Farrer L A, Cupples L A, van Duijn C M, Kurz A, Zimmer R, Müller U, Green R C, Clarke V, Shoffner J, Wallace D C
Department of Neurology, Boston University School of Medicine, MA 02118, USA.
Ann Neurol. 1995 Nov;38(5):797-808. doi: 10.1002/ana.410380515.
Numerous studies have shown that the risk of Alzheimer's disease (AD) is associated with the dose of the epsilon 4 allele of apolipoprotein E (ApoE). However, more than one third of AD patients lack epsilon 4 and many persons having epsilon 4 survive cognitively intact to old age. We evaluated the lifetime risk of disease in 3,999 first-degree relatives of 549 probands who met the criteria for probable or definite AD and whose ApoE genotypes were known. ApoE genotypes for relatives were not determined. After age 65 the risk among relatives was proportional, as much as 7 to 10% at age 85, to the number of epsilon 4 alleles present in the proband. Risks to relatives of ApoE 2/2 and 2/3 probands were nearly identical at all ages to risks for relatives of ApoE 3/3 probands. The expected proportion of relatives having at least one epsilon 4 allele was calculated for each genotype group based on the distribution of parents, sibs, and offspring in the sample. Among relatives in the ApoE 3/3 group, the lifetime risk for AD by age 90 was three times greater than the expected proportion of epsilon 4 carriers, suggesting that factors other than ApoE contribute to AD susceptibility. Furthermore, the 44% risk of AD by age 93 among relatives of ApoE 4/4 probands indicates that as many as 50% of people having at least one epsilon 4 allele do not develop AD. We also found that among male relatives, risk of AD in the ApoE 3/4 group was similar to that for the ApoE 3/3 group but significantly less than the risk for the ApoE 4/4 group. In contrast, among female relatives the risk for the ApoE 3/4 group was nearly twice that for the ApoE 3/3 group and identical to the risk for the ApoE 4/4 group. These findings are consistent with a sex-modification effect of the E4 isoform on disease susceptibility.
大量研究表明，阿尔茨海默病（AD）的风险与载脂蛋白E（ApoE）的ε4等位基因剂量相关。然而，超过三分之一的AD患者缺乏ε4，许多携带ε4的人认知功能完好地活到老年。我们评估了549名符合可能或确诊AD标准且已知ApoE基因型的先证者的3999名一级亲属的终身患病风险。未确定亲属的ApoE基因型。65岁以后，亲属中的患病风险与先证者中存在的ε4等位基因数量成比例，85岁时高达7%至10%。ApoE 2/2和2/3先证者的亲属在各年龄段的风险与ApoE 3/3先证者的亲属风险几乎相同。根据样本中父母、兄弟姐妹和后代的分布情况，计算了每个基因型组中至少有一个ε4等位基因的亲属的预期比例。在ApoE 3/3组的亲属中，90岁时AD的终身风险比ε4携带者的预期比例大三倍，这表明除ApoE外的其他因素也会导致AD易感性。此外，ApoE 4/4先证者的亲属在93岁时患AD的风险为44%，这表明至少有一个ε4等位基因的人中多达50%不会患AD。我们还发现，在男性亲属中，ApoE 3/4组的AD风险与ApoE 3/3组相似，但显著低于ApoE 4/4组的风险。相比之下，在女性亲属中，ApoE 3/4组的风险几乎是ApoE 3/3组的两倍，与ApoE 4/4组的风险相同。这些发现与E4异构体对疾病易感性的性别修饰效应一致。
