There is an urgent need for identifying nondemented individuals at the highest risk of progressing to Alzheimer’s disease (AD) dementia. Here, we evaluated whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo cerebrospinal fluid (CSF) or positron emission tomography (PET) biomarkers of amyloid, and CSF tau pathology to prospectively predict cognitive and clinical decline in 347 cognitive normal (CN; baseline age range = 59.7–90.1, 98.85% white) and 599 mild cognitively impaired (MCI; baseline age range = 54.4–91.4, 98.83% white) individuals from the Alzheimer’s Disease Neuroimaging Initiative 1, GO, and 2. We further investigated the association of PHS with post-mortem amyloid load and neurofibrillary tangles in the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 485, age at death range = 71.3–108.3). In CN and MCI individuals, we found that amyloid and total tau positivity systematically varies as a function of PHS. For individuals in greater than the 50th percentile PHS, the positive predictive value for amyloid approached 100%; for individuals in less than the 25th percentile PHS, the negative predictive value for total tau approached 85%. High PHS individuals with amyloid and tau pathology showed the steepest longitudinal cognitive and clinical decline, even among APOE ε4 noncarriers. Among the CN subgroup, we similarly found that PHS was strongly associated with amyloid positivity and the combination of PHS and biomarker status significantly predicted longitudinal clinical progression. In the ROSMAP cohort, higher PHS was associated with higher post-mortem amyloid load and neurofibrillary tangles, even in APOE ε4 noncarriers. Together, our results show that even after accounting for APOE ε4 effects, PHS may be useful in MCI and preclinical AD therapeutic trials to enrich for biomarker-positive individuals at highest risk for short-term clinical progression.

迫切需要鉴定出罹患阿尔茨海默氏病（AD）痴呆症风险最高的非痴呆症患者。在这里，我们评估了最近验证的多基因危险评分（PHS）是否可以与淀粉样蛋白和CSF tau病理学的已知体内脑脊液（CSF）或正电子发射断层扫描（PET）生物标志物整合，以前瞻性预测347年的认知和临床下降阿尔茨海默氏病神经影像学计划1，GO和2的正常个体（CN；基线年龄范围= 59.7–90.1，98.85％白人）和599轻度认知障碍（MCI；基线年龄范围= 54.4–91.4，98.83％白人）我们在“宗教秩序研究和记忆与衰老项目（ROSMAP）”队列中进一步研究了PHS与验尸后淀粉样蛋白负荷和神经原纤维缠结的关系（N  = 485，死亡年龄= 71.3–108.3）。在CN和MCI个体中，我们发现淀粉样蛋白和总tau阳性系统性地随着PHS的变化而变化。对于PHS大于50％的个体，淀粉样蛋白的阳性预测值接近100％；对于PHS低于25％的个人，总tau的阴性预测值接近85％。患有淀粉样蛋白和tau病理学的高PHS个体即使在APOE中也表现出最严重的纵向认知和临床下降ε4个非载波。在CN亚组中，我们类似地发现PHS与淀粉样蛋白阳性密切相关，并且PHS和生物标记物状态的组合显着预测了纵向临床进展。在ROSMAP队列，高小灵通与较高的验尸淀粉样蛋白负荷和神经纤维缠结相关的，即便是在APOE ε4非携带者。总之，我们的结果表明，即使在考虑了后APOE ε4的影响，小灵通可能是有用的，MCI和临床前AD治疗试验在短期临床进展风险最高的丰富生物标志物阳性者。