Department of Integrative Medical Biology, Umeå University, SE-901 87, Umeå, Sweden.
Umeå Center for Functional Brain Imaging, Umeå University, SE-90 187, Umeå, Sweden.
Alzheimers Res Ther. 2021 Jul 15;13(1):130. doi: 10.1186/s13195-021-00871-y.
Leukocyte telomere length (LTL) has been shown to predict Alzheimer's disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the association between LTL and AD is non-linear and may differ depending on apolipoprotein E (APOE) ε4 allele carriage, the strongest genetic AD predictor.
We analyzed whether baseline LTL in interaction with APOE ε4 predicts AD, by following 1306 initially non-demented subjects for 25 years. Gender- and age-residualized LTL (rLTL) was categorized into tertiles of short, medium, and long rLTLs. Two complementary time-to-event models that account for competing risks were used; the Fine-Gray model to estimate the association between the rLTL tertiles and the cumulative incidence of AD, and the cause-specific hazard model to assess whether the cause-specific risk of AD differed between the rLTL groups. Vascular dementia and death were considered competing risk events. Models were adjusted for baseline lifestyle-related risk factors, gender, age, and non-proportional hazards.
After follow-up, 149 were diagnosed with AD, 96 were diagnosed with vascular dementia, 465 died without dementia, and 596 remained healthy. Baseline rLTL and other covariates were assessed on average 8 years before AD onset (range 1-24). APOE ε4-carriers had significantly increased incidence of AD, as well as increased cause-specific AD risk. A significant rLTL-APOE interaction indicated that short rLTL at baseline was significantly associated with an increased incidence of AD among non-APOE ε4-carriers (subdistribution hazard ratio = 3.24, CI 1.404-7.462, P = 0.005), as well as borderline associated with increased cause-specific risk of AD (cause-specific hazard ratio = 1.67, CI 0.947-2.964, P = 0.07). Among APOE ε4-carriers, short or long rLTLs were not significantly associated with AD incidence, nor with the cause-specific risk of AD.
Our findings from two complementary competing risk time-to-event models indicate that short rLTL may be a valuable predictor of the AD incidence in non-APOE ε4-carriers, on average 8 years before AD onset. More generally, the findings highlight the importance of accounting for competing risks, as well as the APOE status of participants in AD biomarker research.
白细胞端粒长度 (LTL) 已被证明可预测阿尔茨海默病 (AD)，尽管结果不一致。在之前的时间事件分析中，未能考虑 AD、其他痴呆类型和死亡率之间的竞争风险，可能是造成结果不一致的原因之一。此外，先前的研究表明，LTL 与 AD 之间的关联是非线性的，并且可能因载脂蛋白 E (APOE) ε4 等位基因携带情况而异，APOE ε4 是最强的 AD 遗传预测因子。
我们通过对 1306 名最初无痴呆的受试者进行 25 年的随访，分析了基线 LTL 与 APOE ε4 之间是否存在交互作用，从而预测 AD。性别和年龄残差化的 LTL (rLTL) 被分为短、中、长 rLTL 三分位。使用两种互补的考虑竞争风险的时间事件模型；Fine-Gray 模型用于估计 rLTL 三分位与 AD 累积发病率之间的关系，以及特定原因的风险模型用于评估 AD 在 rLTL 组之间的特定原因风险是否存在差异。血管性痴呆和死亡被认为是竞争风险事件。模型调整了基线与生活方式相关的风险因素、性别、年龄和非比例风险。
随访后，149 人被诊断为 AD，96 人被诊断为血管性痴呆，465 人死于非痴呆，596 人保持健康。基线 rLTL 和其他协变量平均在 AD 发病前 8 年进行评估（范围 1-24）。APOE ε4 携带者的 AD 发病率显著增加，特定原因 AD 风险也增加。rLTL-APOE 交互作用显著表明，基线时短 rLTL 与非 APOE ε4 携带者 AD 发病率显著增加相关（亚分布危险比=3.24，CI 1.404-7.462，P=0.005），并且与特定原因 AD 风险增加也有边界关联（特定原因危险比=1.67，CI 0.947-2.964，P=0.07）。在 APOE ε4 携带者中，短或长 rLTL 与 AD 发病率或特定原因 AD 风险均无显著相关性。
我们从两种互补的竞争风险时间事件模型中得出的发现表明，短 rLTL 可能是 AD 非 APOE ε4 携带者平均发病前 8 年 AD 发病率的一个有价值的预测因子。更普遍地说，这些发现强调了在 AD 生物标志物研究中考虑竞争风险以及参与者 APOE 状态的重要性。
