Apolipoprotein E-ε4 allele and familial risk in Alzheimer's disease

Recent studies have found an association between presence of apolipoprotein E (APOE) ε4 allele and Alzheimer's disease (AD). The present study compared the cumulative risk of primary progressive dementia (PPD) in relatives of AD probands carrying at least one copy of the ε4 allele with the relatives of AD probands not carrying ε4 and with relatives of non- demented controls. Our aim was to determine whether the familial aggregation of PPD in relatives of AD probands is primarily due to those carrying ε4. Seventy-seven neuropathologically diagnosed AD patients were obtained as probands through our Alzheimer's Disease Research Center Brain Bank. AD probands were genotyped for APOE. As a comparison group, 198 nondemented probands were also included. Through family informants, demographic and diagnostic data were collected on 382 first-degree relatives (age ≤45 years) of AD probands and 848 relatives of the controls. We found that the cumulative risk of PPD in both relatives of AD probands with and without the ε4 allele was significantly higher than that in the relatives of non- demented controls. However, the increased risk in the relatives of AD probands with the ε4 allele was marginally, but not significantly, lower than the risk in the relatives of probands without ε4. A greater likelihood of death by heart diseases over developing PPD in relatives of AD probands with ε4 (3.1-fold increase) was found compared to relatives of probands without ε4 (1.7-fold increase), especially prior to age 70, although the difference was not statistically significant. The increased familial risk for PPD in the relatives of AD probands with the APOE-ε4 allele relative to controls suggests that familial factors in addition to APOE-ε4 are risk factors for AD. Differential censorship from increased mortality of heart diseases may have prevented a higher incidence of PPD among the relatives of probands with ε4.