Short leukocyte telomeres predict 25-year Alzheimer's disease incidence in non-APOE ε4-carriers.
Short leukocyte telomeres predict 25-year Alzheimer's disease incidence in non-APOE ε4-carriers.
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短白细胞端粒可预测非 APOE ε4 携带者 25 年阿尔茨海默病的发病率。
DOI：
10.1186/s13195-021-00871-y
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发表时间：
2021-07-15
期刊：
影响因子：
--
通讯作者：
Pudas S
中科院分区：
文献类型：
--
作者：
Hackenhaar FS;Josefsson M;Adolfsson AN;Landfors M;Kauppi K;Hultdin M;Adolfsson R;Degerman S;Pudas S
白细胞端粒长度（LTL）已被证明可以预测阿尔茨海默病（AD），尽管不一致。未能解释AD、其他痴呆类型和死亡率之间的竞争风险，可以解释以前的事件发生时间分析中不一致的结果。此外，先前的研究表明，LTL和AD之间的关联是非线性的，并且可能取决于载脂蛋白E（APOE）ε4等位基因携带，这是最强的遗传AD预测因子。我们通过对1306名最初非痴呆的受试者进行25年的随访，分析了基线LTL与APOE ε4相互作用是否能预测AD。性别和年龄残留的LTL（rLTL）分为三分位数的短，中，长rLTL。使用了两种互补的时间-事件模型来解释竞争风险;精细灰色模型用于估计rLTL三分位数与AD累积发病率之间的关联，原因特异性风险模型用于评估rLTL组之间AD的原因特异性风险是否不同。血管性痴呆和死亡被认为是竞争风险事件。模型根据基线生活方式相关风险因素、性别、年龄和非比例风险进行调整。随访后，149人被诊断为AD，96人被诊断为血管性痴呆，465人死亡，596人保持健康。基线rLTL和其他协变量在AD发作前平均8年进行评估（范围1-24）。APOE ε4携带者AD的发病率显著增加，病因特异性AD风险也增加。一个显著的rLTL-APOE相互作用表明，在非APOE ε4携带者中，基线时短rLTL与AD发病率增加显著相关（亚分布风险比= 3.24，CI 1.404-7.462，P = 0.005），以及与AD病因特异性风险增加相关的临界值（病因特异性风险比= 1.67，CI 0.947-2.964，P = 0.07）。在APOE ε4携带者中，短或长rLTL与AD发病率无显著相关性，也与AD的病因特异性风险无显著相关性。我们从两个互补的竞争性风险时间-事件模型的研究结果表明，短rLTL可能是非APOE ε4携带者AD发病率的一个有价值的预测因子，平均在AD发病前8年。更一般地说，这些发现强调了考虑竞争风险的重要性，以及AD生物标志物研究参与者的APOE状态。在线版本包含补充材料，可通过10.1186/s13195-021-00871-y获得。
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. The online version contains supplementary material available at 10.1186/s13195-021-00871-y.
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影响因子：
29
作者：
King KS;Kozlitina J;Rosenberg RN;Peshock RM;McColl RW;Garcia CK
通讯作者：
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对人类端粒动力学和与老年相关疾病的反思。
DOI：
10.1098/rstb.2016.0436
发表时间：
2018-03-05
期刊：
Philosophical transactions of the Royal Society of London. Series B, Biological sciences
影响因子：
--
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通讯作者：
Shay JW
DOI：
10.1186/s13195-020-00712-4
发表时间：
2020-11-04
期刊：
Alzheimer's research & therapy
影响因子：
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