Effects of APOE4 and education on the clinical onset of autosomal dominant Alzheimer’s disease due to the PSEN1 E280A mutation (S39.004)

Abstract

<h3>Objective:</h3> Determine the impact of APOE4 genotype and education on the clinical onset of autosomal dominant Alzheimer’s disease. <h3>Background:</h3> 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. <h3>Design/Methods:</h3> We analyzed retrospective data from 675 presenilin-1 (<i>PSEN1</i>) E280A mutation carriers (141 APOE4 carriers, 534 APOE4 non-carriers) and 594 <i>PSEN1</i> 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 <i>PSEN1</i> 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 <i>PSEN1</i> carriers and non-carriers. <h3>Results:</h3> In <i>PSEN1</i> 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. <h3>Conclusions:</h3> 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. <b>Disclosure:</b> Mr. Barksdale has nothing to disclose. The institution of Dr. Langella has received research support from Alzheimer’s Association. Dr. Vasquez has nothing to disclose. David Fernando Aguillon, Sr. has nothing to disclose. Yinghua Chen has nothing to disclose. Dr. Su has nothing to disclose. Dr. ACOSTA-BAENA has nothing to disclose. Juliana Acosta Uribe has nothing to disclose. Ana Baena has nothing to disclose. Gloria Garcia-Ospina has nothing to disclose. Margarita Giraldo-Chica has nothing to disclose. Victoria Tirado has nothing to disclose. Mrs. Munoz has nothing to disclose. Miss Guzman Martinez has nothing to disclose. Dr. Rios Romenets has nothing to disclose. Mr. Oliveira has nothing to disclose. Dr. Yang has received personal compensation in the range of $500-$4,999 for serving as a invited speaker with Genentech, Inc.. The institution of Clara Vila-Castelar has received research support from Alzheimer’s Association. The institution of Clara Vila-Castelar has received research support from NIA . The institution of Dr. Pruzin has received research support from Alzheimer’s Association. Dr. Ghisays has received personal compensation for serving as an employee of Banner Alzheimer’s Institute. Joseph Arboleda-Velasquez has nothing to disclose. Dr. Kosik has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Rainwater Foundation. The institution of Dr. Kosik has received research support from National Institute of Health. The institution of Dr. Kosik has received research support from Hillblom Foundation. The institution of Dr. Kosik has received research support from Adelson Medical Foundation. The institution of Dr. Kosik has received research support from Alzheimer Association/Rainwater Foundation. The institution of Dr. Kosik has received research support from Thome Memorial FOundation. Dr. Reiman has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Denali, Green Valley, Zinfandel, and Takeda. Dr. Reiman has received stock or an ownership interest from Alkahest, Alzheon, Aural Analytics, Denali, and United Neuroscience.. Dr. Reiman has received intellectual property interests from a discovery or technology relating to health care. Dr. Reiman has received personal compensation in the range of $500-$4,999 for serving as a Member, National Advisory Council on Aging (NACA) with NIA. Francisco Lopera has nothing to disclose. Dr. Quiroz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Quiroz has received intellectual property interests from a discovery or technology relating to health care.