. Common Variants in Psychiatric Risk Genes Predict Brain Structure at Birth. Cereb Cortex. 2013 Jan 2; PubMed.

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  1. This is a timely and important study that supports other research demonstrating phenotypic differences between ApoE4 carriers and non-carriers that precede the symptomatic expression of Alzheimer's disease. It is a potentially important enough study that 1) it deserves replication before accepted as proven, and 2) ApoE4 gene dose effects should be sought. If, indeed, there is an ApoE4 effect in heterozygotes, one might expect a stronger effect in homozygotes. That said, the evidence that ApoE4 carriers have any clinically meaningful impairments relative to non-carriers during childhood and adolescence exists, but is relatively scant, and our own research has failed to show any significant difference in intellectual or occupational outcomes between adult ApoE4 carriers and non-carriers with similar educational backgrounds (1). Nonetheless, this is an important study that warrants further research.

    References:

    . Apolipoprotein E and intellectual achievement. J Am Geriatr Soc. 2002 Jan;50(1):49-54. PubMed.

  2. This study reports that ApoE4 is associated in neonates with a decrease in the volume of distinct brain areas affected in AD, such as the hippocampus, and with an increase, which is presumably compensatory, in the volume of other brain areas such as the parietal lobe. These findings have important implications with regard to both the mechanisms underlying the effects of ApoE4 and the functional clinical consequences of these effects. Previous studies in AD and corresponding cellular and animal models revealed that ApoE4 impairs neuronal plasticity and repair. The current finding that ApoE4 affects brain development in neonates, together with the documented pathological effects of ApoE4 in AD and following head trauma, suggests that the effects of ApoE4 on the brain are particularly pronounced when plasticity and repair mechanisms are most active and needed. It is interesting to note that the IQ scores in late childhood are not affected by ApoE4 (Taylor et al., 2011), and that there have even been reports that ApoE4 is associated with cognitive benefits at a young age (Wright et al., 2003). It is thus possible that, while the cellular and molecular effects of ApoE4 are accentuated during brain development and aging, their overall pathological consequences can be compensated for in the developing brain but not late in life. The current finding that in neonates ApoE4 associates with increases in the volume of some brain areas is consistent with this hypothesis. Accordingly, the study of ApoE4-driven processes in neonates and very young mice may provide clues to the mechanisms underlying the effects of ApoE4 and how they can be counteracted by the young, but not the aging, brain.

    The current study was biased intentionally towards parents with a psychiatric history. Previous studies suggest that the pathological effects of ApoE4 are accentuated by a "second hit" such as head injury or the elevation of brain Aβ. It would be of interest to extend the current study to parents, particularly mothers, with different histories, and to determine the extent to which this modulates the effects of ApoE4.

    References:

    . IQ, educational attainment, memory and plasma lipids: associations with apolipoprotein E genotype in 5995 children. Biol Psychiatry. 2011 Jul 15;70(2):152-8. PubMed.

    . Apolipoprotein E genotype predicts 24-month bayley scales infant development score. Pediatr Res. 2003 Dec;54(6):819-25. PubMed.

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