Autosomal dominant Alzheimer’s disease (ADAD) is genetically determined, but variability in age of symptom onset suggests it may be influenced by additional genetic and environmental risk factors. Although the e⁴ allele of the apolipoprotein E (APOE4) gene and education level both influence clinical onset of dementia in sporadic Alzheimer’s disease (AD), it is unclear whether APOE4 affects onset of ADAD. Here, we investigated the effects of APOE4 and education on the clinical onset of ADAD.

We analyzed retrospective data from 675 presenilin-1 (PSEN1) E280A mutation carriers (141 APOE4 carriers, 534 APOE4 non-carriers) and 594 PSEN1 non-carriers (148 APOE4 carriers, 446 APOE4 non-carriers) from a Colombian kindred with ADAD. We used the Mini-Mental State Examination (MMSE) as a proxy for clinical impairment. Model parameters in both PSEN1 carriers and non-carriers were estimated using a Hamiltonian Markov chain Monte Carlo method. The age-related trajectories of APOE4 carriers versus non-carriers were compared in both PSEN1 carriers and non-carriers.

In PSEN1 carriers, lower MMSE scores began to significantly differentiate APOE4 carriers from non-carriers at age 45, the average age of mild cognitive impairment onset in this kindred. Years of education moderated the effect of APOE such that APOE4 carriers with lower educational levels had lower average MMSE scores in comparison to APOE4 non-carriers.

Our findings suggest 1) age-related changes in global cognitive function may be accelerated in ADAD mutation carriers who are APOE4 carriers, compared to APOE4 non-carriers; and 2) higher educational levels may have a protective effect against cognitive impairment, even in the presence of genetic risk factors. Further longitudinal studies are necessary to clarify the impact of both education and APOE4 genotype on ADAD clinical progression.