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Early life Myelination Mediates the Effects of the APOE Genotype on Cognitive Development1Neurosurgery, Westchester Medical Center, Valhalla, NY, United States, 2Pediatrics, Women and Infant's Hospital, Providence, RI, United States, 3Pediatrics, Brown University Warren Alpert School of Medicine, Providence, RI, United States, 4University of Wisconsin, Madison, WI, United States
Synopsis
A growing focus in Alzheimer’s Disease (AD) research is understanding the earliest preclinical structural changes associated with the disorder. In prior studies our group has shown differences in early myelin content based on APOE genotype and we recently have shown preliminary results that APOE effects early longitudinal myelin and cognitive development. Nevertheless, these results fail to explain how differences in early brain anatomy lead to differences in cognitive development. This is the first study to explore and analyze if differences in early cognitive development based on APOE genotype is explained by differences in early myelin development in a large cohort of healthy neurotypical infants and young children stratified by presence or absence of at least one APOE ε4 allele.
Introduction
A growing focus in Alzheimer’s Disease (AD) research is understanding the earliest preclinical structural changes associated with the disorder. The apolipoprotein E (APOE) ε4 allele is the major genetic risk factor for developing AD. This gene is found in about one fourth of the general population and about 60% of individuals with AD dementia1-3. In prior studies our group has shown differences in early myelin content based on APOE genotype and we recently have shown preliminary results that APOE effects early longitudinal myelin and cognitive development4,5. Nevertheless, these results fail to explain how differences in early brain anatomy lead to differences in cognitive development.Purpose
This is the first study to explore and analyze if differences in early cognitive development based on APOE genotype is explained by differences in early myelin development in a large cohort of healthy neurotypical infants and young children stratified by presence or absence of at least one APOE ε4 allele.Methods
Longitudinal mcDESPOT data was successfully obtained from 223 infants (total of 403 imaging datasets) grouped according to APOE genotype. Subjects were between the ages of 3 months to 5 years and all data was acquired on a Siemens Tim Trio scanner during non-sedated sleep or while watching a movie. McDESPOT 3 pool post processing was used to calculate quantitative myelin water fraction (MWF) maps. In order to explore the role of differential myelin development on differential cognitive development a mediation analysis was performed. This analysis classified participant genotype as the main independent variable, myelin development parameters as the mediator and cognitive maturation parameters as the dependent variable. Myelin development parameters for each specific anatomical region within each subject along with cognitive development parameters for each cognitive composite score (obtained from the Mullens Scales for Early Learning) for each subject were obtained through mixed effects modeling6. Mediation analysis was performed with bootstrapping in a structural equation modeling framework. The Baron and Kenny steps for mediation were enforced in order to verify a true mediation relationship. Significant myelin model parameter mediation effects on the APOE genotype to cognitive model parameter relationships were defined as defined as p < 0.000819 (p < 0.05, corrected for 61 brain regions)Results
Using mixed effects modeling individual myelin parameters were calculated for each subject in each neuroanatomical region analyzed. Additionally, cognitive parameters for Early Learning Composite (ELC - a surrogate measure of IQ), Verbal Developmental Quotient (VDQ), and Non Verbal Developmental Quotient (NVDQ) were calculated for each subject. APOE genotype to NVDQ relationships were significantly mediated by the APOE genotype to α myelin development parameter (inflection in rate of myelin development) relationship in the insula, caudate, and medial lemniscus; by the APOE genotype to β myelin development parameter (onset of myelination) in the frontal lobe and uncinate fasiculus; by the APOE genotype to γ myelin development parameter (early rate of myelin formation) in the external capsule and medial leminiscus; and by the APOE genotype to η myelin development parameter (later rate of myelin development) in the cingulate gyrus, and frontal lobe6. APOE genotype to ELC relationships were significantly mediated by differential myelin development with regards to the α parameter in the caudate and insula; to the β parameter in the posterior corona radiata, uncinate fasciculus; to the γ parameter in the medial lemniscus, and putamen; and to the η parameter in the cerebral peduncle and cingulate gyrus. APOE genotype to VDQ relationships were significantly mediated by differential myelin development with respect to the α parameter in the insula, and cerebral peduncle; with respect to the β parameter in the cingulate gyrus, and uncinate fasiculus; with respect to the γ parameter in the medial lemniscus, and putamen; and with respect to the η parameter in the frontal and temporal lobe.Discussion/Conclusion
This is the first study to show that the longitudinal cognitive developmental differences based on APOE genotype can be explained by the myelin differences. Through the successful implementation of a true mediation analysis we show that the APOE genotype dependent myelin development, both positively and negatively mediates ELC, VDQ, and NVDQ scores. This provides significant insight that the presence of an altered longitudinal myelin trajectory in specific neuroanatomical locations provides insight for why ε4 carriers have an initial lower ELC, NVDQ, and VDQ scores. Reasons for this are still unclear, and as the first study to observe this relationship we hope that further work will continue to explore the role of myelin development as a mediator between APOE genotype and cognitive performance.Acknowledgements
No acknowledgement found.References
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