Ohm T G, Scharnagl H, März W, Bohl J
Institute of Anatomy, Charité, Humboldt-University, Berlin, Germany.
Acta Neuropathol. 1999 Sep;98(3):273-80. doi: 10.1007/s004010051080.
In recent research, apolipoprotein-E (apoE) polymorphism has been shown to influence the formation of neurofibrillary changes and the accumulation of beta/A4-amyloid, the histopathological hallmarks of Alzheimer's disease (AD). Clinical studies associate the apoE allele epsilon4 with earlier onset of the disease, although the clinical speed of progression remains unchanged. Time course estimates have also provided evidence which indicates that the clinical phase of AD constitutes only 10-20% of the total time span needed for the development of this slowly progressing degenerative brain disorder. Due to the lack of reliable clinical tests for the detection of pre-symptomatic stages of AD, we set out with an autopsy approach to monitor neuropathology of the long pre-clinical phase of AD. This study examined beta/A4-peptide deposition and the formation of neurofibrillary changes staged according to the Braaks' classification in groups of individuals matched for age and sex with different genotypes. In comparison with epsilon3 homozygotes, the presence of the epsilon4 allele is statistically associated with a higher stage of beta/A4-peptide deposition and neurofibrillary change formation (chi2-test, P<0.01 for beta/A4-stage and P<0.001 for neurofibrillary changes). The effect of the epsilon2 allele differs. Its presence is associated with a lower stage of neurofibrillary pathology in individuals below the age of 80 but with a higher stage thereafter compared to age- and sex-matched epsilon3 homozygotes. Accordingly, the statistical juxtaposition of individuals over 80 years with epsilon4 alleles and those with epsilon2 alleles showed no significant difference with respect to the stages. Our findings indicate that apoE-variants have different effects on the speed of histopathology formation, even in the pre-clinical stages of AD. This suggests that clinical onset, course and pathogenesis of AD are influenced by the apoE genotype.
在最近的研究中，载脂蛋白E（apoE）多态性已被证明会影响神经原纤维变化的形成以及β/A4淀粉样蛋白的积累，而这两者是阿尔茨海默病（AD）的组织病理学特征。临床研究将apoE ε4等位基因与该疾病的较早发病相关联，尽管临床进展速度保持不变。时间进程估计也提供了证据，表明AD的临床阶段仅占这种缓慢进展的退行性脑部疾病发展所需总时间跨度的10 - 20%。由于缺乏用于检测AD症状前阶段的可靠临床测试，我们采用尸检方法来监测AD漫长临床前期的神经病理学变化。本研究在年龄和性别匹配但具有不同基因型的个体组中，检查了β/A4肽沉积以及根据Braaks分类法分期的神经原纤维变化的形成情况。与ε3纯合子相比，ε4等位基因的存在在统计学上与更高阶段的β/A4肽沉积和神经原纤维变化形成相关（卡方检验，β/A4阶段P<0.01，神经原纤维变化P<0.001）。ε2等位基因的影响有所不同。在80岁以下个体中，其存在与较低阶段的神经原纤维病理学相关，但在80岁及以上个体中，与年龄和性别匹配的ε3纯合子相比，其存在与更高阶段相关。因此，对80岁以上携带ε4等位基因的个体与携带ε2等位基因的个体进行统计学并列比较，在分期方面没有显示出显著差异。我们的研究结果表明，即使在AD的临床前期，apoE变体对组织病理学形成速度也有不同影响。这表明AD的临床发病、病程和发病机制受apoE基因型影响。
