APOE ε4 Genotype, Amyloid, and Clinical Disease Progression in Cognitively Normal Older Adults

Background: In cognitively normal (CN) older adults, carriage of the apolipoprotein E (APOE) epsilon 4 allele is associated with increased risk for dementia of the Alzheimer type (AD-dementia). It is unclear whether this occurs solely through APOE epsilon 4 increasing amyloid-beta (A beta) accumulation or through processes independent of A beta. Objective: To determine the extent and nature to which APOE epsilon 4 increases risk for clinical disease progression in CN older adults. Methods: Data from the total (n = 765) and A beta-imaged (n = 423) CN cohort in the Australian Imaging, Biomarker and Lifestyle (AIBL) Study of Ageing was analyzed using Cox proportional hazard models to estimate epsilon 4 risk for clinical disease progression over a 72-month follow-up. Results: With A beta status unknown and risk from demographic characteristics controlled, epsilon 4 carriage increased risk for clinical disease progression over 72 months by 2.66 times compared to risk of non-epsilon 4 carriage. Re-analysis with A beta status included showed that abnormally high A beta increased risk for clinical disease progression over 72 months by 2.11 times compared to risk of low A beta. However, with A beta level known, epsilon 4 carriage was no longer predictive of clinical disease progression. Conclusion: In CN older adults, the risk of epsilon 4 for clinical disease progression occurs through the effect of epsilon 4 increasing A beta levels.