Department of Neurology, Mayo Clinic, Rochester, Minnesota.
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
JAMA Neurol. 2018 Nov 1;75(11):1347-1354. doi: 10.1001/jamaneurol.2018.3139.
Transactive response DNA-binding protein 43 (TDP-43) is associated with Alzheimer disease (AD), progressive hippocampal atrophy, and cognitive decline. The apolipoprotein E (APOE) ε4 allele is strongly associated with β-amyloid (Aβ) aggregation and risk of AD, but its association with TDP-43 is unknown.
To determine whether the APOE ε4 allele is a risk factor for TDP-43.
DESIGN, SETTING, PARTICIPANTS: This cross-sectional, genetic-histologic study analyzed APOE genotype, TDP-43 status (positive vs negative), Aβ status (positive vs negative), and tau neurofibrillary tangle stage (B0, Braak stage 0; B1, Braak stages I-II; B2, Braak stages III-IV; B3, Braak stage ≥ V). We fit structural equation models to map the association between APOE and TDP-43, Aβ, and tau, accounting for age and hippocampal sclerosis. We identified 751 participants with an AD pathological spectrum diagnosis and completed Aβ, tau, and TDP-43 data who were enrolled in the Mayo Clinic Alzheimer Disease Research Center, Mayo Clinic Alzheimer Disease Patient Registry, or the population based Mayo Clinic Study of Aging and died between May 12, 1999, and December 31, 2015. However, 13 were excluded from the analyses because of missing APOE data, leaving a total of 738 participants.
Transactive response DNA-binding protein 43 was the main outcome of interest. We hypothesized that the APOE ε4 allele would be significantly directly and indirectly associated with TDP-43.
The 751 study participants were older (median age [interquartile range], 87 years [51-105 years]), 395 (54%) were women, and 324 (44%) were APOE ε4 carriers. The patients died between May 12, 1999, and December 31, 2015. Accounting for age, Aβ, and tau, APOE ε4 had a direct association with TDP-43 (estimate [SE], 0.31 (0.11); P = .01). The association was present among individuals with an intermediate to high likelihood of having AD (neurofibrillary tangle stage B2/B3; n = 604 [81.8%]; estimate [SE], 0.51 [0.11]; P < .001), with a similar trend for those with a low likelihood of having AD (B1; n = 134 [18.2%]; estimate [SE], 0.54 [0.32]; P = .10). We also found an indirect association of APOE ε4 with TDP-43 via Aβ and tau (estimate [SE], 0.34 [0.06]; P < .001), which was similar in magnitude to the direct association and an indirect association of APOE ε4 with hippocampal sclerosis via TDP-43 (estimate [SE], 0.65 [0.26]; P = .01).
The study's findings, which mapped a system of risk factors and outcomes, showed that the APOE ε4 allele appears to be a risk factor for TDP-43 independently of Aβ in patients with AD.
反式作用响应 DNA 结合蛋白 43（TDP-43）与阿尔茨海默病（AD）、进行性海马萎缩和认知能力下降有关。载脂蛋白 E（APOE）ε4 等位基因与β-淀粉样蛋白（Aβ）聚集和 AD 风险强烈相关，但与 TDP-43 的关系尚不清楚。
确定 APOE ε4 等位基因是否是 TDP-43 的风险因素。
设计、地点、参与者：本横断面、遗传组织学研究分析了 APOE 基因型、TDP-43 状态（阳性与阴性）、Aβ 状态（阳性与阴性）和 tau 神经原纤维缠结阶段（B0，Braak 阶段 0；B1，Braak 阶段 I-II；B2，Braak 阶段 III-IV；B3，Braak 阶段≥V）。我们拟合结构方程模型，以映射 APOE 与 TDP-43、Aβ 和 tau 之间的关联，同时考虑年龄和海马硬化。我们确定了 751 名患有 AD 病理谱诊断的参与者，并完成了 Aβ、tau 和 TDP-43 数据的分析，他们参加了 Mayo 诊所阿尔茨海默病研究中心、Mayo 诊所阿尔茨海默病患者登记处或基于人群的 Mayo 诊所衰老研究，并于 1999 年 5 月 12 日至 2015 年 12 月 31 日期间死亡。然而，由于缺少 APOE 数据，有 13 人被排除在分析之外，因此共有 738 名参与者。
TDP-43 是主要关注的结果。我们假设 APOE ε4 等位基因将与 TDP-43 显著直接和间接相关。
751 名研究参与者年龄较大（中位数年龄[四分位距]，87 岁[51-105 岁]），395 名（54%）为女性，324 名（44%）为 APOE ε4 携带者。患者于 1999 年 5 月 12 日至 2015 年 12 月 31 日死亡。考虑到年龄、Aβ 和 tau，APOE ε4 与 TDP-43 直接相关（估计值[SE]，0.31[0.11]；P=.01）。在具有中高度 AD 可能性的个体中，这种关联存在（神经原纤维缠结阶段 B2/B3；n=604[81.8%]；估计值[SE]，0.51[0.11]；P<0.001），对于 AD 可能性较低的个体，也存在类似的趋势（B1；n=134[18.2%]；估计值[SE]，0.54[0.32]；P=0.10）。我们还发现 APOE ε4 通过 Aβ 和 tau 与 TDP-43 间接相关（估计值[SE]，0.34[0.06]；P<0.001），其与直接相关的程度相似，并且 APOE ε4 通过 TDP-43 与海马硬化间接相关（估计值[SE]，0.65[0.26]；P=0.01）。
该研究的发现绘制了一个风险因素和结果的系统图，表明 APOE ε4 等位基因似乎是 AD 患者 TDP-43 的一个独立于 Aβ 的风险因素。
