Alzheimer’s Disease (AD) is a complex polygenic neurodegenerative disorder. Its genetic risk’s relationship with all-cause dementia may be influenced by the plasma proteome. Up to 40,139 UK Biobank participants aged ≥ 50y at baseline assessment (2006–2010) were followed-up for ≤ 15 y for dementia incidence. Plasma proteomics were performed on a sub-sample of UK Biobank participants (k = 1,463 plasma proteins). AD polygenic risk scores (PRS) were used as the primary exposure and Cox proportional hazards models were conducted to examine the AD PRS-dementia relationship. A four-way decomposition model then partitioned the total effect (TE) of AD PRS on dementia into an effect due to mediation only, an effect due to interaction only, neither or both. The study found that AD PRS tertiles significantly increased the risk for all-cause dementia, particularly among women. The study specifically found that AD PRS was associated with a 79% higher risk for all-cause dementia for each unit increase (HR = 1.79, 95% CI: 1.70–1.87, P < 0.001). Eighty-six plasma proteins were significantly predicted by AD PRS, including a positive association with PLA2G7, BRK1, the glial acidic fibrillary protein (GFAP), neurofilament light chain (NfL), and negative with TREM2. Both GFAP and NfL significantly interacted synergistically with AD PRS to increase all-dementia risk (> 10% of TE is pure interaction), while GFAP was also an important consistent mediator in the AD PRS-dementia relationship. In summary, we detected significant interactions of NfL and GFAP with AD PRS, in relation to dementia incidence, suggesting potential for personalized dementia prevention and management.

阿尔茨海默病 （AD） 是一种复杂的多基因神经退行性疾病。其遗传风险与全因痴呆的关系可能受到血浆蛋白质组的影响。多达 40,139 名在基线评估 （2006-2010） 时年龄≥ 50 岁的英国生物样本库参与者被随访≤ 15 年的痴呆发生率。对英国生物样本库参与者的子样本（k = 1,463 个血浆蛋白）进行血浆蛋白质组学研究。使用 AD 多基因风险评分 （PRS） 作为主要暴露，并进行 Cox 比例风险模型以检查 AD PRS 与痴呆的关系。然后，四向分解模型将AD PRS对痴呆的总效应（TE）划分为仅由于中介的影响，仅由于相互作用的影响，两者都不是或两者兼而有之。研究发现，AD PRS 三分位数显着增加了全因痴呆的风险，尤其是在女性中。该研究特别发现，AD PRS 与每增加一个单位，全因痴呆的风险增加 79% 相关 （HR = 1.79,95% CI： 1.70-1.87，P < 0.001）。 AD PRS 显著预测 86 种血浆蛋白，包括与 PLA2G7 、 BRK1 、神经胶质酸性纤维蛋白 （GFAP） 、神经丝轻链 （NfL） 呈正相关，与 TREM2 呈负相关。GFAP 和 NfL 均与 AD PRS 显著协同作用，以增加全痴呆风险 （> 10% 的 TE 是纯相互作用），而 GFAP 也是 AD PRS-痴呆关系中的重要一致介质。总之，我们检测到 NfL 和 GFAP 与 AD PRS 与痴呆发病率相关的显着相互作用，表明个性化痴呆预防和管理的潜力。