APOE4 Protects the Cognitive Development in Children with Heavy Diarrhea Burdens in Northeast Brazil

Abstract

Polymorphisms in the apolipoprotein E (APOE) have constituted the major rationale to identify potential risk groups for developing late-onset Alzheimer's disease and help to predict recovery of cognitive function after brain injury. However, the APOE impact on cognitive development in children living in poor areas of the developing world, where we have discovered profound significant associations of early childhood diarrhea (at 0-2 y) with lasting impairments of growth, cognition, and school performance, is not known. Therefore, we conducted APOE genotyping in 72 Brazilian shantytown children under active surveillance since birth, using purified DNA extracted from buccal cell samples. We found a high frequency of APOE4 alleles (18% versus 9-11% expected) in children with lower diarrhea burdens. When we examined the children who experienced the heavier diarrhea burdens (greater than or equal to the median of seven illnesses in the first 2 y of life), those with APOE4 did significantly better in the coding subtest (p=0.01) when compared with APOE4-negative children with similar diarrhea burdens. Positive correlations between the APOE4 occurrence and coding scores remained, even after adjusting for family income, maternal education, and breast-feeding. Moreover, the APOE4-positive group, under heavy burdens of diarrhea, had preserved semantic fluency and the mean difference in fluency scores, p=0.025, a standardized coefficient for disproportional verbal fluency impairment. Our findings show that APOE4 is relatively common in favela children and suggest a protective role of the APOE4 allele in children with a history of heavy burdens of diarrhea in their first 2 y of life.

Apolipoprotein E knockout mice have accentuated malnutrition with mucosal disruption and blunted insulin-like growth factor I responses to refeeding

“…In addition, these mice recovered promptly from the malnutrition stress by rapidly gaining weight and skeletal growth and by healing the intestinal mucosal lesions, including adaptive enhancement of the intestinal absorptive area, as measured by villus area and height, as compared with the apoE-ko mice. These findings suggest that apoE has a critical role in intestinal maturation and adaptation to undernutrition, supporting our initial findings that apoE polymorphisms have cognitive developmental consequences after early childhood diarrhea in Brazilian shantytown children [53], and that this model may be helpful in elucidating potential mechanisms and approaches to improving the devastating long-term effects of undernutrition in developing children. The mechanisms and the role of apoE in enterocytes' adaptive responses during intestinal maturation and adaptation remain to be explored.…”

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

“…Interestingly, in our pilot studies with Brazilian shantytown children, we found that children with APOE4 had fewer Giardia infections (measured by positive stools), suggesting a possible role of APOE4 reducing Giardia and overall infection rates [49]. Therefore, we raised the hypothesis that the cholesterol bioavailability might be shifted from the parasite, which cannot synthesize cholesterol per se, to the developing brain.…”

Evolution of the human lifespan and diseases of aging: Roles of infection, inflammation, and nutrition

“…Two examples are under discussion, for which the evidence must be considered as preliminary. In hepatitis C infections, apoE4 carriers incurred less fibrotic damage by allele dose (114,115), whereas Brazilian slum children carrying apoE4 showed less diarrhea and associated impairments of cognitive development (116,117).…”