Effects of family history and apolipoprotein E ε4 status on cognitive decline in the absence of Alzheimer dementia: The cache county study

Objective: To evaluate the influences of a family history of Alzheimer dementia (FHxAD) and the apolipoprotein E ε4 genotype (APOE ε4) on cognitive decline. Design, Setting, and Participants: Residents of Cache County, Utah, aged 65 years or older, were invited to participate. At baseline, 2957 participants provided DNA for genotyping of APOE and a detailed FHxAD. They also completed the Modified Mini-Mental State Examination. Cognitive status was reexamined after 3 and 7 years. We used mixed-effects models to examine the association among FHxAD, APOE ε4, and cognitive trajectories. Main Outcome Measure: Modified Mini-Mental State Examination score trajectories over time. Results: Compared with participants who did not have APOE ε4 or an FHxAD, those with APOE ε4 scored lower on the Modified Mini-Mental State Examination at baseline (-0.70 points; 95% confidence interval [CI], -1.15 to -0.24). Participants with an FHxAD and APOE ε4 differed less, if at all, in baseline score (-0.46 points; 95% CI, -1.09 to 0.16) but declined faster during the 7-year study (-9.75 points [95% CI, -10.82 to -8.67] vs -2.91 points [95% CI, -3.37 to -2.44]). After exclusion of participants who developed prodromal AD or incident dementia, the group with an FHxAD and APOE ε4 declined much less during the 7-year study (-1.54; 95% CI, -2.59 to -0.50). Conclusions: Much of the association among FHxAD, APOE ε4, and cognitive decline may be attributed to undetected incipient (latent) disease. In the absence of latent disease, the 2 factors do not appear individually to be associated with cognitive decline, although they may be additive.