Gray matter maturation and cognition in children with different APOE ε genotypes
Linda Chang1, Vanessa Douet2, Cinnamon Bloss2
1From the Department of Medicine (L.C., V.D., K.L., A.P., T.E.), John A. Burns School of Medicine, University of Hawaii and The Queen's Medical Center, Honolulu; Department of Psychiatry, School of Medicine (C.B.), Departments of Psychiatry and Cognitive Science (T.L.J., N.A.), and Department of Pathology (S.S.M.), University of California San Diego, La Jolla; Department of Psychiatry (J.F., D.N.K.), University of Massachusetts Medical School, Boston; Department of Psychiatry and Behavioral Sciences (D.G.A.), University of California, Davis; Departments of Pediatrics and Investigative Medicine (J.G.), Yale Child Health Research Center, Yale University School of Medicine, New Haven, CT; Boston Children's Hospital (W.E.K.), Harvard Medical School, Boston, MA; Sackler Institute for Developmental Psychobiology (B.J.C.), Weil Cornell Medical College, New York, NY; Department of Pediatrics (E.S.), University of Southern California, Los Angeles; and Children's Hospital (E.S.), Los Angeles, CA. lchang@hawaii.edu.
Insights
Apolipoprotein E (APOE) ε4 and ε2 genotypes impact brain development in children, affecting gray matter maturation and cognitive functions. These genetic variations may indicate early risks for future neurological issues, highlighting the need for early intervention.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- The apolipoprotein E (APOE) gene, specifically its ε4 allele, is linked to neurodegenerative diseases and altered brain development.
- Understanding the impact of different APOE ε genotypes on brain maturation in children is crucial for identifying early risk factors.
Purpose of the Study:
- To investigate differences in gray matter maturation and cognitive development among children with six distinct APOE ε genotypes.
- To specifically examine the influence of APOE ε4 and ε2 alleles on brain development and cognition in pediatric populations.
Main Methods:
- Utilized data from 1,187 healthy children (aged 3-20 years) from the Pediatric Imaging Neurocognition and Genetics Study.
- Employed 3-tesla MRI and FreeSurfer for automated morphometry to assess macroscopic and microscopic gray matter structures.
- Assessed cognitive functions using the NIH Toolbox, analyzing the effects of APOE ε genotypes.
Main Results:
- APOE ε4 carriers exhibited varied age-related brain and cognitive changes, including smaller hippocampi (ε2ε4), lower hippocampal fractional anisotropy (younger ε4ε4), larger medial orbitofrontal cortex (ε3ε4), and thinner entorhinal cortex (ε4ε4).
- Younger ε4ε4 children showed deficits in executive function and working memory, while younger ε2ε4 children had poorer attention.
- Brain structure variations, such as larger parietal gyri (younger ε2ε4) or smaller hippocampi (younger ε4ε4), correlated with attention and working memory performance.
Conclusions:
- Findings confirm and extend previous research on altered brain development in APOE ε4-carrier children.
- APOE ε4ε4 and ε2ε4 genotypes may adversely affect brain development and aging, particularly at younger and older ages within the studied range.
- Studying APOE ε polymorphisms in children can identify individuals who may benefit from early interventions for future brain injury and dementia prevention.
Objective:
The aims of the current study were to determine whether children with the 6 different APOE ε genotypes show differences in gray matter maturation, particularly for those with ε4 and ε2 alleles, which are associated with poorer outcomes in many neurologic disorders.
Methods:
A total of 1,187 healthy children (aged 3-20 years, 52.1% boys, 47.9% girls) with acceptable data from the cross-sectional Pediatric Imaging Neurocognition and Genetics Study were evaluated for the effects of 6 APOE ε genotypes on macroscopic and microscopic cortical and subcortical gray matter structures (measured with 3-tesla MRI and FreeSurfer for automated morphometry) and on cognition (NIH Toolbox).
Results:
Among APOE ε4 carriers, age-related changes in brain structures and cognition varied depending on genotype, with the smallest hippocampi in ε2ε4 children, the lowest hippocampal fractional anisotropy in younger ε4ε4 children, the largest medial orbitofrontal cortical areas in ε3ε4 children, and age-dependent thinning of the entorhinal cortex in ε4ε4 children. Younger ε4ε4 children had the lowest scores on executive function and working memory, while younger ε2ε4 children performed worse on attention tasks. Larger parietal gyri in the younger ε2ε4 children, and thinner temporal and cingulate isthmus cortices or smaller hippocampi in the younger ε4ε4 children, predicted poorer performance on attention or working memory.
Conclusions:
Our findings validated and extended prior smaller studies that showed altered brain development in APOE ε4-carrier children. The ε4ε4 and ε2ε4 genotypes may negatively influence brain development and brain aging at the extremes of age. Studying APOE ε polymorphisms in young children may provide the earliest indicators for individuals who might benefit from early interventions or preventive measures for future brain injuries and dementia.
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