Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease

Dean, Douglas C.; Jerskey, Beth A.; Chen, Kewei; Protas, Hillary; Thiyyagura, Pradeep; Roontiva, Auttawat; O’Muircheartaigh, Jonathan; Dirks, Holly; Waskiewicz, Nicole; Lehman, Katie; Siniard, Ashley L.; Turk, Mari; Hou, Xue; Madsen, Sarah K.; Thompson, Paul M.; Fleisher, Adam; Huentelman, Matthew J.; Deoni, Sean; Reiman, Eric M.

doi:10.1001/jamaneurol.2013.4544

Cited by 224 publications

(209 citation statements)

References 42 publications

(52 reference statements)

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“…[1][2][3][4] In addition, APOE e4 may influence brain development. [5][6][7] However, the APOE e4 allele demonstrates antagonistic pleiotropy, with deleterious effects on cognition, brain morphometry, and activation primarily after 55 years of age, but no negative 8 or even beneficial effects in adults younger than 50 years 9,10 and children aged 6 to 15 years. [11][12][13] Compared to non-e4 carriers, healthy children carrying e4 (8-20 years) tended to have thinner entorhinal cortex, 5 while healthy infants carrying e4 showed altered brain measures in regions affected by AD.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13] Compared to non-e4 carriers, healthy children carrying e4 (8-20 years) tended to have thinner entorhinal cortex, 5 while healthy infants carrying e4 showed altered brain measures in regions affected by AD. 6,7 Whether these structural differences influence cognitive performance in children with e4 remains controversial.…”

Section: Discussionmentioning

confidence: 99%

“…Image processing included verification of protocol compliance and quality assurance. Automated morphometry using a modified FreeSurfer software was performed on the whole brain, and 7 subcortical and 20 cortical regions of interest (ROIs) from the standard FreeSurfer atlas were selected based on reported APOE e effects in children 5 and neonates, 6,7 or patients with AD. 4 Fractional anisotropy (FA) (corrected for B 0 inhomogeneities) in the same 7 subcortical ROIs was also assessed, since FA in these regions often increases during neurodevelopment.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, cortical surface areas were smallest in e2e4 but largest in e3e4 or e4e4. Hence, combining all e4 carriers might have attenuated or abolished group differences compared to non-e4 carriers, [5][6][7]12,14,40 and the larger parietal volumes in the youngest e2e4 children or the thinnest isthmus gyrus and temporal poles in the youngest e4e4 children might have been missed. In fact, our e4 carriers collectively had nonsignificantly thicker temporal lobes, contrasting with thinner entorhinal cortices in a prior study of healthy e4 children.…”

Section: Figurementioning

confidence: 99%

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Gray matter maturation and cognition in children with different APOE ε genotypes

et al. 2016

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Objective: The aims of the current study were to determine whether children with the 6 different APOE e genotypes show differences in gray matter maturation, particularly for those with e4 and e2 alleles, which are associated with poorer outcomes in many neurologic disorders.Methods: A total of 1,187 healthy children (aged 3-20 years, 52.1% boys, 47.9% girls) with acceptable data from the cross-sectional Pediatric Imaging Neurocognition and Genetics Study were evaluated for the effects of 6 APOE e genotypes on macroscopic and microscopic cortical and subcortical gray matter structures (measured with 3-tesla MRI and FreeSurfer for automated morphometry) and on cognition (NIH Toolbox).Results: Among APOE e4 carriers, age-related changes in brain structures and cognition varied depending on genotype, with the smallest hippocampi in e2e4 children, the lowest hippocampal fractional anisotropy in younger e4e4 children, the largest medial orbitofrontal cortical areas in e3e4 children, and age-dependent thinning of the entorhinal cortex in e4e4 children. Younger e4e4 children had the lowest scores on executive function and working memory, while younger e2e4 children performed worse on attention tasks. Larger parietal gyri in the younger e2e4 children, and thinner temporal and cingulate isthmus cortices or smaller hippocampi in the younger e4e4 children, predicted poorer performance on attention or working memory.Conclusions: Our findings validated and extended prior smaller studies that showed altered brain development in APOE e4-carrier children. The e4e4 and e2e4 genotypes may negatively influence brain development and brain aging at the extremes of age. Studying APOE e polymorphisms in young children may provide the earliest indicators for individuals who might benefit from early interventions or preventive measures for future brain injuries and dementia. Neurology ® 2016;87:585-594 GLOSSARY AD 5 Alzheimer disease; FA 5 fractional anisotropy; GAF 5 genetic ancestry factor; GAM 5 general additive model; PING 5 Pediatric Imaging, Neurocognition, and Genetics; ROI 5 region of interest; SES 5 socioeconomic status; WM 5 working memory.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Gray matter maturation and cognition in children with different APOE ε genotypes

et al. 2016

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“…Infants carrying ε4 alleles have less white and gray matter in areas of the parietal and temporal lobes, but more frontal lobe matter (a phenomenon showing some thematic resemblance to PASA; Dean et al 2014). Despite its long-held connection to dementia onset in the DS population (Coppus et al 2008;Deb et al 2000;Forte et al 2007;Hardy et al 1994;Lai et al 1999;Lambert et al 1996;Prasher et al 1997Prasher et al , 2008Royston et al 1994Royston et al , 1996, APOE status might also affect the course of neurocognitive growth and decline in those with trisomy 21.…”

Section: Apoe Statusmentioning

confidence: 99%

Assessing Cognitive Improvement in People with Down Syndrome: Important Considerations for Drug-Efficacy Trials

Fernandez

Reeves

2015

Cognitive Enhancement

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Experimental research over just the past decade has raised the possibility that learning deficits connected to Down syndrome (DS) might be effectively managed by medication. In the current chapter, we touch on some of the work that paved the way for these advances and discuss the challenges associated with translating them. In particular, we highlight sources of phenotypic variability in the DS population that are likely to impact performance assessments. Throughout, suggestions are made on how to detect meaningful changes in cognitive-adaptive function in people with DS during drug treatment. The importance of within-subjects evaluation is emphasized.

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Adolescent Cognitive Aptitudes and Later-in-Life Alzheimer Disease and Related Disorders

et al. 2018

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Key Points Question What are the associations between specific adolescent cognitive abilities and Alzheimer disease and related disorders in later life? Findings In this cohort study of 43 014 men and 42 749 women, lower adolescent memory for words, in women, and lower mechanical reasoning, in men, were associated with higher odds of Alzheimer disease and related disorders in later life. Meaning Low performance on certain specific measures of cognitive ability may indicate future risk of Alzheimer disease and related disorders as early as adolescence.

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Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease

Cited by 224 publications

References 42 publications

Gray matter maturation and cognition in children with different APOE ε genotypes

Gray matter maturation and cognition in children with different APOE ε genotypes

Assessing Cognitive Improvement in People with Down Syndrome: Important Considerations for Drug-Efficacy Trials

Adolescent Cognitive Aptitudes and Later-in-Life Alzheimer Disease and Related Disorders

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