Jeong Sohyun, Lin Lisha, Leone Alvaro-Pascual, Hsu Yi-Hsiang
Department of Pharmacy Practice, College of Pharmacy, Massachusetts College of Pharmacy and Health Science, Boston, MA, USA.
Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.
J Alzheimers Dis. 2025 May;105(1):107-119. doi: 10.1177/13872877251326107. Epub 2025 Mar 25.
BackgroundThe inherent genetic effects were not established between type 2 diabetes (T2DM) and Alzheimer's disease and related dementia (ADRD).ObjectiveWe aimed to investigate the association between T2DM and ADRD by integrating T2DM polygenic risk score (PRS) and applying matching in every subgroup.MethodsWe utilized UK Biobank First-occurrences datasets. T2DM were 1:1 matched to non-T2DM using propensity scores generated by 8 covariates; age at diagnosis, sex, cerebrovascular disease, ischemic heart disease, hypertensive disorders, lipid disorders, obesity, and mood disorders. T2DM PRS was additionally matched in T2DM PRS matched analysis. Subgroup analyses by age at diagnosis, sex, and genotype were performed with the same matching criteria within each subgroup. Cox proportional hazard and Fine & Gray competing risk model were utilized.ResultsIn T2DM PRS unmatched cohort, 24,583 T2DM were 1:1 matched to non-T2DM. The mean age at diagnosis was around 62 years old, with females constituting around 40%. Up to 25-year follow-up, ADRD rate/1000 person-years was 0.88 versus 1.52 (Non-T2DM versus T2DM); PRS unmatched (cHR: 1.72, 95% CI: 1.46-2.03) and matched (cHR:1.75, 95% CI: 1.47-2.09). Except for older age onset (≥75 years), the other subgroups demonstrated significantly increased ADRD risks in T2DM. T2DM PRS was higher in non-ADRD group across all subgroups. Contrarily, T2DM PRS was higher in ADRD in younger onset group (<55 years).ConclusionsT2DM is one of the strong risk factors of ADRD but genetic T2DM effect does not contribute to ADRD risk. However, a genetic link might be present in younger age onset group.
背景
2型糖尿病（T2DM）与阿尔茨海默病及相关痴呆症（ADRD）之间的内在遗传效应尚未明确。
目的
我们旨在通过整合T2DM多基因风险评分（PRS）并在每个亚组中应用匹配方法来研究T2DM与ADRD之间的关联。
方法
我们使用了英国生物银行首次发病数据集。利用由8个协变量生成的倾向得分将T2DM与非T2DM进行1:1匹配；诊断年龄、性别、脑血管疾病、缺血性心脏病、高血压疾病、脂质紊乱、肥胖和情绪障碍。在T2DM PRS匹配分析中还对T2DM PRS进行了匹配。在每个亚组内根据相同的匹配标准按诊断年龄、性别和基因型进行亚组分析。使用Cox比例风险模型和Fine & Gray竞争风险模型。
结果
在T2DM PRS未匹配队列中，24,583例T2DM与非T2DM进行了1:1匹配。诊断时的平均年龄约为62岁，女性约占40%。长达25年的随访中，ADRD发病率/1000人年在非T2DM组为1.52，在T2DM组为0.88；PRS未匹配（校正风险比：1.72，95%置信区间：1.46 - 2.03）和匹配（校正风险比：1.75，95%置信区间：1.47 - 2.09）。除了老年发病（≥75岁）外，其他亚组中T2DM的ADRD风险显著增加。在所有亚组中，非ADRD组的T2DM PRS更高。相反，在年轻发病组（<55岁）中，ADRD组的T2DM PRS更高。
结论
T2DM是ADRD的强风险因素之一，但T2DM的遗传效应并不导致ADRD风险。然而在年轻发病组中可能存在遗传联系。
