Anatomically-distinct genetic associations of APOE ɛ4 allele load with regional cortical atrophy in Alzheimer's disease
Abstract
APOE epsilon4 is the best-established genetic risk factor for sporadic Alzheimer's disease (AD). However, while homozygotes show greater disease susceptibility and earlier age of onset than heterozygotes, they may not show faster rates of clinical progression. We hypothesize that there are differential APOE epsilon4 allele-load dependent influences on neuropathology across the brain. Our aim was to define the relationship between APOE epsilon4 allele load and regionally-specific brain cortical atrophy in Alzheimer's Disease (AD). For this reason voxel-based morphometry (VBM) was performed using T1-weighted MR images from 83 AD patients, contrasting regional cortical grey matter by APOE epsilon4 load according to either dominant or genotypic models. Patients fulfilled NINCDS-ADRDA criteria and were genotyped for APOE epsilon4 (15 epsilon4/epsilon4, 39 epsilon4/- and 29-/-). We observed that grey matter volume (GMV) decreased additively with increasing allele load in the medial (MTL) and anterior temporal lobes bilaterally. By contrast, a 2 degree-of-freedom genotypic model suggested a dominant effect of the APOE epsilon4 allele in the left temporal lobe. Brain regions showing a significant APOE epsilon4 allele load effect on GMV in AD included only some of those typically described as having greatest amyloid plaque deposition and atrophy. Temporal regions appeared to show a dominant effect of APOE epsilon4 allele load instead of the additive effect previously strongly associat…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
APOE ε4 is associated with more severe medial temporal tau pathology, neurodegeneration, and memory impairment in clinical studies.
“APOE ε4 is associated with more severe medial temporal tau pathology, neurodegeneration, and memory impairment”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Filippini et al 2009
Cites
Arnold, S. E., Hyman, B. T., Flory, J., Damasio, A. R., & Van Hoesen, G. W. (1991) · Cerebral Cortex · doi:10.1093/cercor/1.1.103 · Cited by 1,380 · see citing works
Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease
Meyer-Luehmann, M., Spires-Jones, T. L., Prada, C., Garcia-Alloza, M., de Calignon, A., Rozkalne, A., Koenigsknecht-Talboo, J., Holtzman, D. M., Bacskai, B. J., & Hyman, B. T. (2008) · Nature · doi:10.1038/nature06616 · Cited by 987 · see citing works
Devi, L., Prabhu, B. M., Galati, D. F., Avadhani, N. G., & Anandatheerthavarada, H. K. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1469-06.2006 · Cited by 792 · see citing works
Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology
Nagy, Z., Esiri, M. M., LeGris, M., & Matthews, P. M. (1999) · Acta Neuropathologica · doi:10.1007/s004010050997 · Cited by 85 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Wolk, D. A., Dickerson, B. C., Initiative, T. A. D. N., Weiner, M., Aiello, M., Aisen, P., Albert, M. S., Alexander, G., Anderson, H. S., Anderson, K., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001412107 · Cited by 248 · see citing works
Self-citationThe APOE ɛ4 allele modulates brain white matter integrity in healthy adults
Heise, V, Filippini, N., Ebmeier, K. P., & Mackay, C. E. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.90 · Cited by 152 · see citing works
Self-citationFalse positives in neuroimaging genetics using voxel-based morphometry data
Silver, M., Montana, G., & Nichols, T. E. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2010.08.049 · Cited by 146 · see citing works
Self-citationTzioras, M., Davies, C., Newman, A., Jackson, R., & Spires‐Jones, T. (2019) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12529 · Cited by 147 · see citing works
Cacciaglia, R., Molinuevo, J. L., Falcón, C., Brugulat‐Serrat, A., Sánchez‐Benavides, G., Gramunt, N., Esteller, M., Morán, S., Minguillón, C., Fauria, K., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.01.016 · Cited by 124 · see citing works
ApoE influences regional white-matter axonal density loss in Alzheimer's disease
Slattery, C. F., Zhang, J., Paterson, R. W., Foulkes, A. J. M., Carton, A., Macpherson, K., Mancini, L., Thomas, D. L., Modat, M., Toussaint, N., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.04.021 · Cited by 102 · see citing works
Understanding the cause of sporadic Alzheimer’s disease
Zetterberg, H., & Mattsson, N. (2014) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2014.915740 · Cited by 73 · see citing works
ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease
Li, Y., Macyczko, J. R., Liu, C.-C., & Bu, G. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.03.011 · Cited by 61 · see citing works
O'Dwyer, L., Lamberton, F., Matura, S., Scheibe, M., Miller, J., Rujescu, D., Prvulovic, D., & Hampel, H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0036024 · Cited by 34 · see citing works
Non-parametric Survival Analysis of EPG5 Gene with Age at Onset of Alzheimer’s Disease
Wang, K.-S., Liu, X., Xie, C., Liu, Y., & Xu, C. (2016) · Journal of Molecular Neuroscience · doi:10.1007/s12031-016-0821-9 · Cited by 12 · see citing works
- Authors
- Filippini, N., Rao, A., Wetten, S., Gibson, R. A., Borrie, M., Guzman, D., Kertesz, A., Loy-English, I., Williams, J., Nichols, T., Whitcher, B., & Matthews, P. M.
- Affiliations
- University of Oxford (GB)
- GlaxoSmithKline (United Kingdom) (GB)
- Western University (CA)
- University of Ottawa (CA)
- Cardiff University (GB)
- Corresponding author
- Matthews, Paul M.
- ORCID
- Venue
- NeuroImage
- Publisher
- Elsevier BV
- Published
- 2009-02
- Volume
- 44
- Issue
- 3
- Pages
- 724-728
- ISSN
- 1053-8119 (ISSN-L)
- OpenAlex
- W2017456650
- Cited by
- 143
- References
- 4
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 6 · 2023: 6 · 2022: 2 · 2021: 9 · 2020: 7 · 2019: 14 · 2018: 9 · 2017: 14 · 2016: 11 · 2015: 4 · 2014: 12 · 2013: 16 · 2012: 10
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- NeuroImage (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APOE ε4, Alzheimer's disease, cortical atrophy, gray matter volume, medial temporal lobe, anterior temporal lobe, genetic risk factors, disease progression, amyloid plaques, voxel-based morphometry
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Atrophy, Female, Genotype, Humans, Magnetic Resonance Imaging, Male, Temporal Lobe, Genetic Predisposition to Disease, Apolipoprotein E4
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
