Effects of APOE4 and education on the clinical onset of autosomal dominant Alzheimer's disease due to the PSEN1 E280A mutation
Nicholas Barksdale 1, Stephanie Langella2, Daniel Vasquez3, David Aguillon3, Yinghua Chen4, Yi Su4, Natalia Acosta Baena5, Juliana Acosta Uribe3, Ana Baena3, Gloria Garcia-Ospina5, Margarita Giraldo-Chica3, Victoria Tirado3, Claudia Muñoz3, Claudia Guzmán3, Silvia Ríos-Romenets3, Gabriel Oliveira2, Hyun-Sik Yang6, Clara Vila-Castelar2, Jeremy Pruzin7, Valentina Ghisays4, Joseph Arboleda-Velasquez8, Kenneth Kosik9, Eric Reiman10, Francisco Lopera3, Yakeel T. Quiroz2
1Vanderbilt University, 2Massachusetts General Hospital, Harvard Medical School, 3Grupo de Neurociencias de Antioquia de la Universidad de Antioquia, Medellín, Colombia, 4Banner Alzheimer's Institute, Phoenix, Arizona, 5Universidad de Antioquia, 6Brigham and Women's Hospital, Harvard Medical School, 7Brigham and Women's Hospital, 8Schepens Eye Research Institute, Harvard Medical School, 9University of California Santa Barbara, 10Banner Alzheimer's Institute
Objective:
Determine the impact of APOE4 genotype and education on the clinical onset of autosomal dominant Alzheimer’s  disease.
Background:

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.

Design/Methods:

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.

Results:

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.

Conclusions:

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.

10.1212/WNL.0000000000202215