Clinical and pathological correlates of apolipoprotein E ε4 in Alzheimer's disease
Abstract
Inheritance of the apolipoprotein E (apoE) ε4 allele is associated with a high likelihood of developing Alzheimer's disease (AD). The pathophysiologic basis of this genetic influence is unknown. We reasoned that understanding the influence of apoE ε4 on the clinical course and neuropathological features of AD may provide tests of potential mechanisms. We carried out a prospective longitudinal study to compare the age of onset, duration, and rate of progression of 359 AD patients to apoE genotype. Thirty‐one of the individuals who died during the study were available for quantitative neuropathological evaluation. Statistically unbiased stereological counts of neurofibrillary tangles (NFTs) and Aβ deposits were assessed in a high‐order association cortex, the superior temporal sulcus. Analysis of clinical parameters compared with apoE genotype showed that the ε4 allele is associated with an earlier age of onset but no change in rate of progression of dementia. Quantitative neuropathological assessment revealed that NFTs were strongly associated with clinical measures of dementia duration and severity but not with apoE genotype. Aβ deposition, by contrast, was not related to clinical features but was elevated in association with apoE ε4. These results indicate that apoE ε4 is associated with selective clinical and neuropathological features of AD and support hypotheses that focus on an influence of apoE ε4 on amyloid deposition.
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 apoE ε4 allele is associated with an earlier age of AD onset.
“The apoE ε4 allele is also associated with an earlier age of AD onset (Gomez-Isla et al., 1996; Roses, 1996).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Gomez-Isla et al., 1996
Cites
Blessed, G., Tomlinson, B. E., & Roth, M. (1968) · British Journal of Psychiatry · doi:10.1192/bjp.114.512.797 · Cited by 4,117 · see citing works
Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease
Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T., & Hyman, B. T. (1992) · Neurology · doi:10.1212/wnl.42.3.631 · Cited by 2,668 · see citing works
Self-citationDiagnosis of Alzheimer's Disease
Khachaturian, Z. S. (1985) · Archives of Neurology · doi:10.1001/archneur.1985.04060100083029 · Cited by 2,499 · 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
Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A. Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I., & Selkoe, D. J. (1992) · Nature · doi:10.1038/360672a0 · Cited by 1,757 · see citing works
Ma, J., Yee, A., Brewer, H. B., Das, S., & Potter, H. (1994) · Nature · doi:10.1038/372092a0 · Cited by 871 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Oxidative Damage Is the Earliest Event in Alzheimer Disease
Nunomura, A., Perry, G., Aliev, G., Hirai, K., Takeda, A., Balraj, E. K., Jones, P. K., Ghanbari, H., Wataya, T., Shimohama, S., et al. (2001) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/60.8.759 · Cited by 1,885 · see citing works
Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer’s Disease
Gómez-Isla, T., Price, J. L., McKeel Jr., D. W., Morris, J. C., Growdon, J. H., & Hyman, B. T. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-14-04491.1996 · Cited by 1,796 · see citing works
“…Z ϭ 1.72, p ϭ 0.09, NS). strong or no relationship between the number of amyloid SPs and the duration or severity of illness (Price et al., 1991; Terry et al., 1991; Arriagada et al., 1992a; Berg et al., 1993; Bouras et al., 1993; Hyman et al., 1993; Nagy et al., 1995; Gómez-Isla et al., 1996).”
BackgroundInfluentialSelf-citationThe 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
Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease
Gómez‐Isla, T., Hollister, R., West, H., Mui, S., Growdon, J. H., Petersen, R. C., Parisi, J. E., & Hyman, B. T. (1997) · Annals of Neurology · doi:10.1002/ana.410410106 · Cited by 1,489 · see citing works
Self-citationEarly Aβ accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain
Ingelsson, M., Fukumoto, H., Newell, K. L., Growdon, J. H., Hedley–Whyte, E. T., Frosch, M. P., Albert, M. S., Hyman, B. T., & Irizarry, M. C. (2004) · Neurology · doi:10.1212/01.wnl.0000115115.98960.37 · Cited by 666 · see citing works
Self-citationRate of medial temporal lobe atrophy in typical aging and Alzheimer's disease
Jack, C. R., Petersen, R. C., Xu, Y., O'Brien, P. C., Smith, G. E., Ivnik, R. J., Tangalos, E. G., & Kokmen, E. (1998) · Neurology · doi:10.1212/wnl.51.4.993 · Cited by 666 · see citing works
Berg, L., McKeel, D. W., Miller, J. P., Storandt, M., Rubin, E. H., Morris, J. C., Baty, J., Coats, M., Norton, J., Goate, A. M., et al. (1998) · Archives of Neurology · doi:10.1001/archneur.55.3.326 · Cited by 657 · see citing works
Irizarry, M. C., Soriano, F., McNamara, M., Page, K. J., Schenk, D., Games, D., & Hyman, B. T. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-18-07053.1997 · Cited by 497 · see citing works
Self-citationThe importance of neuritic plaques and tangles to the development and evolution of AD
Tiraboschi, P., Hansen, L. A., Thal, L. J., & Corey-Bloom, J. (2004) · Neurology · doi:10.1212/01.wnl.0000129697.01779.0a · Cited by 477 · see citing works
Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury
Ikonomovic, M. D., Uryu, K., Abrahamson, E. E., Ciallella, J. R., Trojanowski, J. Q., Lee, V. M.-Y., Clark, R. S., Marion, D. W., Wisniewski, S. R., & DeKosky, S. T. (2004) · Experimental Neurology · doi:10.1016/j.expneurol.2004.06.011 · Cited by 399 · see citing works
A novel GSK-3β inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo
Serenó, L., Coma, M., Rodríguez, M., Sánchez-Ferrer, P., Sánchez, M. B., Gich, I., Agulló, J. M., Pérez, M., Avila, J., Guardia-Laguarta, C., et al. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.05.025 · Cited by 368 · see citing works
Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β
Koffie, R. M., Hashimoto, T., Tai, H.-C., Kay, K. R., Serrano-Pozo, A., Joyner, D., Hou, S., Kopeikina, K. J., Frosch, M. P., Lee, V. M., et al. (2012) · Brain · doi:10.1093/brain/aws127 · Cited by 327 · see citing works
Self-citationSex differences in cognitive impairment in Alzheimer’s disease
Laws, K. R., Irvine, K., & Gale, T. M. (2016) · World Journal of Psychiatry · doi:10.5498/wjp.v6.i1.54 · Cited by 307 · see citing works
In vivo measurement of widespread synaptic loss in Alzheimer’s disease with SV2A PET
Mecca, A. P., Chen, M., O'Dell, R. S., Naganawa, M., Toyonaga, T., Godek, T. A., Harris, J. E., Bartlett, H. H., Zhao, W., Nabulsi, N. B., et al. (2020) · Alzheimer's & Dementia · doi:10.1002/alz.12097 · Cited by 288 · 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
Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid β Peptide
Hashimoto, T., Serrano-Pozo, A., Hori, Y., Adams, K. W., Takeda, S., Banerji, A. O., Mitani, A., Joyner, D., Thyssen, D. H., Bacskai, B. J., et al. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.1542-12.2012 · Cited by 294 · see citing works
Self-citationApolipoprotein 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
Urbanc, B., Cruz, L., Le, R., Sanders, J., Ashe, K. H., Duff, K., Stanley, H. E., Irizarry, M. C., & Hyman, B. T. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.222433299 · Cited by 237 · see citing works
Self-citationSerrano-Pozo, A., Muzikansky, A., Gómez-Isla, T., Growdon, J. H., Betensky, R. A., Frosch, M. P., & Hyman, B. T. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3182933788 · Cited by 226 · see citing works
Self-citationAPOE ε4 allele predicts faster cognitive decline in mild Alzheimer disease
Cosentino, S., Scarmeas, N., Helzner, E., Glymour, M. M., Brandt, J., Albert, M., Blacker, D., & Stern, Y. (2008) · Neurology · doi:10.1212/01.wnl.0000304038.37421.cc · Cited by 214 · see citing works
Bondolfi, L., Calhoun, M., Ermini, F., Kuhn, H. G., Wiederhold, K.-H., Walker, L., Staufenbiel, M., & Jucker, M. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-02-00515.2002 · Cited by 213 · see citing works
Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease
Vemuri, P., Wiste, H. J., Weigand, S. D., Knopman, D. S., Shaw, L. M., Trojanowski, J. Q., Aisen, P. S., Weiner, M., Petersen, R. C., Jack, C. R., et al. (2010) · Annals of Neurology · doi:10.1002/ana.21953 · Cited by 195 · see citing works
Caspase-2 cleavage of tau reversibly impairs memory
Zhao, X., Kotilinek, L. A., Smith, B., Hlynialuk, C., Zahs, K., Ramsden, M., Cleary, J., & Ashe, K. H. (2016) · Nature Medicine · doi:10.1038/nm.4199 · Cited by 187 · 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
Self-citationAgosta, F., Vossel, K. A., Miller, B. L., Migliaccio, R., Bonasera, S. J., Filippi, M., Boxer, A. L., Karydas, A., Possin, K. L., & Gorno-Tempini, M. L. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812697106 · Cited by 178 · see citing works
DaRocha-Souto, B., Coma, M., Pérez-Nievas, B. G., Scotton, T. C., Siao, M., Sánchez-Ferrer, P., Hashimoto, T., Fan, Z., Hudry, E., Barroeta, I., et al. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.09.002 · Cited by 180 · see citing works
Self-citationRibé, E. M., Pérez, M., Puig, B., Gich, I., Lim, F., Cuadrado, M., Sesma, T., Catena, S., Sánchez, B., Nieto, M., et al. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.05.027 · Cited by 162 · see citing works
LANGE, K. L., BONDI, M. W., SALMON, D. P., GALASKO, D., DELIS, D. C., THOMAS, R. G., & THAL, L. J. (2002) · Journal of the International Neuropsychological Society · doi:10.1017/s1355617702870096 · Cited by 129 · see citing works
Predicting progression from normal cognition to mild cognitive impairment for individuals at 5 years
Albert, M., Zhu, Y., Moghekar, A., Mori, S., Miller, M. I., Soldan, A., Pettigrew, C., Selnes, O., Li, S., & Wang, M.-C. (2018) · Brain · doi:10.1093/brain/awx365 · Cited by 118 · see citing works
Circulating Biomarkers of Cognitive Decline and Dementia
Solfrizzi, V., D'Introno, A., Colacicco, A. M., Capurso, C., Todarello, O., Pellicani, V., Capurso, S. A., Pietrarossa, G., Santamato, V., Capurso, A., et al. (2006) · Clinica Chimica Acta · doi:10.1016/j.cca.2005.06.015 · Cited by 120 · see citing works
Add Alzheimer's disease to the list of autoimmune diseases
D’Andrea, M. R. (2005) · Medical Hypotheses · doi:10.1016/j.mehy.2004.08.024 · Cited by 113 · see citing works
Aβ-amyloid and Tau Imaging in Dementia
Villemagne, V. L., Doré, V., Bourgeat, P., Burnham, S. C., Laws, S., Salvado, O., Masters, C. L., & Rowe, C. C. (2017) · Seminars in Nuclear Medicine · doi:10.1053/j.semnuclmed.2016.09.006 · Cited by 110 · see citing works
Gender 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
Lipid metabolism in Alzheimer’s disease
Liu, Q., & Zhang, J. (2014) · Neuroscience Bulletin · doi:10.1007/s12264-013-1410-3 · Cited by 101 · see citing works
Soeda, Y., Saito, M., Maeda, S., Ishida, K., Nakamura, A., Kojima, S., & Takashima, A. (2019) · Journal of Alzheimer’s Disease · doi:10.3233/jad-181001 · Cited by 84 · see citing works
Apolipoprotein E and Alzheimer's disease: the protective effects of ApoE2 and E3
Rebeck, G. W., Kindy, M., & LaDu, M. J. (2002) · Journal of Alzheimer's Disease · doi:10.3233/jad-2002-4304 · Cited by 89 · see citing works
Self-citationApoE gene and exceptional longevity: Insights from three independent cohorts
Garatachea, N., Emanuele, E., Calero, M., Fuku, N., Arai, Y., Abe, Y., Murakami, H., Miyachi, M., Yvert, T., Verde, Z., et al. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.02.004 · Cited by 84 · see citing works
Neural substrates of cognitive and behavioral deficits in atypical Alzheimer's disease
von Gunten, A., Bouras, C., Kövari, E., Giannakopoulos, P., & Hof, P. R. (2006) · Brain Research Reviews · doi:10.1016/j.brainresrev.2005.11.003 · Cited by 75 · see citing works
Nochlin, D., Bird, T. D., Nemens, E. J., Ball, M. J., & Sumi, S. M. (1998) · Annals of Neurology · doi:10.1002/ana.410430124 · Cited by 75 · see citing works
Qian, J., Betensky, R. A., Hyman, B. T., & Serrano-Pozo, A. (2021) · Neurology · doi:10.1212/wnl.0000000000011883 · Cited by 71 · see citing works
Self-citationA subset of senile dementia with high incidence of the apolipoprotein E ϵ2 allele
Ikeda, K., Akiyama, H., Arai, T., Sahara, N., Mori, H., Usami, M., Sakata, M., Mizutani, T., Wakabayashi, K., & Takahashi, H. (1997) · Annals of Neurology · doi:10.1002/ana.410410522 · Cited by 55 · see citing works
Relationship of neurofibrillary pathology to cerebral amyloid angiopathy in Alzheimer's disease
Williams, S., Chalmers, K., Wilcock, G. K., & Love, S. (2005) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2005.00663.x · Cited by 49 · see citing works
Use of Genetic Variation as Biomarkers for Alzheimer's Disease
Reitz, C., & Mayeux, R. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.04945.x · Cited by 24 · see citing works
- Authors
- Gomez‐Isla, T., West, H. L., Rebeck, G. W., Harr, S. D., Growdon, J. H., Locascio, J. J., Perls, T. T., Lipsitz, L. A., & Hyman, B. T.
- Affiliations
- Massachusetts General Hospital (US)
- Corresponding author
- Hyman, Bradley T.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 1996-01
- Volume
- 39
- Issue
- 1
- Pages
- 62-70
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2106900897
- Cited by
- 378
- References
- 6
- Citations by year
- 2025: 1 · 2024: 7 · 2023: 2 · 2022: 4 · 2021: 9 · 2020: 11 · 2019: 3 · 2018: 5 · 2017: 12 · 2016: 14 · 2015: 12 · 2014: 15 · 2013: 10 · 2012: 13
- FWCI
- 18.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG-08487, AG 12406, P50AG005134)
- 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
- APOE ε4, Alzheimer's disease, age of onset, disease progression, neurofibrillary tangles, amyloid-beta deposition, superior temporal sulcus, genetic risk
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Apolipoproteins E, Base Sequence, Female, Genotype, Humans, Male, Middle Aged, Molecular Sequence Data, Prospective Studies, Severity of Illness Index, Temporal Lobe, Age of Onset, Disease Progression, 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
