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BACKGROUND: Alleles of the apolipoprotein E (APOE) gene modulate risk for Alzheimer's disease, with carriers of the epsilon4 allele being at increased risk and carriers of the epsilon2 allele possibly at decreased risk compared with non-carriers. Our aim was to determine whether possession of an epsilon4 allele would confer children with a neural substrate that might render them at risk for Alzheimer's disease, and whether carriers of the epsilon2 allele might have a so-called protective cortical morphology. METHODS: 239 healthy children and adolescents were genotyped and had repeated neuroanatomic MRI (total 530 scans). Mixed model regression was used to determine whether the developmental trajectory of the cortex differed by genotype. FINDINGS: Cortical thickness of the left entorhinal region was significantly thinner in epsilon4 carriers than it was in non-epsilon4 carriers (3.79 [SE 0.06] mm, range 1.54-5.24 vs 3.94 [0.03] mm, 2.37-6.11; p=0.03). There was a significant stepwise increase in cortical thickness in the left entorhinal regions, with epsilon4 carriers having the thinnest cortex and epsilon2 carriers the thickest, with epsilon3 homozygotes occupying an intermediate position (left beta 0.11 [SE 0.05], p=0.02). Neuroanatomic effects seemed fixed and non-progressive, with no evidence of accelerated cortical loss in young healthy epsilon4 carriers. INTERPRETATION: Alleles of the apolipoprotein E gene have distinct neuroanatomic signatures, identifiable in childhood. The thinner entorhinal cortex in individuals with the epsilon4 allele might contribute to risk of Alzheimer's disease.

Original publication




Journal article


Lancet Neurol

Publication Date





494 - 500


Adolescent, Adult, Age Factors, Apolipoproteins E, Brain Mapping, Cerebral Cortex, Child, Female, Functional Laterality, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Interventional, Male, Models, Biological, Observation, Polymorphism, Genetic, RNA, Messenger, Regression, Psychology, Reverse Transcriptase Polymerase Chain Reaction