The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Imaging and rare APOE alleles: Alzheimer disease as a developmental disorder
Abstract
The association between genetic variants in APOE and risk of Alzheimer disease (AD) is well known and there exists a considerable body of research into how the 3 major isoforms of APOE -encoded ApoE (ε2, ε3, and ε4) contribute to AD pathology.1 These investigations have largely focused on how these different isoforms differentially modulate β-amyloid aggregation and clearance, but a growing body of research suggests these alleles also have important developmental effects that may set up a neuroanatomical vulnerability to AD. Shaw et al.2 were the first to demonstrate that ε4 carriers exhibited cortical thinning and reduced volumes in AD-vulnerable brain regions during adolescence. Several years later, Knickmeyer et al.3 demonstrated that this effect was already present at birth, suggesting an origin in prenatal brain development. Complementary work in mice expressing human ApoE isoforms indicated that the ε4 allele reduces dendritic spine density as early as 1 month of age (approximately equivalent to a prepubertal child). The ε2 allele resulted in longer dendritic spines and increased complexity at 1 month of age.4 In addition, several studies have reported better cognitive performance in young ε4 carriers, indicating possible pleiotropic effects on cognition across the lifespan, such that ε4-related benefits in childhood reverse to become risk factors for cognitive impairment and dementia in later life.5 However, a 2012 meta-analysis found no beneficial results of the ε4 allele on cognition in children, adolescents, and young adults.6
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“the 53 genes are overexpressed in ‘adolescence’ and ‘young adult’ brain tissues in BrainSpan103, a transcriptomic atlas of the developing human brain, which is consistent with accumulating evidence suggesting Alzheimer’s disease may start decades before the onset of disease104,105”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [104]
Citations
Cites
Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases
Huang, Y., & Mahley, R. W. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.025 · Cited by 829
Shaw, P., Lerch, J. P., Pruessner, J. C., Taylor, K. N., Rose, A. B., Greenstein, D., Clasen, L., Evans, A., Rapoport, J. L., & Giedd, J. N. (2007) · The Lancet Neurology · doi:10.1016/s1474-4422(07)70106-0 · Cited by 257
ApoE4 Decreases Spine Density and Dendritic Complexity in Cortical Neurons In Vivo
Dumanis, S. B., Tesoriero, J. A., Babus, L. W., Nguyen, M. T., Trotter, J. H., Ladu, M. J., Weeber, E. J., Turner, R. S., Xu, B., Rebeck, G. W., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4026-09.2009 · Cited by 220
Revision of the apolipoprotein E compensatory mechanism recruitment hypothesis
Han, S. D., & Bondi, M. W. (2008) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2008.02.006 · Cited by 158
Common Variants in Psychiatric Risk Genes Predict Brain Structure at Birth
Knickmeyer, R. C., Wang, J., Zhu, H., Geng, X., Woolson, S., Hamer, R. M., Konneker, T., Lin, W., Styner, M., & Gilmore, J. H. (2014) · Cerebral Cortex · doi:10.1093/cercor/bhs401 · Cited by 149
Self-citationAPOE ε4 and cognitive function in early life: A meta-analysis.
Ihle, A., Bunce, D. J., & Kliegel, M. (2012) · Neuropsychology · doi:10.1037/a0026769 · Cited by 84
Gray matter maturation and cognition in children with different APOE ε genotypes
Chang, L., Douet, V., Bloss, C. S., Lee, K., Pritchett, A., Jernigan, T. L., Akshoomoff, N. A., Murray, S. S., Frazier, J. A., Kennedy, D. N., et al. (2016) · Neurology · doi:10.1212/wnl.0000000000002939 · Cited by 81
Hostage, C. A., Choudhury, K. R., Doraiswamy, P. M., Petrella, J. R., & Initiative, A. D. N. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054483 · Cited by 71
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Sorted by citations
Alzheimer Disease Genetics Consortium (ADGC), Kunkle, B. W., The European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, P. A. E. R. F. A. D. C. (., Grenier-Boley, B., Sims, R., Bis, J. C., Damotte, V., Naj, A. C., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0358-2 · Cited by 2,946
Neurodevelopmental Vulnerability in Alzheimer's Disease and Frontotemporal Dementia
Siguier, P. L. M., Planton, M., Pages, B., Gérard, F., Rafiq, M., Wolfrum, M., Archambault, O., Damour, A., Guidolin, V., Pefferkorn, P., et al. (2025) · European Journal of Neurology · doi:10.1111/ene.70322 · Cited by 4
Beazley, P. I. (2023) · BJPsych Bulletin · doi:10.1192/bjb.2023.60 · Cited by 1
Metadata
- Authors
- Knickmeyer, R. C., & Ross, M. E.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Venue
- Neurology
- Published
- 2016-08-09
- Volume
- 87
- Issue
- 6
- Pages
- 558-559
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- OpenAlex
- W2464588109
- Cited by
- 3
- References
- 8
- Citations by year
- 2025: 1 · 2023: 1 · 2019: 1
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- 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
- apolipoprotein E, APOE ε4, APOE ε2, Alzheimer's disease, neuroimaging, cortical thinning, brain development, dendritic spines, cognitive performance, amyloid-beta
- MeSH terms
- Alzheimer Disease, Developmental Disabilities, Humans, Apolipoprotein E4
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