Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease
Abstract
Background The APOE epsilon4 allele has emerged as a major genetic factor for Alzheimer disease (AD), and its presence has been associated with an increase in beta-amyloid senile plaques (SPs) and neuritic plaques (NPs). Whether it affects neurofibrillary tangle (NFT) accumulation or cholinergic losses in AD remains controversial. In contrast, the epsilon2 allele has been reported to decrease the risk for AD. However, its effect on neuropathologic and neurochemical markers of disease is unclear. Objective To investigate the relationship between APOE genotype and both pathologic severity and cholinergic dysfunction in AD. Methods In an autopsy series of 296 patients with AD, APOE genotype was determined in blood or postmortem brain tissue. NPs and NFTs were counted in the midfrontal (MF), inferior parietal (IP), and superior temporal (ST) cortices and the hippocampus. Choline acetyltransferase (ChAT) activity was assessed in the MF, IP, and ST cortices. Results Compared with patients with no epsilon4 alleles, epsilon4 carriers (patients with either one or two epsilon4 alleles) did not differ significantly with regard to any pathologic or neurochemical measures, except for increased ST NPs. However, when cases were stratified into three groups according to the number of epsilon4 alleles, patients with two epsilon4 alleles had significantly more NPs and NFTs in all neocortical regions than those with either one or no epsilon4 alleles. The association of the epsilon4/4 genotype w…
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?
The ε4 allele is the strongest common genetic risk factor for sporadic AD.
“The ε4 allele is the strongest common genetic risk factor for sporadic AD”
From Plasma ApoE proteotyping for ApoE ε4 stratification in the anti-amyloid therapies era (2026) · cites this paper as [7]
The ε4 allele influences disease risk, age at onset, and multiple aspects of the biological phenotype in a dose-dependent manner.
“influencing disease risk, age at onset, and multiple aspects of the biological phenotype in a dose-dependent manner [6, 7].”
From Plasma ApoE proteotyping for ApoE ε4 stratification in the anti-amyloid therapies era (2026) · cites this paper as [7]
A more conclusive study with many more subjects strongly suggested that apoε4 allele dosage is associated with increased neuritic plaques in AD.
“Nonetheless, a more conclusive study with many more subjects strongly suggested that apoε4 allele dosage is associated with increased neuritic plaques in AD (Tiraboschi et al., 2004).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Tiraboschi et al., 2004
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920 · see citing works
Apolipoprotein E ε4 allele, AD pathology, and the clinical expression of Alzheimer’s disease
Bennett, D. A., Wilson, R. S., Schneider, J. A., Evans, D. A., Aggarwal, N. T., Arnold, S. E., Cochran, E. J., Berry-Kravis, E., & Bienias, J. L. (2003) · Neurology · doi:10.1212/01.wnl.0000042478.08543.f7 · Cited by 282 · see citing works
Olichney, J. M., Hansen, L. A., Galasko, D., Saitoh, T., Hofstetter, C. R., Katzman, R., & Thal, L. J. (1996) · Neurology · doi:10.1212/wnl.47.1.190 · Cited by 216 · see citing works
Self-citationGender and age modify the association between APOE and AD-related neuropathology
Ghebremedhin, E., Schultz, C., Thal, D. R., Rüb, U., Ohm, T. G., Braak, E., & Braak, H. (2001) · Neurology · doi:10.1212/wnl.56.12.1696 · Cited by 108 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Amyloid Precursor Protein Processing and Alzheimer's Disease
O'Brien, R. J., & Wong, P. C. (2011) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-061010-113613 · Cited by 2,061 · see citing works
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · see citing works
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425 · see citing works
Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,227 · see citing works
“allele, which markedly increases risk and reduces the age of onset (46), likely by accelerating the onset of brain Aβ accumulation (6-9).”
Apolipoprotein E in Alzheimer’s disease and other neurological disorders
Verghese, P. B., Castellano, J. M., & Holtzman, D. M. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70325-2 · Cited by 857 · see citing works
Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders
Mahley, R. W. (2016) · Journal of Molecular Medicine · doi:10.1007/s00109-016-1427-y · Cited by 837 · see citing works
Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
Holtzman, D. M., Herz, J., & Bu, G. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006312 · Cited by 782 · see citing works
History and progress of hypotheses and clinical trials for Alzheimer’s disease
Liu, P.-P., Xie, Y., Meng, X.-Y., & Kang, J.-S. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0063-8 · Cited by 723 · see citing works
Linking Aβ and Tau in Late-Onset Alzheimer's Disease: A Dual Pathway Hypothesis
Small, S. A., & Duff, K. (2008) · Neuron · doi:10.1016/j.neuron.2008.11.007 · Cited by 546 · see citing works
Apolipoprotein E–dependent accumulation of Alzheimer disease–related lesions begins in middle age
Kok, E., Haikonen, S., Luoto, T., Huhtala, H., Goebeler, S., Haapasalo, H., & Karhunen, P. J. (2009) · Annals of Neurology · doi:10.1002/ana.21696 · Cited by 299 · see citing works
Changing perspectives regarding late-life dementia
Fotuhi, M., Hachinski, V., & Whitehouse, P. J. (2009) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.175 · Cited by 291 · see citing works
Effect of<i>APOE</i>genotype on amyloid plaque load and gray matter volume in Alzheimer disease
Drzezga, A., Grimmer, T., Henriksen, G., Mühlau, M., Perneczky, R., Miederer, I., Praus, C., Sorg, C., Wohlschläger, A., Riemenschneider, M., et al. (2009) · Neurology · doi:10.1212/wnl.0b013e3181a2e8d0 · Cited by 248 · see citing works
The Utility of Cerebral Blood Flow as a Biomarker of Preclinical Alzheimer’s Disease
Hays, C. C., Zlatar, Z. Z., & Wierenga, C. E. (2016) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0261-z · Cited by 213 · see citing works
Huynh, T.-P. V., Davis, A. A., Ulrich, J. D., & Holtzman, D. M. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r075481 · Cited by 210 · see citing works
Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition
Rodriguez, G. A., Tai, L. M., LaDu, M. J., & Rebeck, G. W. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-111 · Cited by 193 · see citing works
Serrano‐Pozo, A., Qian, J., Monsell, S. E., Betensky, R. A., & Hyman, B. T. (2015) · Annals of Neurology · doi:10.1002/ana.24369 · Cited by 176 · see citing works
APOE ε2 is associated with intact cognition but increased Alzheimer pathology in the oldest old
Berlau, D. J., Corrada, M. M., Head, E., & Kawas, C. H. (2009) · Neurology · doi:10.1212/01.wnl.0000343853.00346.a4 · Cited by 185 · see citing works
Suri, S., Heise, V., Trachtenberg, A. J., & Mackay, C. E. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.10.010 · Cited by 183 · see citing works
Apolipoprotein E and cholesterol in aging and disease in the brain
de Chaves, E. P., Narayanaswami, V., Christoffersen, C., & Nielsen, L. B. (2008) · Future Lipidology · doi:10.2217/17460875.3.5.505 · Cited by 164 · see citing works
Castellano, J. M., Deane, R., Gottesdiener, A. J., Verghese, P. B., Stewart, F. R., West, T., Paoletti, A. C., Kasper, T. R., DeMattos, R. B., Zlokovic, B. V., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206446109 · Cited by 154 · see citing works
APP Function and Lipids: A Bidirectional Link
Grimm, M. O. W., Mett, J., Grimm, H. S., & Hartmann, T. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00063 · Cited by 104 · see citing works
Hirsch-Reinshagen, V., & Wellington, C. L. (2007) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e32813aeabf · Cited by 61 · see citing works
Exercise-Induced Modulation of Neuroinflammation in Models of Alzheimer’s Disease
Kelly, Á. M. (2018) · Brain Plasticity · doi:10.3233/bpl-180074 · Cited by 55 · see citing works
Mathur, R., Ince, P. G., Minett, T., Garwood, C. J., Shaw, P. J., Matthews, F. E., Brayne, C., Simpson, J. E., Wharton, S. B., & on behalf of the MRC Cognitive Function and Ageing Neuropathology Study Group (2015) · PLOS ONE · doi:10.1371/journal.pone.0118463 · Cited by 52 · see citing works
Henningfield, C. M., Arreola, M. A., Soni, N., Spangenberg, E. E., & Green, K. N. (2022) · Glia · doi:10.1002/glia.24105 · Cited by 40 · see citing works
Plasma ApoE proteotyping for ApoE ε4 stratification in the anti-amyloid therapies era
Coraglia, F., Cecchetti, G., Rugarli, G., Spinelli, E. G., Ghirelli, A., Pisano, S., Canu, E., Filippi, M., & Agosta, F. (2026) · Alzheimer's Research & Therapy · doi:10.1186/s13195-026-02089-2 · Cited by 1 · see citing works
Berlau, D. J., Kahle-Wrobleski, K., Head, E., Goodus, M., Kim, R., & Kawas, C. (2007) · Archives of Neurology · doi:10.1001/archneur.64.8.1193
- Authors
- Tiraboschi, P., Hansen, L. A., Masliah, E., Alford, M., Thal, L. J., & Corey-Bloom, J.
- Affiliations
- University of California San Diego (US)
- From the Dipartimento di Scienze Neurologiche (Dr. Tiraboschi), Ospedale Niguarda Ca’ Granda, Milano, Italy; and Department of Neurosciences (Drs. Tiraboschi, Hansen, Masliah, Alford, Thal, and Corey-Bloom), University of California, San Diego, La Jolla, and Neurology Service (Drs. Thal and Corey-Bloom), VA San Diego Healthcare System, San Diego, CA.
- Venue
- Neurology
- Published
- 2004-06-08
- Volume
- 62
- Issue
- 11
- Pages
- 1977-1983
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- OpenAlex
- W2117156629
- Cited by
- 226
- References
- 5
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 9 · 2023: 12 · 2022: 15 · 2021: 13 · 2020: 13 · 2019: 11 · 2018: 7 · 2017: 12 · 2016: 12 · 2015: 13 · 2014: 13 · 2013: 9 · 2012: 11
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG05131, P50AG005131)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, APOE genotype, APOE ε4, APOE ε2 allele, neuropathology, neuritic plaques, neurofibrillary tangles, cholinergic dysfunction, choline acetyltransferase, amyloid plaques, genetic risk, neocortex
- MeSH terms
- Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Apolipoproteins E, Brain, California, Choline O-Acetyltransferase, Female, Follow-Up Studies, Gene Frequency, Genotype, Humans, Male, Middle Aged, Nerve Tissue Proteins, Cohort Studies, Single-Blind Method, Neurofibrillary Tangles, Age of Onset, Genetic Predisposition to Disease, Apolipoprotein E4, Apolipoprotein E2, Plaque, Amyloid
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
