Cited by 269Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCognitive Abilities and Testing

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Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease: A Cross-sectional Imaging Study

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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 N., Hua, Xue, Madsen, Sarah K., Thompson, Paul M., Fleisher, Adam S., Huentelman, Matthew J., Deoni, Sean C. L., Reiman, Eric M.·2014·JAMA Neurology

DOI 10.1001/jamaneurol.2013.4544PMC PMC4056558

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Abstract

IMPORTANCE: Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies. OBJECTIVE: To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD. DESIGN, SETTING, AND PARTICIPANTS: Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status. MAIN OUTCOMES AND MEASURES: Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age. RESULTS: Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions. CONCLUSIONS AND RELEVANCE: While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the genetic predisposition to AD. It raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.

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Authors: Dean, D. C., Jerskey, B. A., Chen, K., Protas, H., Thiyyagura, P., Roontiva, A., O'Muircheartaigh, J., Dirks, H., Waskiewicz, N., Lehman, K., Siniard, A. L., Turk, M. N., Hua, X., Madsen, S. K., Thompson, P. M., Fleisher, A. S., Huentelman, M. J., Deoni, S. C. L., & Reiman, E. M.
Affiliations: Brown University (US)
University of Arizona (US)
Banner Alzheimer’s Institute (US)
Advanced Baby Imaging Lab, School of Engineering, Brown University, Providence, Rhode Island7Department of Neuroimaging, King’s College London, Institute of Psychiatry, London, England
Translational Genomics Research Institute (US)
University of California, Los Angeles (US)
University of California San Diego (US)
Corresponding author: Deoni, Sean C. L.
ORCID: Dean, Douglas C.
Jerskey, Beth A.
Chen, Kewei
Protas, Hillary
Thiyyagura, Pradeep
Hua, Xue
Thompson, Paul M.
Fleisher, Adam S.
Huentelman, Matthew J.
Deoni, Sean C. L.
Reiman, Eric M.
Venue: JAMA Neurology
Publisher: American Medical Association (AMA)
Published: 2014-01-01
Volume: 71
Issue: 1
Pages: 11
ISSN: 2168-6149 (ISSN-L)
DOI: 10.1001/jamaneurol.2013.4544
PMC: PMC4056558
OpenAlex: W2160816909
Cited by: 263
References: 41
Citations by year: 2026: 10 · 2025: 15 · 2024: 18 · 2023: 24 · 2022: 14 · 2021: 15 · 2020: 20 · 2019: 27 · 2018: 19 · 2017: 19 · 2016: 25 · 2015: 25 · 2014: 29
FWCI: 19.13
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: JAMA Neurology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Research Portal (King's College London) (submittedVersion)
Funders: Wellcome Trust (096195)
National Institute on Aging (P30-AG-19610, R01AG031581, P30AG019610)
National Institute of Mental Health (R01MH087510)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Social Sciences › Psychology › Experimental and Cognitive Psychology › Cognitive Abilities and Testing
Keywords: late-onset Alzheimer's disease, APOE ε4, genetic risk, infants, myelin water fraction, white matter, gray matter volume, brain development, precuneus, cingulate cortex, lateral temporal cortex, occipitotemporal cortex, frontal lobe, early detection, Alzheimer's disease prevention
MeSH terms: Alleles, Alzheimer Disease, Child, Preschool, Cross-Sectional Studies, Heterozygote, Humans, Infant, Magnetic Resonance Imaging, Genetic Variation, Age of Onset, Genetic Predisposition to Disease, Early Diagnosis, Apolipoprotein E4, Cerebrum

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Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease: A Cross-sectional Imaging Study

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