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Apolipoprotein E  4 Allele and Familial Aggregation of Alzheimer Disease
Maria Martinez, PhD;
Dominique Campion, PhD, MD;
Alexis Brice, MD;
Didier Hannequin, MD;
Bruno Dubois, MD;
Olivier Didierjean, RA;
Agnès Michon, MD;
Catherine Thomas-Anterion, MD;
Michèle Puel, MD;
Thierry Frebourg, PhD, MD;
Yves Agid, PhD, MD;
Françoise Clerget-Darpoux, PhD
Arch Neurol. 1998;55:810-816.
Objective To investigate the relationship among risk for Alzheimer disease (AD), familial aggregation of AD, and the apolipoprotein E (apoE)  4 allele in first-degree relatives of probands with AD and known apoE genotype.
Patients 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.
Design and Methods 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 4 allele by deriving the expected proportions of relatives with 0, 1, or 2 apoE 4 alleles conditionally on the proband's genotype.
Results Cumulative LTR for AD among first-degree relatives increased significantly with the number of 4 alleles present in the proband. By 90 years of age, LTRs in relatives of probands with 3/3, 3/4, and 4/4 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 4 carriers but not among relatives of non-4 carriers. The predicted proportion of 4 carriers in relatives of probands with 3/3 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 4 allele. Although aggregation of AD in families of probands with the 4 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 4 allele, even by 90 years of age.
Conclusion Our results support the hypothesis that the apoE 4 allele enhances AD susceptibility, but putative factors enhancing risk for AD remain to be found.
From Hôpital Saint-Louis (Dr Martinez), Hôpital de la Salpétrière (Drs Brice, Dubois, Michon, and Agid and Mr Didierjean) and Château de Longchamp (Dr Clerget-Darpoux), Institut National de la Santé et de la Recherche Médicale, Paris, France; the Department of Research, Centre Hospitalier Régional, Sotteville Les Rouen, France (Dr Campion); the Neurology Clinic (Dr Hannequin) and the Laboratory of Molecular Genetics (Dr Frebourg), Centre Hospitalier Universitaire de Rouen, France; the Neurology Clinic, Centre Hospitalier Universitaire de St Etienne, France (Dr Thomas-Anterion); and the Neurology Service, Hôpital de Purpan, Toulouse, France (Dr Puel).
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