APOLIPOPROTEIN-E GENOTYPE IN PATIENTS WITH ALZHEIMERS-DISEASE - IMPLICATIONS FOR THE RISK OF DEMENTIA AMONG RELATIVES

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 a nd many persons having epsilon 4 survive cognitively intact to old age . We evaluated the lifetime risk of disease in 3,999 first-degree rela tives of 549 probands who met the criteria for probable or definite AD and whose ApoE genotypes were known. ApoE genotypes for relatives wer e not determined. After age 65 the risk among relatives was proportion al, 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 proband s were nearly identical at all ages to risks for relatives of ApoE 3/3 probands. The expected proportion of relatives having at least one ep silon 4 allele was calculated for each genotype group based on the dis tribution of parents, sibs, and offspring in the sample. Among relativ es ia 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, sug gesting 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 e psilon 4 allele do not develop AD. We also found that among male relat ives, risk of AD in the ApoE 3/4 group was similar to that for the Apo E 3/3 group but significantly less than the risk for the ApoE 4/4 grou p. 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 ris k for the ApoE 4/4 group. These findings are consistent with a sex-mod ification effect of the E4 isoform on disease susceptibility.