Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people
Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people
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DOI：
10.1136/jnnp.2004.054445
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发表时间：
2005-09-01
影响因子：
11
通讯作者：
Arnold, SE
中科院分区：
文献类型：
--
作者：
Bennett, DA;Schneider, JA;Arnold, SE
背景资料：载脂蛋白E（apolipoprotein E，APOE）e4等位基因与认知水平相关的神经生物学变化尚不清楚，目的：验证淀粉样蛋白负荷可以解释（介导）APOE e4等位基因与死亡前认知水平相关的假说。有44名临床诊断为阿尔茨海默病的受试者和50名没有痴呆的受试者参加了宗教秩序研究。他们接受了APOE等位基因状态的测定，在生命的最后一年进行了全面的认知测试，并在死亡时进行了脑尸检。从六个脑区域定量淀粉样蛋白β占据的皮质面积百分比和tau阳性神经元缠结的密度，并取平均值以产生淀粉样蛋白负荷和神经元缠结的汇总测量值。多元回归分析被用来研究淀粉样蛋白负荷是否可以解释等位基因状态对认知水平的影响，控制年龄，性别，和教育程度。结果：拥有至少一个APOE e4等位基因与接近死亡的认知功能水平较低（p = 0.04）。e4等位基因的影响减少了近60%，在控制淀粉样蛋白负荷的影响后不再显着，而有一个强大的负相关。淀粉样蛋白和认知之间的关系（p = 0.001）。因为先前的工作已经表明神经元缠结可以解释淀粉样蛋白对认知的关联，我们接下来检查淀粉样蛋白是否可以解释等位基因状态对缠结的影响。在一系列回归分析中，e4与缠结密度相关（p = 0.002），但E4等位基因的影响减少了50%以上，并不再显着控制后的影响淀粉样load.Conclusion：这些研究结果是一致的事件序列，即E4等位基因通过淀粉样蛋白沉积和随后的缠结形成，造成认知障碍。
Background: The neurobiological changes underlying the association of the apolipoprotein E (APOE) e4 allele with level of cognition are poorly understood.Objective: To test the hypothesis that amyloid load can account for (mediate) the association of the APOE e4 allele with level of cognition assessed proximate to death.Methods: There were 44 subjects with clinically diagnosed Alzheimer's disease and 50 without dementia, who had participated in the Religious Orders Study. They underwent determination of APOE allele status, had comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of tau positive neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multiple regression analyses were used to examine whether amyloid load could account for the effect of allele status on level of cognition, controlling for age, sex, and education.Results: Possession of at least one APOE e4 allele was associated with lower level of cognitive function proximate to death (p = 0.04). The effect of the e4 allele was reduced by nearly 60% and was no longer significant after controlling for the effect of amyloid load, whereas there was a robust inverse association. between amyloid and cognition (p = 0.001). Because prior work had suggested that neurofibrillary tangles could account for the association of amyloid on cognition, we next examined whether amyloid could account for the effect of allele status on tangles. In a series of regression analyses, e4 was associated with density of tangles (p = 0.002), but the effect of the e4 allele was reduced by more than 50% and was no longer significant after controlling for the effect of amyloid load.Conclusion: These findings are consistent with a sequence of events whereby the e4 allele works through amyloid deposition and subsequent tangle formation to cause cognitive impairment.