Apolipoprotein E Genotype Predicts 24-Month Bayley Scales Infant Development Score

Abstract

Apolipoprotein E (APOE) regulates cholesterol and fatty acid metabolism, and may mediate synaptogenesis during neurodevelopment. To our knowledge, the effects of APOE4 isoforms on infant development have not been studied. This study was nested within a cohort of mother-infant pairs living in and around Mexico City. A multiple linear regression model was constructed using the 24-mo Mental Development Index (MDI) of the Bayley Scale as the primary outcome and infant APOE genotype as the primary risk factor of interest. Regression models stratified on APOE genotype were constructed to explore effect modification. Of 311 subjects, 53 (17%) carried at least one copy of the APOE4 allele. Mean (SD) MDI scores among carriers with at least one copy of APOE4 were 94.1 (14.3) and among E3/E2 carriers were 91.2 (14.0). After adjustment for covariates, APOE4 carrier status was associated with a 4.4 point (95% confidence interval: 0.1-8.7; p ϭ 0.04) higher 24-mo MDI. In the stratified regression models, the negative effects for umbilical cord blood lead level on 24-mo MDI score was approximately 4-fold greater among APOE3/APOE2 carriers than among APOE4 carriers. These results suggest that subjects with the E4 isoform of APOE may have advantages over those with the E2 or E3 isoforms with respect to early life neuronal/brain development. Apolipoprotein E (ApoE, protein; APOE, gene) is an intracellular cholesterol and fatty acid transport protein that plays an important role in neuronal metabolism. The gene for this protein has been localized on chromosome 19, and there are three common alleles-E2, E3, and E4 -which differ only on the basis of one or two amino acids on positions 112 and 158 (1, 2). ApoE is unique among lipoproteins in that it is involved in the recovery response of injured nerve tissue (3). In the brain, ApoE is synthesized by astrocytes and secreted into the extracellular space, where it then binds to cholesterol. There it is taken up by neurons via various ApoE receptors and incorporated into cell membrane structures and myelin (4, 5). The metabolism of cholesterol is believed to play a major role in neurite outgrowth and synaptogenesis (1-3), processes that are critical to neurodevelopment. Although the APOE4 isoform has been demonstrated to be an important risk factor for neurodegeneration, the role of ApoE genetic variants in neurodevelopment is also becoming increasingly apparent (6 -8).In conjunction with our understanding of the role of cholesterol and ApoE in neurodevelopment is an increasing recognition that genetic factors that alter the host response to environmental toxins may be particularly important during critical developmental windows that occur during fetal life (9, 10). Because cholesterol and fatty acids are critical to brain development, genetic factors that regulate their metabolism may influence development independently or may serve as modifiers of the response to maternal diet or maternal exposure to Received November 8, 2002; accepted May 26, 2003

Positive Effects of Cholinergic Stimulation Favor Young APOE ɛ4 Carriers

“…These findings support the recent proposition of APOE e4 antagonistic pleitropy (Han and Bondi, 2008;Wright et al, 2003), whereby the e4 variant might have contrasting effects across the lifespan. Our results suggest that this labile cognitive profile of e4 carriers may be related to and influenced by the integrity of the cholinergic system.…”

Apolipoprotein E4 as a Predictor of Outcomes in Pediatric Mild Traumatic Brain Injury

“…Indeed, the only difference between groups reflected better performance on the VMI among children with the allele. Other studies have reported better neuropsychological test performance among individuals with the e4 allele following TBI (Blackman et al, 2005;Han et al, 2007), and some researchers posit that the allele may serve a protective function during neurodevelopment (Oria et al, 2005;Wright et al, 2003). However, our findings of a positive effect are limited to only one cognitive outcome measure, and hence may not be robust.…”

Role of apolipoprotein E4 in protecting children against early childhood diarrhea outcomes and implications for later development

“…Hence the associations of APOE4 with protection against diarrhea and its subsequent cognitive decline seen in our studies and in those Mexican infants [70] bolster the need for experimental documentation of these relationships, their causality, and the ability of specific micronutrients to ameliorate the lasting effects of malnutrition in individuals lacking APOE4.…”