Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology
Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology
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DOI：
10.1212/01.wnl.0000070182.02537.84
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发表时间：
2003-07-22
期刊：
影响因子：
9.9
通讯作者：
Refolo, LM
中科院分区：
文献类型：
--
作者：
Pappolla, MA;Bryant-Thomas, TK;Refolo, LM
背景：流行病学和实验数据表明，胆固醇可能在阿尔茨海默病（AD）的发病机制中起作用。在AD转基因动物模型中，对胆固醇血症的调节会极大地改变淀粉样蛋白病理。
目的：确定人脑中淀粉样蛋白沉积与总胆固醇血症（TC）之间是否存在关系。
方法：作者回顾了40岁以上患者的尸检病例，并将胆固醇血症与淀粉样蛋白沉积的有无（淀粉样蛋白阳性与淀粉样蛋白阴性受试者）以及胆固醇血症与淀粉样蛋白负荷相关联。通过免疫组织化学和图像分析测量人脑中的淀粉样蛋白负荷。为消除载脂蛋白E（apoE）异构体对胆固醇水平的影响，对病例进行基因分型，并对apoE3/3受试者进行重复分析。
结果：在最年轻的受试者（40 - 55岁）中，胆固醇血症与早期淀粉样蛋白沉积（老年斑的弥漫型）的存在相关（对于所有apoE异构体，p = 0.000；对于apoE3/3受试者，p = 0.009）。在该组中，胆固醇血症从181增加到200时，发生淀粉样蛋白沉积的几率几乎增加了两倍，且与apoE异构体无关。逻辑回归模型显示出一致的结果（麦克法登ρ² = 0.445）。随着样本年龄的增加（>55岁：p = 0.491），有淀粉样蛋白和无淀粉样蛋白的受试者之间平均TC的差异消失，这可能反映了心血管死亡等其他可能性的影响。TC和淀粉样蛋白负荷不是线性相关的，这表明淀粉样蛋白的积累还涉及其他因素。
结论：血清高胆固醇血症可能是AD淀粉样蛋白病理发展的一个早期危险因素。
Background: Epidemiologic and experimental data suggest that cholesterol may play a role in the pathogenesis of AD. Modulation of cholesterolemia in transgenic animal models of AD strongly alters amyloid pathology. Objective: To determine whether a relationship exists between amyloid deposition and total cholesterolemia (TC) in the human brain. Methods: The authors reviewed autopsy cases of patients older than 40 years and correlated cholesterolemia and presence or absence of amyloid deposition (amyloid positive vs amyloid negative subjects) and cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. To remove the effect of apoE isoforms on cholesterol levels, cases were genotyped and duplicate analyses were performed on apoE3/3 subjects. Results: Cholesterolemia correlates with presence of amyloid deposition in the youngest subjects (40 to 55 years) with early amyloid deposition (diffuse type of senile plaques) (p = 0.000 for all apoE isoforms; p = 0.009 for apoE3/3 subjects). In this group, increases in cholesterolemia from 181 to 200 almost tripled the odds for developing amyloid, independent of apoE isoform. A logistic regression model showed consistent results (McFadden rho(2) = 0.445). The difference in mean TC between subjects with and without amyloid disappeared as the age of the sample increased (>55 years: p = 0.491), possibly reflecting the effect of cardiovascular deaths among other possibilities. TC and amyloid load were not linearly correlated, indicating that there are additional factors involved in amyloid accumulation. Conclusions: Serum hypercholesterolemia may be an early risk factor for the development of AD amyloid pathology.