Effects of APOE ε4 on Brain Development Apparent in Childhood

Brain DNA
Brain DNA
Those with ε4 homozygosity have the highest odds ratio of the earliest Alzheimer's onset.

Carriers of the APOE ε4 genotype show alterations in brain development as early as childhood, suggesting that the polymorphism may help identify individuals who may benefit from early interventions for neurological diseases.

The results confirm the findings of smaller, prior studies that showed carriers of the APOE ε4 genotype were more likely to develop Alzheimer’s disease than carriers of the ε2 and ε3 variants. There are 6 possible gene variants: ε2ε2, ε3ε3, ε4ε4, ε2ε3, ε2ε4, ε3ε4.

In this study, researchers led by Linda Chang, MD, of the University of Hawaii in Honolulu, evaluated the effects of the 6 APOE ε genotypes in 1187 healthy children (aged 3–20 years, 52.1% boys, 47.9% girls) via MRI and cognitive assessments.

Genotype appeared to influence age-related changes in brain structures and cognition in all APOE ε4 carriers, with the smallest hippocampi noted in ε2ε4 carriers; the lowest hippocampal fractional anisotropy in younger ε4ε4 carriers; the largest medial orbitofrontal cortical areas in ε3ε4 carriers; and age-dependent thinning of the entorhinal cortex in ε4ε4 carriers.

When evaluating cognition, the researchers found that younger ε4ε4 carriers had the lowest scores on executive function and working memory, while younger ε2ε4 carriers scored worse on attention tasks. Both larger parietal gyri in younger ε2ε4 carriers and thinner temporal and cingulated isthmus cortices or smaller hippocampi in younger ε4ε4 carriers predicted worse performance on measures of attention and working memory.

“… ε4 homozygosity might slow maturation of the hippocampus and cortical thickness, which in turn might negatively affect white matter and attention,” the authors wrote. “Mirroring these findings, older individuals with ε4 homozygosity had the highest prevalence for Alzheimer’s disease (50%–91%) and the greatest hippocampal and temporal lobe atrophy among genotypes.”

Notably, ε2ε4 carriers have a low odds ratio of Alzheimer’s until age 50, but the highest odds at age 70, while those with ε4 homozygosity have the highest odds ratio of the earliest Alzheimer’s onset, at approximately 68 years old.

“Given the urgent need to determine how early patients with AD should receive interventions or preventive treatments, a thorough understanding of how AD risk genes, such as APOE ε4, might independently or interactively influence the brain across the ages, is needed,” the authors concluded.


Chang L, Douet V, Bloss C, et al. Gray matter maturation and cognition in children with different APOE ε genotypes. Neurology. 2016;87:1–10.