APOE genotype and cognitive decline in a middle-aged cohort

Background: Most longitudinal studies of nondemented persons have reported greater cognitive decline among APOE ε4 carriers vs noncarriers. However, most studies involved elderly samples (aged 65+) and were not large enough to examine the three APOE alleles separately. Methods: Change in cognitive function was examined over a 6-year period using three neuropsychological tests among four APOE genotype groups (ε2/2 + ε2/3, ε3/3 (referent), ε4/2 + ε4/3, ε4/4). The population-based sample included 1,693 African Americans and 6,202 Caucasians initially ages 47 to 68. Results: There was increasingly greater cognitive decline from the ε2 group to the ε4/4 group in Caucasians for two of the three tests. The combination of APOE ε4 with hypercholesterolemia or diabetes showed the greatest cognitive decline. Among African Americans, only the test measuring psychomotor speed showed associations with APOE genotype. Conclusions: APOE ε4 is associated with greater cognitive decline in middle-aged Caucasian individuals, with a reduced decline among ε2 carriers. This suggests that the processes by which APOE genotype mediates dementia risk are operative well in advance of overt dementia.