Does ApoE4 Risk Begin in the Womb?

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.

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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 ARF related news story on Jagust et al., 2012; ARF related news story on Sheline et al., 2010; ARF related news story on 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

Comments

  1. I think this is consistent with a theme that is gradually emerging in the literature: ApoE has effects on the brain that are not simply related to its effect on the processing of Aβ. One always has to be concerned about the issue of multiple comparisons when so many statistical tests are run, but the authors seem to have handled that appropriately.

    What this paper says is that there are developmental effects of ApoE on the brain. There are a number of studies showing ApoE effects on brain structure and function in older people, but it's been difficult to tell whether this was related to early AD. There have been a small number of studies showing changes of glucose metabolism or brain activation in ApoE4 carriers who were young, and a couple of studies suggesting reduced brain volumes in ApoE4 carriers in childhood and adolescence. This work now extends those findings to an age where the only plausible explanation for brain structural change seems to be developmental. It is especially interesting that volume loss is particularly notable in the medial temporal lobe. It is also interesting that the increases in brain volume are in the parietal lobe. These are both, of course, brain regions affected by AD.

    The study does not tell us precisely what these volume changes mean, or how they may relate to AD risk. I do think the results are consistent with our recent findings (Jagust et al., 2012) inasmuch as they support the idea that ApoE affects the brain in ways unrelated to Aβ. Our findings of reduced metabolism in older ApoE4 carriers regardless of fibrillar amyloid status are certainly consistent with a lifelong or developmental effect. However, the brain regions affected metabolically by ApoE in our paper were much more widespread than those reported by Knickmeyer et al. This could reflect the fact that we're measuring different things (we measured metabolism; they measured structure), or that the ages of our subjects are extremely different.

    In any case, these are more data, combined with a limited number of human studies and a moderate number of animal studies, that suggest that ApoE affects the brain very early in life in ways that are independent from Aβ. How this relates to AD risk is very important and needs to be examined.

    View all comments by William Jagust

  2. This is a very interesting study looking at an incredible dataset of MRI scans from 272 infants. The size of the study is one of its great strengths, so when the researchers are analyzing ApoE genotype, they have enough individuals to make interesting comparisons (156 ApoE3/3 vs. 66 ApoE3/4). The exciting finding is that from whole brain scans, the researchers identified significant ApoE4-associated reductions in the hippocampus and other parts of the temporal lobe—areas that would be associated with early degeneration in Alzheimer's disease. The researchers found ApoE4-associated increases in other brain regions, such as parts of the parietal lobe. These findings add to a small but growing literature showing that ApoE4 affects brain structure and function in the absence of Alzheimer's-related pathological changes. The reductions in the temporal lobe, since they may persist through life, could be causally related to the increased risk of Alzheimer's disease in ApoE4 individuals. Thus, inheritance of ApoE4 may affect the risk of disease decades before amyloid plaques begin to accumulate.

    View all comments by Adam Green

  3. Very interesting study, and the outcome is important and worth considering seriously.

    View all comments by Hemachandra Reddy

  4. 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:

    Caselli RJ, Hentz JG, Osborne D, Graff-Radford NR, Barbieri CJ, Alexander GE, Hall GR, Reiman EM, Hardy J, Saunders AM. Apolipoprotein E and intellectual achievement. J Am Geriatr Soc. 2002 Jan;50(1):49-54. PubMed.

    View all comments by Richard Caselli
    • User Profile Image Jon Valla
      Grand Canyon University
    • Posted:

    This interesting paper adds to the growing literature of brain imaging studies examining the effects of ApoE in young subjects. It is novel work in that it moves the imaging timepoint younger than the previous imaging studies performed mostly in young adults (reviewed in part in Wolf et al., 2012). Therefore, this paper provides support for the early nature of ApoE-associated modifications of brain structure. Prior work in ApoE mice has shown early decreases in dendritic spine density and alterations in morphology (Dumanis et al., 2010). However, human data are lacking on this issue. Further, this work lends credence to examining the impacts of ApoE on brain physiology beyond its interactions with amyloid, including potential effects on inflammation and energetics, among others, in addition to development.

    References:

    Dumanis SB, Tesoriero JA, Babus LW, Nguyen MT, Trotter JH, Ladu MJ, Weeber EJ, Turner RS, Xu B, Rebeck GW, Hoe HS. ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo. J Neurosci. 2009 Dec 2;29(48):15317-22. PubMed.

    Wolf AB, Caselli RJ, Reiman EM, Valla J. APOE and neuroenergetics: an emerging paradigm in Alzheimer's disease. Neurobiol Aging. 2013 Apr;34(4):1007-17. PubMed.

    View all comments by Jon Valla
    • User Profile Image Ivan Maksimovich
      Clinic of Cardiovascular Diseases named after Most Holy John Tobolsky
    • Posted:

    This work is very interesting, given the number of MRI studies conducted to obtain statistically reliable data among newborns carrying ApoE4. The work shows that the initial decrease in the volume of both the hippocampus and the temporal lobes of the brain is seen among newborn infants, and therefore occurs in utero. This raises the possibility of future AD development. According to our data, no research of this kind has ever been conducted.

    The data in this paper have much in common with our research. We were able to reveal that children who descend from AD patients develop hypotrophic changes in the temporal and frontal-parietal brain regions at the ages of eight to 12; microcirculatory disorders are identified in the same regions as well (1,2).

    Similar changes were observed among their parents and grandparents, and are generally specific to the development of AD in its later stages (3,4).

    References:

    Maksimovich IV, Polyaev YA. The Importance of Early Diagnosis of Dyscircular Angiopathy of Alzheimer's Type in the Study of Heredity of Alzheimer's Disease. J Alzheimer's & Dementia, 6, 4, Supp. e 4, July 2010

    Maksimovich IV. Certain New Aspects of Etiology and Pathogenesis of Alzheimer's Disease. Adv Alzheimer Dis. 2012 Dec;1(3):68-76.

    Maksimovich IV. The Tomography Dementia Rating Scale (TDR) – the Rating Scale of Alzheimer's Disease Stages. Health. 2012 Sep;4(9A):712-9.

    Maksimovich IV. Vascular factors in Alzheimer’s disease. Health. 2012 Sep; 4(9A):735-42.

    View all comments by Ivan Maksimovich

  7. 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:

    Taylor AE, Guthrie PA, Smith GD, Golding J, Sattar N, Hingorani AD, Deanfield JE, Day IN. 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.

    Wright RO, Hu H, Silverman EK, Tsaih SW, Schwartz J, Bellinger D, Palazuelos E, Weiss ST, Hernandez-Avila M. Apolipoprotein E genotype predicts 24-month bayley scales infant development score. Pediatr Res. 2003 Dec;54(6):819-25. PubMed.

    View all comments by Daniel Michaelson

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References

News Citations

  1. Does ApoE4 Lower Brain Metabolism Independently of Aβ?
  2. A Foreshadowing? ApoE4 Disrupts Brain Connectivity in Absence of Aβ
  3. ApoE4 Linked to Default Network Differences in Young Adults

Paper Citations

  1. Taylor AE, Guthrie PA, Smith GD, Golding J, Sattar N, Hingorani AD, Deanfield JE, Day IN. 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.
  2. Wright RO, Hu H, Silverman EK, Tsaih SW, Schwartz J, Bellinger D, Palazuelos E, Weiss ST, Hernandez-Avila M. Apolipoprotein E genotype predicts 24-month bayley scales infant development score. Pediatr Res. 2003 Dec;54(6):819-25. PubMed.
  3. Jagust WJ, Landau SM, . Apolipoprotein E, not fibrillar β-amyloid, reduces cerebral glucose metabolism in normal aging. J Neurosci. 2012 Dec 12;32(50):18227-33. PubMed.
  4. Sheline YI, Morris JC, Snyder AZ, Price JL, Yan Z, D'Angelo G, Liu C, Dixit S, Benzinger T, Fagan A, Goate A, Mintun MA. APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42. J Neurosci. 2010 Dec 15;30(50):17035-40. PubMed.
  5. Filippini N, Macintosh BJ, Hough MG, Goodwin GM, Frisoni GB, Smith SM, Matthews PM, Beckmann CF, Mackay CE. Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7209-14. PubMed.

External Citations

  1. Apolipoprotein E4

Further Reading

Papers

  1. Jagust WJ, Landau SM, . Apolipoprotein E, not fibrillar β-amyloid, reduces cerebral glucose metabolism in normal aging. J Neurosci. 2012 Dec 12;32(50):18227-33. PubMed.
  2. Sheline YI, Morris JC, Snyder AZ, Price JL, Yan Z, D'Angelo G, Liu C, Dixit S, Benzinger T, Fagan A, Goate A, Mintun MA. APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42. J Neurosci. 2010 Dec 15;30(50):17035-40. PubMed.
  3. Filippini N, Macintosh BJ, Hough MG, Goodwin GM, Frisoni GB, Smith SM, Matthews PM, Beckmann CF, Mackay CE. Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7209-14. PubMed.

Primary Papers

  1. 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. 2013 Jan 2; PubMed.

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