Apolipoprotein E genotype in patients with alzheimer's disease: Implications for the risk of dementia among relatives

Abstract

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.

Genetics of Alzheimer's Disease: A Centennial Review

“…controlling for ApoE genotype also found similar evidence supporting the presence of factors other than ApoE accounting for risk of AD [ [14][15][16]. In these studies, presence of an ApoE ε4 allele in the proband increased AD susceptibility in the relatives.…”

Contribution of Apolipoprotein E and Cathepsin D Genotypes to the Familial Aggregation of Alzheimer’s Disease

“…These studies are difficult to compare since comparison groups, diagnostic criteria and definition of familiality varied considerably. In agreement with our study, some authors studied the risk of AD in relatives stratified by the genotype of index subjects: according to Farrer et al [46] and Breitner et al [47], the risk of relatives of AD subjects and subjects from the general population increased with the presence of an apolipoprotein E4 allele. In contrast, Li et al [48] observed an increased risk of AD in relatives of AD patients in comparison with relatives of controls, which was independent of the presence of an apolipoprotein E4 allele in the patients.…”

Activation of estrogen receptor α increases and estrogen receptor β decreases apolipoprotein E expression in hippocampus in vitro and in vivo

“…Moreover, the presence of one or more ApoE4 alleles conferred a substantially greater risk of AD to women than to men (51). Epidemiological data indicate that women are particularly susceptible to the adverse effects of a single copy of ApoE4 isoform in that women with the ApoE3͞4 allele had the same risk of AD as the women with the ApoE4͞4 allele (50,52,53). A direct comparison of E4 heterozygous men and women revealed a significant 2-fold increased risk of AD in women (52).…”