To determine whether the ε4 allele affects rates of cognitive decline and brain atrophy during the mild cognitive impairment (MCI) and dementia stages of Alzheimer’s Disease (AD).

APOE ε4 allele carriers are more likely to develop late-onset AD at earlier ages, and are at an increased risk for transitioning from MCI to AD. Despite this, the prevailing view is that possessing the e4 allele does not change the rate of dementia progression.

A linear mixed model was used to analyze longitudinal cognitive and brain volumetric data of 64 ε3/ε3, 93 ε3/ε4, and 40 ε4/ε4 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants who during the study transitioned from MCI to AD dementia. 

Participants with ε3/ε4 and ε4/ε4 genotypes showed faster decline on MMSE (β = -.27 and -.45) and CDR-SB (β = .05 and .32) scales during the MCI stage and on MMSE (β = -.81 and -.1.11), ADAS-11 (β = .50 and .55), CDR-SB (β = .50 and .86), and MOCA (β = -.87 and -.1.64) scales after transition, with the last two measures showing significant ε4 allele-dose effects. The ε4 effect during the AD stage was more prevalent in participants who converted before the age of 75.5 years and in females. ε4 carriers also demonstrated faster atrophy rates of the whole brain, the hippocampus, and the middle temporal gyrus after transitioning to dementia but not during the MCI stage.

The ε4 allele is associated with a faster rate of AD progression. Our observations suggest that the APOE genotype not only controls AD risk but also modulates mechanisms of neurodegeneration underlying disease advancement. Our findings are also significant for future AD clinical trial designs.