Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study.

IF 8.5 3区医学 Q1 CLINICAL NEUROLOGY

Jpad-Journal of Prevention of Alzheimers Disease Pub Date : 2023-01-01 DOI:10.14283/jpad.2023.115

H Zou, S Luo, H Liu, M W Lutz, D A Bennett, B L Plassman, K A Welsh-Bohmer

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Abstract

Background: 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.

Objectives: 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.

Design: A phase 3, double-blind, placebo-controlled, randomized clinical trial.

Setting: Academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA.

Participants: Cognitively normal older adults aged 65 to 83.

Intervention: Pioglitazone tablet.

Measurements: 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.

Results: 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.

Conclusions: 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.

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TOMM40'523 变异和 APOE 对 4 年认知纵向变化的基因型影响：TOMMORROW研究

背景：据报道，TOMM40的523多T长度多态性（rs10524523）会影响APOE ε3/3携带者的纵向认知测试表现。之前的研究结果并不一致。目前还不清楚特定的APOE和TOMM40基因型是否会导致AD临床前阶段纵向认知表现的异质性：为了确定这些基因对早期AD临床前阶段纵向认知变化的影响，我们利用最近结束的TOMMORROW研究中的临床试验数据，考察了APOE和TOMM40基因型对神经心理学测试表现的影响：3期双盲安慰剂对照随机临床试验：地点：澳大利亚、德国、瑞士、英国和美国的学术附属机构和私人研究诊所：干预措施：吡格列酮片剂：干预措施：吡格列酮片剂：TOMMORROW试验的参与者根据APOE基因型（APOE ε3/3、APOE ε3/4、APOE ε4/4）进行分层。APOE ε3/3携带者按TOMM40'523基因型进一步分层。最终分析数据集包括 1,330 名 APOE ε3/3 携带者和 7,001 次就诊。线性混合模型用于比较不同APOE组和不同TOMM40'523基因型的APOE ε3/3携带者的认知能力下降率：APOE ε3/4和APOE ε4/4基因型与APOE ε3/3基因型相比，在整体认知、外显记忆和语言表达方面的表现更差。此外，在四年的观察中，与带有TOMM40'523-S/VL和VL/VL基因型的APOE ε3/3携带者相比，带有TOMM40'523-S/S基因型的APOE ε3/3携带者与带有TOMM40'523-S/VL和VL/VL基因型的APOE ε3/4和APOE ε4/4携带者相比，在总体认知、执行功能和注意力处理测试中表现出更好的总体认知能力和更快的认知能力下降速度：结论：我们认为，APOE和TOMM40基因型可能会单独导致AD前MCI阶段的认知异质性。在临床试验中，控制这种基因变异性对于减缓认知能力下降的速度和/或预防临床前AD症状的出现非常重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Jpad-Journal of Prevention of Alzheimers Disease CLINICAL NEUROLOGY-

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7.80%

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期刊介绍： The JPAD « Journal of Prevention of Alzheimer’Disease » will publish reviews, original research articles and short reports to improve our knowledge in the field of Alzheimer prevention including : neurosciences, biomarkers, imaging, epidemiology, public health, physical cognitive exercise, nutrition, risk and protective factors, drug development, trials design, and heath economic outcomes. JPAD will publish also the meeting abstracts from Clinical Trial on Alzheimer Disease (CTAD) and will be distributed both in paper and online version worldwide.