Longitudinal Studies Section, National Institute on Aging, 251 Bayview Blvd M04B332, Baltimore, MD, 21224, USA.
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.
Geroscience. 2024 Oct;46(5):4883-4894. doi: 10.1007/s11357-024-01228-7. Epub 2024 Jun 3.
Experiencing decline in both cognition and mobility is associated with a substantially higher dementia risk than cognitive decline only. Metabolites associated with both cognitive and mobility declines may be early predictors of dementia and reveal specific pathways to dementia. We analyzed data from 2450 participants initially free of dementia who had 613 metabolites measured in plasma in 1998-1999 (mean age = 75.2 ± 2.9 years old, 37.8% Black, 50% women) from the Health, Aging and Body Composition study. Dementia diagnosis was determined by race-specific decline in 3MS scores, medication use, and hospital records through 2014. Cognition and mobility were repeatedly measured using 3MS and a 20-m walking test up to 10 years, respectively. We examined metabolite associations with changes in 3MS (n = 2046) and gait speed (n = 2019) using multivariable linear regression adjusted for age, sex, race, and baseline performance and examined metabolite associations with dementia risk using Cox regression. During a mean follow-up of 9.3 years, 534 (21.8%) participants developed dementia. On average, 3MS declined 0.47/year and gait declined 0.04 m/sec/year. After covariate adjustment, 75 metabolites were associated with cognitive decline, and 111 metabolites were associated with gait decline (FDR-adjusted p < 0.05). Twenty-six metabolites were associated with both cognitive and gait declines. Eighteen of 26 metabolites were associated with dementia risk (p < 0.05), notably amino acids, glycerophospholipids (lysoPCs, PCs, PEs), and sphingolipids. Results remained similar after adjusting for cardiovascular disease or apolipoprotein E ɛ4 carrier status. During aging, metabolomic profiles of cognitive decline and mobility decline show distinct and shared signatures. Shared metabolomic profiles suggest that inflammation and deficits in mitochondria and the urea cycle in addition to the central nervous system may play key roles in both cognitive and mobility declines and predict dementia. Future studies are warranted to investigate longitudinal metabolite changes and metabolomic markers with dementia pathologies.
认知和行动能力下降均与痴呆风险显著升高相关，这一风险高于单纯认知下降。与认知和行动能力下降均相关的代谢物可能是痴呆的早期预测指标，并揭示了通向痴呆的特定途径。我们分析了来自健康、衰老和身体成分研究（Health, Aging and Body Composition study）的 2450 名最初无痴呆症且在 1998-1999 年血浆中测量了 613 种代谢物的参与者的数据（平均年龄 75.2 ± 2.9 岁，37.8%为黑人，50%为女性）。痴呆症的诊断是根据 3MS 评分的种族特异性下降、药物使用和 2014 年之前的医院记录确定的。认知和行动能力分别使用 3MS 和 20 米步行测试在 10 年内重复测量。我们使用多变量线性回归检查了代谢物与 3MS 变化（n=2046）和步态速度变化（n=2019）之间的关联，该回归模型调整了年龄、性别、种族以及基线表现。我们使用 Cox 回归检查了代谢物与痴呆症风险之间的关联。在平均 9.3 年的随访期间，534 名（21.8%）参与者患上了痴呆症。平均而言，3MS 每年下降 0.47 分，步态每年下降 0.04 米/秒。经过协变量调整后，有 75 种代谢物与认知能力下降有关，111 种代谢物与步态下降有关（经 FDR 调整的 p < 0.05）。26 种代谢物与认知和步态下降均有关。26 种代谢物中有 18 种与痴呆症风险相关（p < 0.05），其中包括氨基酸、甘油磷脂（溶血磷脂酰胆碱、磷脂酰胆碱、磷脂酰乙醇胺）和神经酰胺。在调整心血管疾病或载脂蛋白 E ɛ4 携带者状态后，结果仍然相似。在衰老过程中，认知能力下降和行动能力下降的代谢组学特征表现出明显的和共同的特征。共同的代谢组学特征表明，炎症以及线粒体和尿素循环的缺陷，除了中枢神经系统以外，可能在认知和行动能力下降中发挥关键作用，并预测痴呆症。未来的研究需要调查纵向代谢物变化和具有痴呆病理的代谢组学标志物。
