APOE e4 genotype, amyloid, and clinical disease progression in cognitively normal older adults

Document Type

Journal Article


IOS Press


Centre of Excellence for Alzheimer’s Disease Research and Care / School of Medical and Health Sciences




Originally published as: Hollands, S., Lim, Y. Y., Laws, S. M., Villemagne, V. L., Pietrzak, R. H., Harrington, K., ... & Rainey-Smith, S. R. (2017). APOEɛ4 Genotype, Amyloid, and Clinical Disease Progression in Cognitively Normal Older Adults. Journal of Alzheimer's Disease. 57(2) 411 - 422. Original article available here


Background: In cognitively normal (CN) older adults, carriage of the apolipoprotein E (APOE) ɛ4 allele is associated with increased risk for dementia of the Alzheimer type (AD-dementia). It is unclear whether this occurs solely through APOE ɛ4 increasing amyloid-β (Aβ) accumulation or through processes independent of Aβ.

Objective: To determine the extent and nature to which APOE ɛ4 increases risk for clinical disease progression in CN older adults.

Methods: Data from the total (n = 765) and Aβ-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 ɛ4 risk for clinical disease progression over a 72-month follow-up.

Results: With Aβ status unknown and risk from demographic characteristics controlled, ɛ4 carriage increased risk for clinical disease progression over 72 months by 2.66 times compared to risk of non-ɛ4 carriage. Re-analysis with Aβ status included showed that abnormally high Aβ increased risk for clinical disease progression over 72 months by 2.11 times compared to risk of low Aβ. However, with Aβ level known, ɛ4 carriage was no longer predictive of clinical disease progression.

Conclusion: In CN older adults, the risk of ɛ4 for clinical disease progression occurs through the effect of ɛ4 increasing Aβ levels.