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Does ApoE4 Risk Begin in the Womb?

Adapted from a story that originally appeared on the Alzheimer Research Forum.

15 January 2013. Apolipoprotein E4 makes people prone to Alzheimer’s disease, but scientists don't know when that risk begins to manifest. Could it even be in the womb? New research suggests that the genetic variant can influence brain structure as early as infancy. Using magnetic resonance imaging (MRI) to study babies two weeks post-gestational term, Rebecca Knickmeyer and colleagues found that the regional brain volume was different in ApoE4 carriers relative to ApoE3 homozygotes. The changes were in AD-relevant brain areas. The finding “re-emphasizes how important the prenatal and early postnatal period may be for outcomes many years in the future,” said Knickmeyer, who is at the University of North Carolina, Chapel Hill. Published January 2 in Cerebral Cortex, the study also examined how other genetic variants linked to autism, schizophrenia, and other psychiatric illnesses affect brain structure.

In this first-ever neonatal MRI study incorporating genetics, Knickmeyer and senior author John Gilmore, also of the University of North Carolina, examined 272 babies. Mothers had normal ultrasounds and no major medical problems. However, 40 percent of the infants had a parent with a psychiatric illness. The researchers intentionally enriched their sample in this way, since studying only healthy volunteers makes it harder to pick up genetic effects that associate with illness.

The researchers used two MRI approaches to analyze brain volume—automated region-of-interest volumetry and tensor-based morphometry. They correlated the MRI data with ApoE4, and with other genetic variants linked to psychiatric illness, i.e., in genes for disrupted-in-schizophrenia 1 (DISC1), catechol-O-methyltransferase (COMT), neuregulin 1 (NRG1), estrogen receptor α (ESRα), brain-derived neurotrophic factor (BDNF), and glutamate decarboxylase 1 (GAD1). The MRI methods are complementary; automated volumetry looks at global volume and large brain regions, whereas the morphometry measures the brain point by point.

Relative to ApoE3 homozygotes, newborns carrying ApoE4 developed smaller temporal areas and smaller hippocampi—brain regions that typically degenerate in AD. Volume losses show up in similar areas in adults who carry an ApoE4 allele. Curiously, the researchers found that ApoE4 associated with a larger parietal lobe, another brain area that succumbs to AD, though usually later in the disease. The parietal gains “may be unique to infants and young children and could be beneficial,” Knickmeyer noted. Several previous papers have suggested that ApoE4 may confer cognitive benefit during childhood (Taylor et al., 2011; Wright et al., 2003), though the issue is not clear.

Gains and Losses
Newborns with the AD risk variant ApoE4 have smaller temporal areas (blue), whereas some parts of the parietal lobe are enlarged (red). Image courtesy of Rebecca C. Knickmeyer et al. Common Variants in Psychiatric Risk Genes Predict Brain Structure at Birth Cereb. Cortex bhs401 first published online January 2, 2013, doi:10.1093/cercor/bhs401, Fig. 4. Adapted and reprinted with permission of Oxford University Press

Scientists said the new findings are important and seem consistent with other work suggesting that ApoE4 disrupts brain metabolism and connectivity even in the absence of, or prior to, AD pathology (see Jagust et al., 2012; Sheline et al., 2010; Filippini et al., 2009). Bill Rebeck and Adam Green of Georgetown University, Washington, DC, cited the size of the dataset as one of the study’s strengths. “When the researchers analyze ApoE genotype, they have enough individuals to make interesting comparisons (156 ApoE3 homozygotes versus 66 ApoE4 carriers),” they wrote in an e-mail to Alzforum (see full comment below).

In follow-up, Knickmeyer and colleagues will run brain scans on the participants at one, two, four, and six years of age, correlating the MRI with comprehensive behavioral data on motor skills, language, and memory development.—Esther Landhuis.

Knickmeyer RC, Wang J, Zhu H, Geng X, Woolson S, Hamer RM, Konneker T, Lin W, Styner M, Gilmore JH. Common Variants in Psychiatric Risk Genes Predict Brain Structure at Birth. Cereb Cortex. 2 Jan 2013. Abstract