Systemic changes in multiple diseases may influence the onset of dementia. However, the specific temporality between exposure diseases and dementia remains uncertain.

By characterising the full spectrum of temporal disease trajectories before dementia, this study aims to yield a global picture of precursor diseases to dementia and to provide detailed instructions for risk management and primary prevention of dementia.

Using the multicentre, community-based prospective UK Biobank, we constructed disease trajectories before dementia utilising the phenome-wide association analysis, paired directional test and association quantification. Stratified disease trajectories were constructed by dementia subtypes, gender, age of diagnosis and Apolipoprotein E (ApoE) status, respectively.

Our study population comprised 434 266 participants without baseline dementia and 4638 individuals with all-cause dementia. In total, 1253 diseases were extracted as potential components of the disease trajectory before dementia. We identified three clusters of disease trajectories preceding all-cause dementia, initiated by circulatory, metabolic and respiratory diseases occurring approximately 5–15 years before dementia. Cerebral infarction or chronic renal failure following chronic ischaemic heart disease was the specific trajectory before vascular dementia. Apolipoprotein E (ApoE) ε4 non-carriers exhibited more complex trajectories compared with carriers. Lipid metabolism disorders remained in the trajectories regardless of dementia subtypes, gender, age of diagnosis and ApoE status.

This study provides a comprehensive view of the longitudinal disease trajectories before dementia and highlights the potential targets of midlife cardiometabolic dysfunction for dementia screening and prevention.

多种疾病的全身性变化可能影响痴呆的发作。然而，暴露疾病和痴呆之间的特定时间性仍然不确定。

通过描述痴呆前颞部疾病轨迹的全部谱系，本研究旨在产生痴呆前体疾病的全球图片，并为痴呆的风险管理和一级预防提供详细说明。

使用多中心、基于社区的前瞻性英国生物样本库，我们利用表型组范围的关联分析、配对方向测试和关联量化构建了痴呆前的疾病轨迹。分层疾病轨迹分别由痴呆亚型、性别、诊断年龄和载脂蛋白 E （ApoE） 状态构建。

我们的研究人群包括 434 266 名没有基线痴呆的参与者和 4638 名患有全因痴呆的个体。总共提取了 1253 种疾病作为痴呆前疾病轨迹的潜在组成部分。我们确定了全因痴呆之前的三组疾病轨迹，由痴呆前约 5-15 年发生的循环、代谢和呼吸系统疾病引发。慢性缺血性心脏病后的脑梗死或慢性肾功能衰竭是血管性痴呆之前的特定轨迹。与携带者相比，载脂蛋白 E （ApoE） ε4 非携带者表现出更复杂的轨迹。脂质代谢紊乱保持在轨迹中，无论痴呆亚型、性别、诊断年龄和 ApoE 状态如何。

本研究全面介绍了痴呆前的纵向疾病轨迹，并强调了中年心脏代谢功能障碍对痴呆筛查和预防的潜在目标。