Harrington C R, Louwagie J, Rossau R, Vanmechelen E, Perry R H, Perry E K, Xuereb J H, Roth M, Wischik C M
Cambridge Brain Bank Laboratory, University of Cambridge Department of Psychiatry, United Kingdom.
Am J Pathol. 1994 Dec;145(6):1472-84.
Alzheimer's disease (AD) is associated with an increased frequency of the apolipoprotein E type epsilon 4 allele. To address both the disease and the allele specificity of this association, we have examined the apolipoprotein E allele distribution in 255 elderly persons including those with autopsy-confirmed AD, senile dementia of the Lewy body type (SDLT), vascular dementia, Parkinson's disease (PD) or Huntington's disease and in nondemented controls either with or without coronary complications. The epsilon 4 allele frequency was increased in SDLT (0.365) and AD (0.328) as compared with controls (0.147), PD (0.098), or Huntington's chorea (0.171). Coronary disease and vascular dementia were associated with marginally higher epsilon 4 allele frequencies than in controls. In PD, amyloid beta-protein accumulated to a greater extent in those cases possessing an epsilon 4 allele than in those without. Those PD cases with dementia were not distinguished from either controls or PD cases without dementia, whether tested biochemically or by apolipoprotein E genotype. It is the comparison of the results in AD and SDLT that yielded the most significant findings. There was a 1.8-fold excess of amyloid beta-protein in AD as compared with controls, and the levels in SDLT were intermediate between those in AD and controls. In contrast, AD was discriminated from both controls and SDLT by the substantial accumulation of paired helical filament tau and phosphorylated tau (both increased more than 20-fold as compared with controls). SDLT was nevertheless characterized by an increased epsilon 4 allele frequency in the absence of significant tau pathology (at least 10-fold less than that in AD). These findings indicate that tau processing is more specifically associated with AD than is amyloid beta-protein accumulation and that presence of the epsilon 4 allele is not an etiological factor that accounts for tau pathology.
阿尔茨海默病（AD）与载脂蛋白Eε4等位基因频率增加有关。为了研究这种关联的疾病特异性和等位基因特异性，我们检测了255名老年人的载脂蛋白E等位基因分布情况，这些老年人包括尸检确诊的AD患者、路易体痴呆型（SDLT）、血管性痴呆、帕金森病（PD）或亨廷顿病患者，以及有或无冠状动脉并发症的非痴呆对照者。与对照组（0.147）、PD组（0.098）或亨廷顿舞蹈症组（0.171）相比，SDLT组（0.365）和AD组（0.328）的ε4等位基因频率升高。冠心病和血管性痴呆与略高于对照组的ε4等位基因频率相关。在PD组中，携带ε4等位基因的病例比未携带该等位基因的病例中β淀粉样蛋白积累程度更高。那些患有痴呆的PD病例，无论是通过生化检测还是载脂蛋白E基因型检测，都无法与对照组或无痴呆的PD病例区分开来。AD和SDLT的结果比较产生了最显著的发现。与对照组相比，AD组的β淀粉样蛋白含量高出1.8倍，SDLT组的水平介于AD组和对照组之间。相比之下，AD组与对照组和SDLT组的区别在于成对螺旋丝tau和磷酸化tau的大量积累（两者均比对照组增加20倍以上）。然而，SDLT的特征是在没有明显tau病理改变的情况下ε4等位基因频率增加（至少比AD组少10倍）。这些发现表明，与β淀粉样蛋白积累相比，tau加工与AD的相关性更具特异性，并且ε4等位基因的存在不是导致tau病理改变的病因。
