Itzhaki R F, Lin W R, Shang D, Wilcock G K, Faragher B, Jamieson G A
Molecular Neurobiology Laboratory, Department of Optometry and Vision Sciences, UMIST, Manchester.
Lancet. 1997 Jan 25;349(9047):241-4. doi: 10.1016/S0140-6736(96)10149-5.
The apolipoprotein E epsilon 4 (APOE-epsilon 4) allele is a risk factor for Alzheimer's disease (AD), but it is neither essential nor sufficient for development of the disease. Other factors-genetic or environmental-must therefore have a role. By means of a PCR we have detected herpes simplex virus type 1 (HSV1) in latent form in brains of elderly people with and without AD. We have postulated that limited reactivation of the virus causes more damage in AD patients than in elderly people without AD because of a difference in the hosts. We now report the APOE genotypes of AD patients and non-AD sufferers with and without HSV1 in brain.
DNA was extracted from 84 samples of brain from 46 AD patients (39 temporal lobe, 39 frontal lobe, three hippocampus) and from 75 samples of brain from 44 non-AD elderly people (33 temporal lobe, 36 frontal lobe, six hippocampus). PCR amplification was used to detect HSV1 thymidine kinase gene and the host APOE gene.
By multiple logistic regression, the APOE-epsilon 4 allele frequency was significantly higher in the patients positive for HSV1 in brain than in the HSV1-negative AD group, the HSV1-positive non-AD group, or the HSV1-negative non-AD group (52.8% vs 10.0%, 3.6%, and 6.3%, respectively). The odds ratio for APOE-epsilon 4 in the HSV1-positive AD group compared with HSV1-negative non-AD group was 16.8 (95% CI 3.61-77.8) and in the HSV1-negative AD group, 1.67 (0.21-13.4). We also compared APOE genotypes of 40 people who had recurrent cold sores and 33 non-sufferers; the APOE-epsilon 4 allele frequencies were 36% and 9%, respectively (p < 0.0001).
These findings suggest that the combination of HSV1 in brain and carriage of an APOE-epsilon 4 allele is a strong risk factor for AD, whereas either of these features alone does not increase the risk of AD. The findings in people with cold sores support our hypothesis that APOE-epsilon 4 and HSV1 together are damaging in the nervous system.
载脂蛋白Eε4（APOE-ε4）等位基因是阿尔茨海默病（AD）的一个风险因素，但它对于该疾病的发生既不是必需的，也不是充分的。因此，其他因素——遗传或环境因素——必定发挥了作用。通过聚合酶链反应（PCR），我们在患有和未患AD的老年人的大脑中检测到了潜伏形式的1型单纯疱疹病毒（HSV1）。我们推测，由于宿主的差异，该病毒的有限再激活在AD患者中比在未患AD的老年人中造成的损害更大。我们现在报告了大脑中存在和不存在HSV1的AD患者及非AD患者的APOE基因型。
从46例AD患者的84份脑样本（39份颞叶、39份额叶、3份海马体）以及44例非AD老年人的75份脑样本（33份颞叶、36份额叶、6份海马体）中提取DNA。采用PCR扩增来检测HSV1胸苷激酶基因和宿主APOE基因。
通过多因素逻辑回归分析，大脑中HSV1呈阳性的患者中APOE-ε4等位基因频率显著高于HSV1呈阴性的AD组、HSV1呈阳性的非AD组或HSV1呈阴性的非AD组（分别为52.8%、10.0%、3.6%和6.3%）。与HSV1呈阴性的非AD组相比，HSV1呈阳性的AD组中APOE-ε4的优势比为16.8（95%可信区间为3.61 - 77.8），而在HSV1呈阴性的AD组中为1.67（0.21 - 13.4）。我们还比较了40例复发性唇疱疹患者和33例非患者的APOE基因型；APOE-ε4等位基因频率分别为36%和9%（p < 0.0001）。
这些研究结果表明，大脑中HSV1与APOE-ε4等位基因携带相结合是AD的一个强风险因素，而单独的这些特征均不会增加AD的风险。唇疱疹患者的研究结果支持了我们的假设，即APOE-ε4和HSV1共同作用会对神经系统造成损害。
