Martinez M, Campion D, Brice A, Hannequin D, Dubois B, Didierjean O, Michon A, Thomas-Anterion C, Puel M, Frebourg T, Agid Y, Clerget-Darpoux F
Hôpital Saint-Louis, Institut National de la Santé et de la Recherche Médicale, Paris, France.
Arch Neurol. 1998 Jun;55(6):810-6. doi: 10.1001/archneur.55.6.810.
To investigate the relationship among risk for Alzheimer disease (AD), familial aggregation of AD, and the apolipoprotein E (apoE) epsilon4 allele in first-degree relatives of probands with AD and known apoE genotype.
Two hundred ninety subjects fulfilling the criteria of the National Institute of Neurological Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association for probable AD were ascertained from March 1, 1992, to December 31, 1996, through consecutive admissions in several university hospitals.
Family data were collected on 1176 first-degree relatives (parents and siblings), aged 40 to 90 years. Most living relatives underwent a clinical examination, whereas we relied on family history for clinical data for deceased or unavailable relatives. First, we conducted standard survival analyses to estimate cumulative lifetime risk (LTR) for AD among relatives and to investigate for sex and apoE genotype effects on LTR. Then, we assessed to what extent clustering of secondary AD could be explained by the apoE epsilon4 allele by deriving the expected proportions of relatives with 0, 1, or 2 apoE epsilon4 alleles conditionally on the proband's genotype.
Cumulative LTR for AD among first-degree relatives increased significantly with the number of epsilon4 alleles present in the proband. By 90 years of age, LTRs in relatives of probands with epsilon3/epsilon3, epsilon3/epsilon4, and epsilon4/epsilon4 genotypes were 29.2%, 46.1%, and 61.4%, respectively. Significant sex-by-apoE genotype interaction effects on LTR were observed. Women had about a 2-fold higher risk for AD than men among relatives of epsilon4 carriers but not among relatives of non-epsilon4 carriers. The predicted proportion of epsilon4 carriers in relatives of probands with epsilon3/epsilon3 genotype remains about 50% lower than the corresponding LTR for AD, indicating that familial clustering of AD is largely due to other factors than the apoE epsilon4 allele. Although aggregation of AD in families of probands with the epsilon4 allele is more prominent, we estimated that AD would not develop in about 30% of female and up to 60% of male relatives carrying at least 1 epsilon4 allele, even by 90 years of age.
Our results support the hypothesis that the apoE epsilon4 allele enhances AD susceptibility, but putative factors enhancing risk for AD remain to be found.
研究阿尔茨海默病（AD）风险、AD家族聚集性以及载脂蛋白E（apoE）ε4等位基因在AD先证者及其已知apoE基因型的一级亲属中的关系。
1992年3月1日至1996年12月31日期间，通过几家大学医院的连续入院病例，确定了290名符合美国国立神经疾病与中风研究所-阿尔茨海默病及相关疾病协会可能AD标准的受试者。
收集了1176名年龄在40至90岁之间的一级亲属（父母和兄弟姐妹）的家庭数据。大多数在世亲属接受了临床检查，而对于已故或无法联系到的亲属，我们依靠家族史获取临床数据。首先，我们进行了标准生存分析，以估计亲属中AD的累积终身风险（LTR），并研究性别和apoE基因型对LTR的影响。然后，通过根据先证者的基因型推导具有0、1或2个apoE ε4等位基因的亲属的预期比例，评估apoE ε4等位基因能够在多大程度上解释继发性AD的聚集情况。
一级亲属中AD的累积LTR随着先证者中存在的ε4等位基因数量显著增加。到90岁时，ε3/ε3、ε3/ε4和ε4/ε4基因型先证者的亲属的LTR分别为29.2%、46.1%和61.4%。观察到性别与apoE基因型对LTR有显著的交互作用。在ε4携带者的亲属中，女性患AD的风险大约是男性的2倍，但在非ε4携带者的亲属中并非如此。ε3/ε3基因型先证者的亲属中ε4携带者的预测比例仍比相应的AD LTR低约50%，这表明AD的家族聚集性很大程度上是由apoE ε4等位基因以外的其他因素导致的。尽管携带ε4等位基因的先证者家庭中AD的聚集更为明显，但我们估计，即使到90岁，携带至少1个ε4等位基因的女性亲属中约30%以及男性亲属中高达60%不会患AD。
我们的结果支持apoE ε4等位基因增强AD易感性的假设，但仍有待发现其他增加AD风险的假定因素。
