Steno Diabetes Center Aarhus, Aarhus University Hospital, Palle Juul-Jensens Blvd. 11, Indgang A, Aarhus, Denmark.
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark.
Eur J Epidemiol. 2022 Dec;37(12):1273-1284. doi: 10.1007/s10654-022-00923-z. Epub 2022 Nov 4.
Whether impaired kidney function is associated with increased risk of developing dementia is unclear. We investigated the association between estimated glomerular filtration rate (eGFR) and dementia. Using a triangulation approach, we performed (1) a prospective study in 90,369 Danes from the Copenhagen General Population Study (CGPS), (2) a meta-analysis in 468,699 Scandinavians (including CGPS) and (3) a two-sample Mendelian randomization study in 218,792-1,004,040 Europeans using summary data from largest publicly available genome wide association studies (GWASs). During up to 15 years of follow-up (CGPS), 2,468 individuals developed dementia. Age and sex standardized percentile of eGFR below versus above the median conferred a multifactorially adjusted hazard ratio of 1.09 (95% confidence interval: 1.01-1.18). In meta-analysis, random-effects risk of dementia was 1.14 (1.06-1.22) for mildly decreased eGFR (60-90 mL/min/1.73 m), 1.31 (0.92-1.87) for moderately decreased eGFR (30-59 mL/min/1.73 m) and 1.91 (1.21-3.01) for severely decreased eGFR (< 30 mL/min/1.73 m), compared to reference eGFR (> 90 mL/min/1.73 m). Using directly comparable eGFR measures (log[eGFR] scaled to one standard deviation, as well as eGFR below versus above 60 mL/min/1.73 m), we found no association with risk of dementia in observational CGPS or in Mendelian randomization analyses. In conclusion, impaired kidney function was associated with modestly increased risk of developing dementia. This was not supported by causal, genetic analyses using a Mendelian randomization approach. However, future stronger genetic instruments for kidney function and larger GWASs with more dementia cases, particularly for the vascular dementia subtype, warrant a re-evaluation of the causal hypothesis.
肾功能受损是否与痴呆风险增加有关尚不清楚。我们研究了估算肾小球滤过率（eGFR）与痴呆之间的关系。我们采用三角方法进行了研究：（1）在哥本哈根普通人群研究（CGPS）的 90369 名丹麦人中进行了一项前瞻性研究；（2）在包括 CGPS 的 468699 名斯堪的纳维亚人中进行了一项荟萃分析；（3）在 218792-1004040 名欧洲人中进行了两样本孟德尔随机化研究，使用了来自最大型公开全基因组关联研究（GWAS）的汇总数据。在长达 15 年的随访期间（CGPS），2468 人患上了痴呆症。年龄和性别标准化 eGFR 低于或高于中位数的百分位数得出的多因素校正后的风险比为 1.09（95%置信区间：1.01-1.18）。荟萃分析中，轻度 eGFR 降低（60-90mL/min/1.73m）的痴呆风险为 1.14（1.06-1.22），中度 eGFR 降低（30-59mL/min/1.73m）的风险为 1.31（0.92-1.87），重度 eGFR 降低（<30mL/min/1.73m）的风险为 1.91（1.21-3.01），而参考 eGFR（>90mL/min/1.73m）。使用可直接比较的 eGFR 测量值（按一个标准差标度的对数[eGFR]，以及 eGFR 低于或高于 60mL/min/1.73m），我们在观察性 CGPS 或孟德尔随机化分析中均未发现痴呆风险与 eGFR 之间存在关联。总之，肾功能受损与发展为痴呆的风险适度增加有关。这一结论并未得到采用孟德尔随机化方法进行的因果、遗传分析的支持。然而，未来需要更强效的肾功能遗传工具以及具有更多痴呆病例的更大型 GWAS，尤其是血管性痴呆亚型，这将需要重新评估这一因果假说。
