Department of Epidemiology, Erasmus MC, University Medical Center, PO Box 2040, Rotterdam, CA, 3000, the Netherlands.
Section of Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
Alzheimers Res Ther. 2024 May 20;16(1):113. doi: 10.1186/s13195-024-01480-1.
The gut-derived metabolite Trimethylamine N-oxide (TMAO) and its precursors - betaine, carnitine, choline, and deoxycarnitine - have been associated with an increased risk of cardiovascular disease, but their relation to cognition, neuroimaging markers, and dementia remains uncertain.
In the population-based Rotterdam Study, we used multivariable regression models to study the associations between plasma TMAO, its precursors, and cognition in 3,143 participants. Subsequently, we examined their link to structural brain MRI markers in 2,047 participants, with a partial validation in the Leiden Longevity Study (n = 318). Among 2,517 participants, we assessed the risk of incident dementia using multivariable Cox proportional hazard models. Following this, we stratified the longitudinal associations by medication use and sex, after which we conducted a sensitivity analysis for individuals with impaired renal function.
Overall, plasma TMAO was not associated with cognition, neuroimaging markers or incident dementia. Instead, higher plasma choline was significantly associated with poor cognition (adjusted mean difference: -0.170 [95% confidence interval (CI) -0.297;-0.043]), brain atrophy and more markers of cerebral small vessel disease, such as white matter hyperintensity volume (0.237 [95% CI: 0.076;0.397]). By contrast, higher carnitine concurred with lower white matter hyperintensity volume (-0.177 [95% CI: -0.343;-0.010]). Only among individuals with impaired renal function, TMAO appeared to increase risk of dementia (hazard ratio (HR): 1.73 [95% CI: 1.16;2.60]). No notable differences were observed in stratified analyses.
Plasma choline, as opposed to TMAO, was found to be associated with cognitive decline, brain atrophy, and markers of cerebral small vessel disease. These findings illustrate the complexity of relationships between TMAO and its precursors, and emphasize the need for concurrent study to elucidate gut-brain mechanisms.
肠道衍生代谢物三甲胺 N-氧化物（TMAO）及其前体 - 甜菜碱、肉碱、胆碱和脱氧肉碱 - 与心血管疾病风险增加有关，但它们与认知、神经影像学标志物和痴呆的关系仍不确定。
在基于人群的鹿特丹研究中，我们使用多变量回归模型研究了 3143 名参与者血浆 TMAO、其前体与认知之间的关系。随后，我们在 2047 名参与者中检查了它们与结构脑 MRI 标志物的联系，并在莱顿长寿研究（n=318）中进行了部分验证。在 2517 名参与者中，我们使用多变量 Cox 比例风险模型评估了痴呆的发病风险。在此之后，我们根据药物使用和性别对纵向关联进行了分层，之后我们对肾功能受损的个体进行了敏感性分析。
总体而言，血浆 TMAO 与认知、神经影像学标志物或痴呆的发生无关。相反，较高的血浆胆碱与较差的认知显著相关（调整后的平均差异：-0.170[95%置信区间（CI）：-0.297；-0.043]）、脑萎缩和更多的脑小血管疾病标志物，如脑白质高信号体积（0.237[95%CI：0.076；0.397]）。相比之下，较高的肉碱与较低的脑白质高信号体积相关（-0.177[95%CI：-0.343；-0.010]）。只有在肾功能受损的个体中，TMAO 似乎会增加痴呆的风险（风险比（HR）：1.73[95%CI：1.16；2.60]）。在分层分析中未观察到明显差异。
与 TMAO 相反，血浆胆碱与认知能力下降、脑萎缩和脑小血管疾病标志物相关。这些发现说明了 TMAO 及其前体之间关系的复杂性，并强调了需要进行并发研究以阐明肠道-大脑机制。
