Apolipoprotein E epsilon4 does not modulate amyloid-β-associated neurodegeneration in preclinical Alzheimer disease.
Apolipoprotein E epsilon4 does not modulate amyloid-β-associated neurodegeneration in preclinical Alzheimer disease.
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DOI：
10.3174/ajnr.a3267
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发表时间：
2013-03
期刊：
影响因子：
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通讯作者：
Alzheimer's Disease Neuroimaging Initiative
中科院分区：
文献类型：
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作者：
Desikan RS;McEvoy LK;Holland D;Thompson WK;Brewer JB;Aisen PS;Andreassen OA;Hyman BT;Sperling RA;Dale AM;Alzheimer's Disease Neuroimaging Initiative
在认知正常的老年人中，阿尔茨海默病（AD）的两种标志蛋白淀粉样蛋白-β (Aβ)和tau蛋白、载脂蛋白E （APOE ε4）的ε4等位基因与神经退行性变之间的关系尚不清楚。我们检查了107名认知健康的老年人，他们接受了纵向磁共振成像和基线腰椎穿刺。在相同的线性混合效应模型下，我们同时研究了APOE ε4基因型与CSF Aβ1-42、CSF p-tau （p-tau181p）和CSF Aβ1-42以及APOE ε4基因型与CSF p-tau181p对内鼻皮层萎缩率的主要和交互作用。我们还研究了APOE ε4、CSF p-tau181p和CSF a - β1-42与其他ad易感神经解剖区域萎缩率的关系。具有主效应和交互效应的完整模型显示，只有CSF p-tau181p和CSF a - β1-42对内鼻皮层萎缩率有显著的相互作用，表明CSF p-tau181p升高和CSF a - β1-42降低的个体随着时间的推移萎缩率升高。APOE ε4基因型与CSF Aβ1-42显著特异相关。而APOE ε4基因型与脑脊液Aβ1-42或脑脊液p-tau181p对内嗅皮质萎缩率的交互作用不显著。我们在其他ad易感区域也发现了类似的结果。基于我们的研究结果和先前的实验证据，我们提出了一个临床前AD的致病级联模型，其中APOE ε4主要通过a β相关机制影响阿尔茨海默病的病理，反过来，a β相关的神经退行性变仅在phospho-tau存在时发生。
Among cognitively normal older individuals, the relationship between the two hallmark proteins of Alzheimer’s disease (AD), amyloid-β (Aβ) and tau, the ε4 allele of apolipoprotein E (APOE ε4), and neurodegeneration is not well understood. We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed effects model, we concurrently investigated main and interactive effects between APOE ε4 genotype and CSF Aβ1-42, CSF phospo-tau (p-tau181p) and CSF Aβ1-42, and APOE ε4 genotype and CSF p-tau181p on entorhinal cortex atrophy rate. We also examined the relationship between APOE ε4, CSF p-tau181p, and CSF Aβ1-42 on atrophy rate of other AD-vulnerable neuroanatomic regions. The full model with main and interactive effects demonstrated a significant interaction only between CSF p-tau181p and CSF Aβ1-42 on entorhinal cortex atrophy rate indicating elevated atrophy over time in individuals with increased CSF p-tau181p and decreased CSF Aβ1-42. APOE ε4 genotype was significantly and specifically associated with CSF Aβ1-42. However, the interaction between APOE ε4 genotype and either CSF Aβ1-42 or CSF p-tau181p on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions. Based upon our findings and building upon prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD where APOE ε4 primarily influences Alzheimer’s pathology via Aβ-related mechanisms and in turn, Aβ-associated neurodegeneration occurs only in the presence of phospho-tau.