低的 ApoE 浓度与认知功能下降有关，但与痴呆发生无关。如预期的那样，AD 的风险从 E2/2 基因型逐渐增加到 E4/4 基因型（趋势 P 值=4.8E-75）。除了证实 APOE2（P=4.73E-79）和 APOE4（P=8.73E-12）与 ApoE 水平的预期和相反关联外，GWAS 分析还揭示了 APOE 区域内的另外 9 个独立信号，它们共同解释了血浆 ApoE 水平变异的约 22%。我们还在 1、4、5、7、11、12 和 20 号染色体上鉴定了 7 个新的位点（P 值范围为 5.49E-08 至 5.36E-10），这些位点解释了 ApoE 水平变异的约 9%。与血浆 ApoE 水平相关的独立变异，尤其是 APOE 区域内的独立变异，也与 AD 风险和大脑中的淀粉样蛋白沉积有关，这表明遗传决定的 ApoE 水平变化可能是 AD 发病的危险因素。这些结果提高了我们对血浆 ApoE 水平遗传决定因素的认识及其在影响 AD 风险方面的潜在价值。
