Longer TOM M40 poly-T variants associated with higher FDDNP-PET medial temporal tau and amyloid binding
Longer TOM M40 poly-T variants associated with higher FDDNP-PET medial temporal tau and amyloid binding
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DOI：
10.1371/journal.pone.0208358
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发表时间：
2018-12-05
期刊：
影响因子：
3.7
通讯作者：
Small, Gary W.
中科院分区：
文献类型：
--
作者：
Siddarth, Prabha;Burggren, Alison C.;Small, Gary W.
背景线粒体外膜转位酶40（TOMM40）与载脂蛋白E（APOE）基因连锁不平衡，与阿尔茨海默病（AD）有关。 TOMM40 通过线粒体神经毒性影响 AD 病理，内侧颞叶 (MTL) 是最有可能识别 AD 相关形态变化早期表现的大脑区域。虽然早期报告表明 TOMM40 较长的多聚 T 等位基因会增加 AD 风险，但这些发现并未在进一步的研究中得到一致重复。我们检查了 TOMM40 和 APOE 对 MTL 中局部脑正电子发射断层扫描 (PET) 2-(1-{6-[(2 [F18]氟乙基)(甲基)氨基]-2-萘亚乙基)丙二腈 (FDDNP) 结合值的影响。方法共有 73 名非痴呆老年人（42 名女性；平均年龄：62.9（10.9）岁）完成对 APOE 和 TOMM40 进行基因分型并接受 FDDNP-PET 扫描。对于 TOMM40，poly-T 序列的长度分为短（14-20 次重复；S）、长（21-29 次重复，L）或非常长（>29 次重复，VL）。使用一般线性模型，我们检查了 TOMM40 和 APOE-4 组之间的内侧颞叶 FDDNP 结合和认知功能。结果分析了 30 名具有 APOE-4 和 L TOMM40 poly-T 长度的个体、11 名非 E4 TOMM40 S/S、14 名非 E4 TOMM40 VL/VL 和 13 名非 E4 TOMM40 VL/VL 的数据。与 TOMM40 SNL 和 APOE-4 携带者相比，TOMM40 S/S 的结合力显着降低。我们没有发现 TOMM40 Poly-T 长度/APOE 风险群体与认知功能之间存在显着关系。结论这是第一份证明非痴呆老年人中更长的 TOMM40 Poly-T 长度与较高的内侧颞斑块和缠结负担之间存在显着关联的报告，这将增强我们识别可能受益于 AD 的受试者的能力。新颖的 AD 治疗方法。
BackgroundThe translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with the apolipoprotein E (APOE) gene, has been implicated in Alzheimer's disease (AD). TOMM40 influences AD pathology through mitochondrial neurotoxicity, and the medial temporal lobe (MTL) is the most likely brain region for identifying early manifestations of AD-related morphology changes. While early reports indicated that the longer length poly-T allele of TOMM40 increases risk for AD, these findings have not been consistently replicated in further studies. We examined the effect of TOMM40 and APOE on regional brain positron emission tomography (PET) 2-(1-{6-[(2 [F18]fluoroethyl) (methyl) amino]-2- naphthyllethylidene)malononitrile (FDDNP) binding values in MTL.MethodsA total of 73 non-demented older adults (42 females; mean age: 62.9(10.9) completed geno-typing for both APOE and TOMM40 and received FDDNP-PET scans. For TOMM40, the lengths of the poly-T sequence were classified as short (14-20 repeats; S), long (21-29 repeats, L) or very long (>29 repeats, VL). Using general linear models, we examined medial temporal lobe FDDNP binding and cognitive functioning between TOMM40 and APOE-4 groups, with age, sex, and education as covariates.ResultsData from 30 individuals with APOE-4 and L TOMM40 poly-T length, 11 non E4 TOMM40 S/S, 14 non E4 TOMM40 SNL and 13 non E4 TOMM40 VL/VL were analyzed. Medial temporal FDDNP binding differed significantly between TOMM40/APOE groups (F(3,62) = 3.3, p = .03). Participants with TOMM40 S/S exhibited significantly lower binding compared to TOMM40 SNL and APOE-4 carriers. We did not find a significant relationship between TOMM40 poly-T lengths/APOE risk groups and cognitive functioning.ConclusionsThis is the first report to demonstrate a significant association between longer TOMM40 poly-T lengths and higher medial temporal plaque and tangle burden in non-demented older adults. Identifying biomarkers that are risk factors for AD will enhance our ability to identify subjects likely to benefit from novel AD treatments.