06 Dec 2013

Though most Alzheimer’s disease develops in old age, new research suggests that its top risk gene, apolipoprotein E4 (ApoE4) influences the development of the brain at the beginning of life. In a magnetic resonance imaging (MRI) study of 162 babies up to 25 months of age, those who inherited the ApoE4 allele lagged behind noncarriers in the rate at which their brains formed myelin, the insulating material around nerve cells. In addition, the volume of cortical areas typically affected in AD was smaller in E4 infants, and frontal areas larger. Reported in the November 29 JAMA Neurology, the data “show that [the ApoE4] risk gene is doing something almost right at the start of brain development,” said Sean Deoni of Brown University, Providence, Rhode Island, who co-led the study with Eric Reiman of Banner Alzheimer’s Institute, Phoenix. Despite methodological challenges that make infant studies hard to execute and interpret, scientists find the new data intriguing and say it is worth exploring how E4-linked neurodevelopmental patterns might make the brain vulnerable to neurodegeneration in later life. The paper gives legs to the provocative idea that Alzheimer’s is, in some measure, a developmental illness.

In people carrying the ApoE4 allele, glucose metabolism in AD-relevant brain areas drops while cognition is still intact (Protas et al., 2013). Moreover, the brain’s network connectivity becomes disrupted in young adults and older E4 carriers without amyloid pathology (see Apr 2009 news story; Dec 2010 news story). Even in healthy children, MRIs have shown cortical thinning and reduced volumes in AD-vulnerable brain regions among ApoE4 carriers (Shaw et al., 2007). In a prior infant analysis, Rebecca Knickmeyer, University of North Carolina, Chapel Hill, and colleagues looked at brain-volume changes in 272 healthy babies, correlating the MRI data with ApoE4 and with genetic variants linked to autism, schizophrenia, and other psychiatric disorders (see Jan 2013 news story). These researchers also found reduced volumes in specific brain regions compared to ApoE4-negative infants.

For the current paper, first author Douglas Dean and colleagues looked at myelination and gray-matter volume in normal infants with no family history of AD or other neurologic or psychiatric disorders. Brown University researchers conducted the scans between 2010 and 2012 as a part of ongoing neuroimaging studies that did not initially focus on AD. “Our goal was to map out normal brain development and study genetic and environmental factors affecting that,” Deoni told Alzforum. Along with the MRI scans, the researchers had stored DNA for genetic analyses. “We were holding saliva samples in the fridge, waiting for something to do with them,” Deoni recalled. At a neuropsychiatry meeting several years ago, Reiman suggested looking for brain abnormalities in relation to one particular gene, ApoE4, and a collaboration was born.

The white-matter MRI analyses suggested that myelination begins a few weeks earlier in E4 carriers than noncarriers. However, by 1 year of age, the noncarriers have caught up, and at 2½ years they have more myelin than E4 carriers in all white-matter areas. Overall, the data suggest that despite starting the process early, E4 babies seem to lay down myelin more slowly than noncarriers.

On gray-matter volumetric scans, the precuneus, posterior/middle cingulate, and occipitotemporal and left lateral temporal regions looked smaller in E4 carriers. These brain regions are among those that succumb to AD first, particularly the precuneus. However, the sample size fell to 59 in this analysis because scans for infants younger than 6 months were excluded because their gray/white matter contrast was insufficient, and many babies in the older subgroup woke during the procedure, disrupting data collection. Typically parents bring babies to the lab in late evening and settle them in nursery rooms near the scanner. Once asleep, the precious study subjects are swaddled and gingerly wheeled in for the 20-minute white-matter scan, which is adjusted to be 25 times quieter than adult scans. Next, the scientists run the higher-resolution volumetric scan, but this procedure generates more of the machine’s characteristic clanking noises and many infants wake during it.

It is difficult to compare studies that use different cohorts and methods, and indeed the volumetric data in the current analysis seemed to disagree with the infant MRI study by Knickmeyer and colleagues. The prior analysis found larger volumes in the precuneus and other parietal areas of E4 carriers, but Dean and colleagues reported the opposite—those regions looked smaller in babies with the risk gene. Knickmeyer suspects the discrepancy arose from low statistical power due to methodological challenges with gray-matter analyses in the current study. Delineating gray matter properly in the infant brain can be tricky. Nevertheless, Knickmeyer finds the myelination data compelling. “As with our findings on gray-matter volume, [their results] suggest that carrying the E4 allele results in an anatomic vulnerability that is present very early in life but does not impact cognitive function until neurodegenerative processes associated with aging come into play,” she noted in an email to Alzforum. In an accompanying editorial, John Growdon and Brad Hyman of Massachusetts General Hospital, Boston, also suggest the current findings “should generate further exploration into molecular mechanisms that link APOE and neurodevelopment.”

How might slower myelination in E4 infants predispose toward neurodegenerative disease later in life? Deoni suspects that ApoE may be important for repairing damaged myelin and that E4 compromises this ability. ApoE mediates the metabolism of two key components of myelin—cholesterol and lipids—and older work has suggested loss of myelin in the AD brain (Malone and Szoke, 1985). If AD pathology wears down myelin, E4 carriers may be slower at repairing the damage, thus making them more susceptible to AD than people without the risk allele, Deoni suggested.

When knocked into experimental mice, human ApoE4 decreases spine density and dendritic complexity in cortical neurons (Dumanis et al., 2009), noted Bill Jagust of the University of California, Berkeley. “That suggests there are developmental effects related to ApoE4.”

Connecting ApoE4-associated myelination defects with later neurodegeneration will require extensive longitudinal study. Thus far, the additional MRI scans suggest that ApoE4-related myelination and gray-matter volumes are becoming more pronounced as the babies get older, Deoni told Alzforum.—Esther Landhuis

Comments

1. • Andrew Wolf
     University of Colorado School of Medicine
   • Posted: 18 Dec 2013

   This is a nice study that adds to the significant literature of brain imaging studies examining the effects of ApoE. It is fairly unique due to the study of infants and the examination of myelination. It will be interesting to see what mechanisms emerge regarding ApoE's role in neurodevelopment (altered cholesterol/lipid metabolism certainly seems plausible) and how ApoE modulation of brain structure may impact risk for AD over a lifetime. Additionally, it lends credence to the idea of ApoE playing a multifactorial role in AD risk.

   View all comments by Andrew Wolf
2. • Ivan Maksimovich
     Clinic of Cardiovascular Diseases named after Most Holy John Tobolsky
   • Posted: 18 Dec 2013

   This is a very important and interesting study on a large MRI sample showing apolipoprotein E4's (ApoE4) influence on the formation of myelin and the development of hypotrophic phenomena in the brain tissue of children in the first two years of life. This process may in turn lead to neurodegeneration and progression of AD. The data obtained have something in common with the data discussed on Alzforum in January 2013, when R. Knickmeyer and colleagues from the University of North Carolina reported hippocampal and temporal lobes hypotrophy in newborns with ApoE4 (Knickmeyer et al., 2013). These studies confirm our data obtained among children aged 8-12 (Maksimovich et al., 2010; Maksimovich, 2012) who were direct descendants of patients suffering from AD and who also had hypotrophic symptoms in hippocampal and temporal lobes tissue in the brain (Maksimovich, 2012; Maksimovich, 2013).

   References:

   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.

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

   Maksimovich IV. Certain new aspects of etiology and pathogenesis of Alzheimer’s disease. Adv Alzheimer Dis. 2012 Dec;1(3):68-76.

   Maksimovich IV. Disorders of cerebrovascular angioarchitectonics and microcirculation in the etiology and pathogenesis of Alzheimer’s disease. Adv Alzheimer Dis. 2013 Dec;(2)4:171-181.

   View all comments by Ivan Maksimovich

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References

News Citations

1. ApoE4 Linked to Default Network Differences in Young Adults 10 Apr 2009
2. A Foreshadowing? ApoE4 Disrupts Brain Connectivity in Absence of Aβ 19 Dec 2010
3. Does ApoE4 Risk Begin in the Womb? 8 Jan 2013

Paper Citations

1. Protas HD, Chen K, Langbaum JB, Fleisher AS, Alexander GE, Lee W, Bandy D, de Leon MJ, Mosconi L, Buckley S, Truran-Sacrey D, Schuff N, Weiner MW, Caselli RJ, Reiman EM. Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for Alzheimer disease. JAMA Neurol. 2013 Mar 1;70(3):320-5. PubMed.
2. Shaw P, Lerch JP, Pruessner JC, Taylor KN, Rose AB, Greenstein D, Clasen L, Evans A, Rapoport JL, Giedd JN. Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol. 2007 Jun;6(6):494-500. PubMed.
3. Malone MJ, Szoke MC. Neurochemical changes in white matter. Aged human brain and Alzheimer's disease. Arch Neurol. 1985 Nov;42(11):1063-6. PubMed.
4. 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.

External Citations

1. ApoE4
2. ongoing neuroimaging studies

Further Reading

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.
2. Protas HD, Chen K, Langbaum JB, Fleisher AS, Alexander GE, Lee W, Bandy D, de Leon MJ, Mosconi L, Buckley S, Truran-Sacrey D, Schuff N, Weiner MW, Caselli RJ, Reiman EM. Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for Alzheimer disease. JAMA Neurol. 2013 Mar 1;70(3):320-5. PubMed.
3. Shaw P, Lerch JP, Pruessner JC, Taylor KN, Rose AB, Greenstein D, Clasen L, Evans A, Rapoport JL, Giedd JN. Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol. 2007 Jun;6(6):494-500. PubMed.

News

1. Does ApoE4 Risk Begin in the Womb? 8 Jan 2013
2. A Foreshadowing? ApoE4 Disrupts Brain Connectivity in Absence of Aβ 19 Dec 2010
3. ApoE4 Linked to Default Network Differences in Young Adults 10 Apr 2009