Segmented Linear Mixed Model Analysis Reveals Association of the APOE ε4 Allele with Faster Rate of Alzheimer's Disease Dementia Progression

Background: APOE epsilon 4 allele carriers present with an increased risk for late-onset Alzheimer's disease (AD), show cognitive symptoms at an earlier age, and are more likely to transition from mild cognitive impairment (MCI) to dementia but despite this, it remains unclear whether or not the epsilon 4 allele controls the rate of disease progression. Objective: To determine the effects of the epsilon 4 allele on rates of cognitive decline and brain atrophy during MCI and dementia stages of AD. Methods: A segmented linear mixed model was chosen for longitudinal modeling of cognitive and brain volumetric data of 73 epsilon 3/epsilon 3, 99 epsilon 3/epsilon 4, and 39 epsilon 4/epsilon 4 Alzheimer's Disease Neuroimaging Initiative participants who transitioned during the study from MCI to AD dementia. Results: epsilon 4 carriers showed faster decline on MMSE, ADAS-11, CDR-SB, and MoCA scales, with the last two measures showing significant epsilon 4 allele-dose effects after dementia transition but not during MCI. The epsilon 4 effect was more prevalent in younger participants and in females. epsilon 4 carriers also demonstrated faster rates of atrophy of the whole brain, the hippocampus, the entorhinal cortex, the middle temporal gyrus, and expansion of the ventricles after transitioning to dementia but not during MCI. Conclusion: Possession of the epsilon 4 allele is associated with a faster progression of dementia due to AD. Our observations support the notion that APOE genotype not only controls AD risk but also differentially regulates mechanisms of neurodegeneration underlying disease advancement. Furthermore, our findings carry significance for AD clinical trial design.