Research Service, VA Boston Healthcare System, Boston, MA, USA.
Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA.
Mol Psychiatry. 2019 Mar;24(3):421-430. doi: 10.1038/s41380-018-0030-8. Epub 2018 Feb 27.
Early identification of younger, non-demented adults at elevated risk for Alzheimer's disease (AD) is crucial because the pathological process begins decades before dementia onset. Toward that end, we showed that an AD polygenic risk score (PRS) could identify mild cognitive impairment (MCI) in adults who were only in their 50s. Participants were 1176 white, non-Hispanic community-dwelling men of European ancestry in the Vietnam Era Twin Study of Aging (VETSA): 7% with amnestic MCI (aMCI); 4% with non-amnestic MCI (naMCI). Mean age was 56 years, with 89% <60 years old. Diagnosis was based on the Jak-Bondi actuarial/neuropsychological approach. We tested six P-value thresholds (0.05-0.50) for single nucleotide polymorphisms included in the ADPRS. After controlling for non-independence of twins and non-MCI factors that can affect cognition, higher PRSs were associated with significantly greater odds of having aMCI than being cognitively normal (odds ratios (ORs) = 1.36-1.43 for thresholds P < 0.20-0.50). The highest OR for the upper vs. lower quartile of the ADPRS distribution was 3.22. ORs remained significant after accounting for APOE-related SNPs from the ADPRS or directly genotyped APOE. Diabetes was associated with significantly increased odds of having naMCI (ORs = 3.10-3.41 for thresholds P < 0.05-0.50), consistent with naMCI having more vascular/inflammation components than aMCI. Analysis of sensitivity, specificity, and negative and positive predictive values supported some potential of ADPRSs for selecting participants in clinical trials aimed at early intervention. With participants 15+ years younger than most MCI samples, these findings are promising with regard to efforts to more effectively treat or slow AD progression.
早期识别处于阿尔茨海默病（AD）高发风险的年轻、非痴呆成年人至关重要，因为病理过程在痴呆症发病前几十年就开始了。为此，我们表明 AD 多基因风险评分（PRS）可以识别仅 50 多岁的轻度认知障碍（MCI）成年人。参与者是越南时代双胞胎衰老研究（VETSA）中的 1176 名白种非西班牙裔社区居住的欧洲裔男性：7%有遗忘性 MCI（aMCI）；4%有无遗忘性 MCI（naMCI）。平均年龄为 56 岁，89%<60 岁。诊断基于 Jak-Bondi 精算/神经心理学方法。我们测试了包含在 ADPRS 中的六个单核苷酸多态性的 P 值阈值（0.05-0.50）。在控制双胞胎的非独立性和可能影响认知的非 MCI 因素后，较高的 PRS 与患有 aMCI 的可能性显著高于认知正常的可能性相关（阈值 P<0.20-0.50 时的优势比（OR）为 1.36-1.43）。ADPRS 分布的上四分位数与下四分位数的最高 OR 为 3.22。在考虑 ADPRS 中与 APOE 相关的 SNP 或直接基因分型 APOE 后，OR 仍然显著。糖尿病与患有 naMCI 的可能性显著增加相关（阈值 P<0.05-0.50 时的 OR 为 3.10-3.41），这与 naMCI 比 aMCI 具有更多的血管/炎症成分一致。敏感性、特异性以及阴性和阳性预测值的分析支持 ADPRS 用于选择临床试验中早期干预的参与者的一些潜力。由于参与者比大多数 MCI 样本年轻 15 岁以上，因此这些发现对于更有效地治疗或减缓 AD 进展的努力是有希望的。
