APOE ε4 and global cognitive functioning in individuals with autosomal dominant Alzheimer’s disease due to the PSEN1 E280A variant

Background: APOE-ε4 allele (APOE4) increases the risk for sporadic Alzheimer’s disease (AD) and is associated with an earlier onset of AD dementia. However, previous studies have shown conflicting results on the association of APOE4 with the age of dementia onset in individuals with autosomal dominant AD (ADAD). Here, we examined the impact of APOE4 genotype on the age-related trajectory of global cognitive function in mutation carriers and non-carriers from the Colombian ADAD kindred. Method: Data were obtained from a retrospective cohort of individuals from the largest known early-onset ADAD kindred, residing in Antioquia, Colombia. Analyses included 675 PSEN1 E280A carriers (ages 18 to 75; 141 with an APOE4 allele: APOE4+, and 534 without an APOE4 allele: APOE4-) and 594 non-carriers. The Mini-Mental State Examination (MMSE) was used to assess global cognitive functioning. Age-related trajectories were derived from cross-sectional log-transformed MMSE scores modeled using a restricted cubic spline model. Model parameters were estimated using a Hamiltonian Markov chain Monte Carlo method to compare APOE4+ versus APOE4- trajectories in the mutation carrier and non-carrier groups and estimate the age at onset of differences in global cognitive functioning. Result: Lower MMSE scores distinguished PSEN1 E280A mutation carriers from non-carriers at age 31.4, approximately 14 years before the average age of mild cognitive impairment (MCI) onset in this cohort. Among PSEN1 E280A mutation carriers, lower scores in MMSE began to significantly differentiate APOE4+ from APOE4- at age 45, the estimated average age of MCI onset in this kindred (figure 1). MMSE scores did not differentiate APOE4+ from APOE4- in those without the PSEN1 E280A mutation. Conclusion: Our findings suggest that age-related changes in cognitive function, as measured by the MMSE, are accelerated in ADAD mutation carriers who are APOE4+, compared to those who are APOE4-. Future longitudinal studies of PSEN1 mutation carriers are needed to further clarify the impact of APOE4 genotype on rates of cognitive decline, heterogeneity of clinical presentation, and clinical progression in the preclinical, MCI, and dementia stages.