背景:据报道,TOMM40中的523poly-T长度多态性(rs10524523)会影响APOEε3/3携带者的纵向认知测试表现。先前研究的结果不一致。还不清楚特定的APOE和TOMM40基因型是否在AD的临床前阶段导致纵向认知表现的异质性。
目的:为了确定这些基因对AD早期临床前阶段纵向认知改变的影响,我们使用最近结束的TOMMORROW研究的临床试验数据来检验APOE和TOMM40基因型对神经心理学测试表现的影响.
方法:第三阶段,双盲,安慰剂对照,随机临床试验。
方法:澳大利亚的学术附属和私人研究诊所,德国,瑞士,英国,和美国。
方法:认知正常的65至83岁的老年人。
方法:吡格列酮片。
方法:根据APOE基因型(APOEε3/3,APOEε3/4,APOEε4/4)对来自TOMMORROW试验的参与者进行分层。APOEε3/3携带者进一步按TOMM40\'523基因型分层。最终分析数据集包括1,330个APOEε3/3携带者和7,001次访问。线性混合模型用于比较APOE组和具有不同TOMM40\'523基因型的APOEε3/3携带者的认知下降率。
结果:与APOEε3/3基因型相比,APOEε3/4和APOEε4/4基因型在全球认知测量方面表现较差,情景记忆,和富有表现力的语言。Further,经过四年的观察,具有TOMM40\'523-S/S基因型的APOEε3/3携带者在全球认知测试中表现出更好的全球认知能力和加速的认知下降率,执行功能,与具有TOMM40\'523-S/VL和VL/VL基因型的APOEε3/3携带者相比,并与APOEε3/4和APOEε4/4携带者相比,注意处理。
结论:我们认为APOE和TOMM40基因型可能独立地导致AD前MCI阶段的认知异质性。控制这种遗传变异性在旨在减缓认知衰退速率和/或预防临床前AD症状发作的临床试验中是重要的。
The 523 poly-T length polymorphism (rs10524523) in TOMM40 has been reported to influence longitudinal cognitive test performance within APOE ε3/3 carriers. The results from prior studies are inconsistent. It is also unclear whether specific APOE and TOMM40 genotypes contribute to heterogeneity in longitudinal cognitive performance during the preclinical stages of AD.
To determine the effects of these genes on longitudinal cognitive change in early preclinical stages of AD, we used the clinical
trial data from the recently concluded TOMMORROW
study to examine the effects of APOE and TOMM40 genotypes on neuropsychological test performance.
A phase 3, double-blind, placebo-controlled, randomized clinical
trial.
Academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA.
Cognitively normal older adults aged 65 to 83.
Pioglitazone tablet.
Participants from the TOMMORROW
trial were stratified based on APOE genotype (APOE ε3/3, APOE ε3/4, APOE ε4/4). APOE ε3/3 carriers were further stratified by TOMM40\'523 genotype. The final analysis dataset consists of 1,330 APOE ε3/3 carriers and 7,001 visits. Linear mixed models were used to compare the rates of decline in cognition across APOE groups and the APOE ε3/3 carriers with different TOMM40\'523 genotypes.
APOE ε3/4 and APOE ε4/4 genotypes compared with the APOE ε3/3 genotype were associated with worse performance on measures of global cognition, episodic memory, and expressive language. Further, over the four years of observation, the APOE ε3/3 carriers with the TOMM40\'523-S/S genotype showed better global cognition and accelerated rates of cognitive decline on tests of global cognition, executive function, and attentional processing compared to APOE ε3/3 carriers with TOMM40\'523-S/VL and VL/VL genotypes and compared to the APOE ε3/4 and APOE ε4/4 carriers.
We suggest that both APOE and TOMM40 genotypes may independently contribute to cognitive heterogeneity in the pre-MCI stages of AD. Controlling for this genetic variability will be important in clinical trials designed to slow the rate of cognitive decline and/or prevent symptom onset in preclinical AD.