Risk Estimates of Dementia by Apolipoprotein E Genotypes From a Population-Based Incidence Study: The Rotterdam Study
Open accessAbstract
OBJECTIVES: To provide risk estimates of dementia and Alzheimer disease as a function of the apolipoprotein E (APOE) genotypes and to assess the proportion of dementia that is attributable to the APOE genotypes. DESIGN: Case-control study nested in a population-based cohort study with a mean (SD) follow-up of 2.1 (0.9) years. SETTING: General population in Rotterdam, the Netherlands. PARTICIPANTS: A total of 134 patients with incident dementia and a random sample of 997 nondemented control subjects. No participant had dementia at baseline. MAIN OUTCOME MEASURES: Odds ratios for dementia and Alzheimer disease, the fraction of dementia attributable to the APOE epsilon4 allele, and the proportion of the variance in age at the onset of dementia explained by the APOE genotypes. RESULTS: Persons with the epsilon4/4 genotype had a more than 10-fold higher risk of dementia (odds ratio, 11.2; 95% confidence interval, 3.6-35.2), and subjects with the epsilon3/4 genotype had a 1.7-fold increased risk of dementia (95% confidence interval, 1.0-2.9) as compared with persons with the epsilon3/3 genotype. The proportion of patients with dementia that is attributable to the epsilon4 allele was estimated to be 20%. The APOE genotypes explained up to 10% of the variance in age at the onset of dementia. The association between the epsilon4 allele and dementia was strongest in the youngest age category and in those with a family history of dementia. CONCLUSIONS: The APOE genotype is an important determinant of the risk of dementia. At a population level, however, other factors than the APOE genotype may play an important role in the cause of dementia.
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APOE remains the only locus repeatedly associated with AAO, but PICALM and BIN1 have also been reported to affect AAO.
“To date, APOE remains the only locus repeatedly associated with AAO8,9, but PICALM and BIN1 have also been reported to affect AAO6,10,11.”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [9]
The Comment section reports that APOE genotypes explained some variance in age at onset of dementia, supporting the APOE–AAO association. The paper does not establish that APOE was the only locus repeatedly associated with AAO; its introduction says APOE's role in age at onset was still controversial. PICALM and BIN1 are attached to other citations in the citing sentence, not this one. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredGenes linked to early-onset AD risk that are expressed primarily in microglia include TREM2, MS4A, ABCA7, ApoE4, CD33, PU.1, and BIN1.
“Genetic studies show that a number of genes that have been linked to early-onset AD risk are expressed primarily in microglia.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [130]
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“The risk attributable to the APOE∗4 allele is 20–29% (Seshadri et al. 1995; Slooter et al. 1998).”
BackgroundQian, J., Wolters, F. J., Beiser, A., Haan, M., Ikram, M. A., Karlawish, J., Langbaum, J. B., Neuhaus, J. M., Reiman, E. M., Roberts, J. S., et al. (2017) · PLOS Medicine · doi:10.1371/journal.pmed.1002254 · Cited by 169 · see citing works
Current status on Alzheimer disease molecular genetics: from past, to present, to future
Bettens, K., Sleegers, K., & Broeckhoven, C. V. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq142 · Cited by 167 · see citing works
“Nonetheless, APOE 14 does not account for all genetic variation in AD (8,9).”
BackgroundHippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes
den Heijer, T., Oudkerk, M., Launer, L. J., van Duijn, C. M., Albert Hofman, D., & Breteler, M. M. B. (2002) · Neurology · doi:10.1212/wnl.59.5.746 · Cited by 169 · see citing works
Self-citationSchiepers, O. J. G., Harris, S. E., Gow, A. J., Pattie, A., Brett, C. E., Starr, J. M., & Deary, I. J. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.137 · Cited by 159 · see citing works
Non-familial Alzheimer's disease is mainly due to genetic factors
Ashford, J. W., & Mortimer, J. A. (2002) · Journal of Alzheimer s Disease · doi:10.3233/jad-2002-4307 · Cited by 153 · see citing works
“A few studies focusing on population incidence of AD have found substantially lower estimates for population attributable risk associated with the APOE-ε 4 allele [14,16,25,54].”
Johnson, S. C., Schmitz, T. W., Trivedi, M. A., Ries, M. L., Torgerson, B. M., Carlsson, C. M., Asthana, S., Hermann, B. P., & Sager, M. A. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0959-06.2006 · Cited by 149 · see citing works
Prince, J. A., Feuk, L., Sawyer, S. L., Gottfries, J., Ricksten, A., Nägga, K., Bogdanović, N., Blennow, K., & Brookes, A. J. (2001) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5200651 · Cited by 141 · see citing works
Chui, H. C., Zheng, L., Reed, B., Vinters, H. V., & Mack, W. J. (2011) · Alzheimer s Research & Therapy · doi:10.1186/alzrt98 · Cited by 141 · see citing works
Neurophysiological Markers of Alzheimer’s Disease: Quantitative EEG Approach
Smailović, U., & Jelić, V. (2019) · Neurology and Therapy · doi:10.1007/s40120-019-00169-0 · Cited by 143 · see citing works
On Jim Watson's APOE status: genetic information is hard to hide
Nyholt, D. R., Yu, C., & Visscher, P. M. (2008) · European Journal of Human Genetics · doi:10.1038/ejhg.2008.198 · Cited by 139 · see citing works
APOE Genotype, Family History of Dementia, and Alzheimer Disease Risk
Huang, W., Qiu, C., Strauss, E. I. V., Winblad, B. G., & Fratiglioni, L. (2004) · Archives of Neurology · doi:10.1001/archneur.61.12.1930 · Cited by 4 · see citing works
“Because of the old age of our study sample, the estimated relative risks in our study were lower than those of previous studies.(3,6,15) Thus, our findings may not be generalizable to the younger-old population.”
BackgroundResultInfluentialBäcker‐Koduah, P., Paul, F., & Dörr, J.-M. (2017) · The EPMA Journal · doi:10.1007/s13167-017-0120-8 · Cited by 129 · see citing works
“However, not all AD patients express the APOEε4 allele which points to additional causative factors [165, 166].”
BackgroundThe apolipoprotein E varepsilon2 allele and decline in episodic memory
Wilson, R. S. (2002) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.73.6.672 · Cited by 161 · see citing works
How to Use an Article About Genetic Association
Attia, J., Ioannidis, J. P. A., Thakkinstian, A., McEvoy, M., Scott, R. J., Minelli, C., Thompson, J. R., Infante‐Rivard, C., & Guyatt, G. H. (2009) · JAMA · doi:10.1001/jama.2008.946 · Cited by 130 · see citing works
Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study
Lee, J. H., Cheng, R., Graff-Radford, N., Foroud, T., & Mayeux, R. (2008) · Archives of Neurology · doi:10.1001/archneur.65.11.1518 · Cited by 132 · see citing works
“A LTHOUGH THE APOLIPOPROtein E ε4 allele (APOE ε4) (OMIM 107741) is the most consistently replicated genetic variant influencing the risk of late-onset Alzheimer disease (LOAD),(1) it explains only 20% of the attributable genetic risk.(2) Daw et al(3) reported that there may be 4 additional genes influencing LOAD risk.”
Developmental and vascular risk factors for Alzheimer's disease
Borenstein, A. R., Wu, Y., Mortimer, J. A., Schellenberg, G. D., McCormick, W. C., Bowen, J. D., McCurry, S. M., & Larson, E. B. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.04.010 · Cited by 125 · see citing works
APOE-ε4 is associated with memory decline in cognitively impaired elderly
Dik, M. G., Jonker, C., Bouter, L. M., Geerlings, M. I., van Kamp, G. J., & Deeg, D. J. H. (2000) · Neurology · doi:10.1212/wnl.54.7.1492 · Cited by 126 · see citing works
Genome-wide Association Studies in Alzheimer’s Disease: A Review
Tosto, G., & Reitz, C. (2013) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-013-0381-0 · Cited by 124 · see citing works
“Although the population attributable risk of APOE ε4 is estimated at 20–50 % [30], the presence of ε4 is neither necessary nor sufficient for development of the disease [31].”
BackgroundPankratz, N., & Foroud, T. (2007) · Genetics in Medicine · doi:10.1097/gim.0b013e31815bf97c · Cited by 125 · see citing works
Insulin resistance in Alzheimer's disease
Dineley, K. T., Jahrling, J. B., & Denner, L. A. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.09.001 · Cited by 124 · see citing works
Genetic diagnosis and prognosis of Alzheimer’s disease: challenges and opportunities
Reitz, C. (2015) · Expert Review of Molecular Diagnostics · doi:10.1586/14737159.2015.1002469 · Cited by 120 · see citing works
“While the population attributable risk for APOE"4 is estimated at 20–50%, [51], the presence of "4 is neither necessary nor sufficient for developing the disease [52].”
BackgroundProspective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects
Engelborghs, S. (2003) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.74.8.1148 · Cited by 120 · see citing works
Devanand, D. P., Pelton, G. H., Zamora, D., Liu, X., Tabert, M. H., Goodkind, M. S., Scarmeas, N., Braun, I. M., Stern, Y., & Mayeux, R. P. (2005) · Archives of Neurology · doi:10.1001/archneur.62.6.975 · Cited by 119 · see citing works
“In studies that compared patients who had AD with healthy controls, the mean odds ratio for heterozygotes was approximately 4 in clinical samples and approximately 2 in community samples, with considerable variability across studies.(2,3) The APOE ε4 allele’s association with AD is not influenced by sex, diminishes af…”
BackgroundRole of Cholesterol in APP Metabolism and Its Significance in Alzheimer’s Disease Pathogenesis
Maulik, M., Westaway, D. A., Jhamandas, J. H., & Kar, S. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8337-y · Cited by 117 · see citing works
“compared to individuals with the ε3 or ε2 forms [40, 41].”
BackgroundDufouil, C., Tzourio, C., Brayne, C., Berr, C., Amouyel, P., & Alpérovitch, A. (2000) · Epidemiology · doi:10.1097/00001648-200005000-00009 · Cited by 117 · see citing works
The keystone of Alzheimer pathogenesis might be sought in Aβ physiology
Puzzo, D., Gulisano, W., Arancio, O., & Palmeri, A. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.08.039 · Cited by 116 · see citing works
“…but apolipoprotein E (APOE) gene, since subjects with the APOE-e4 allele had a more than 10-fold higher risk of dementia (Corder et al., 1993; Slooter et al., 1998); (iv) studies on animal models have demonstrated that if mutations of APP, PS or secretases leading to an increase of Ab burden…”
Engelborghs, S., Sleegers, K., Cras, P. P., Brouwers, N., Serneels, S., Leenheir, E. D., Martin, J. J., Vanmechelen, E., Broeckhoven, C. V., & Deyn, P. P. D. (2007) · Brain · doi:10.1093/brain/awm136 · Cited by 113 · see citing works
“Genomic DNA was extracted from total blood using standard methods and the APOE genotype was determined as described earlier (Slooter et al., 1998).”
MethodJohnson, S. C., La Rue, A., Hermann, B. P., Xu, G., Koscik, R. L., Jonaitis, E. M., Bendlin, B. B., Hogan, K. J., Roses, A. D., Saunders, A. M., et al. (2011) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2010.11.012 · Cited by 112 · see citing works
“In population studies of frequency of APOE variants among AD cases, the proportion without an 34 allele is 36% to 50% [4–6]; thus, approximately 40% to 50% of AD cases require an explanation beyond APOE 34 [7].”
BackgroundAlzheimer’ s disease, oxidative stress and gammahydroxybutyrate
Mamelak, M. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.06.008 · Cited by 108 · see citing works
Qiu, C. (2004) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2003.021493 · Cited by 112 · see citing works
Advances in the prevention of Alzheimer's Disease
Sindi, S., Mangialasche, F., & Kivipelto, M. (2015) · F1000Prime Reports · doi:10.12703/p7-50 · Cited by 111 · see citing works
“The APOE e4 allele increases the risk for AD in a dose-response manner, where those with homozygous e4 allele (two e4 copies) have a higher risk than individuals with heterozygous e4 allele (a combination of one e4 copy, and an alternative copy: e2 or e3 allele), who in turn have a higher risk than individuals with no…”
Ranson, J. M., Rittman, T., Hayat, S. A., Brayne, C., Jessen, F., Blennow, K., van Duijn, C. M., Barkhof, F., Tang, E. Y. H., Mummery, C. J., et al. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00895-4 · Cited by 113 · see citing works
“, 51–95% in APOE ɛ4/ɛ4 and 22–90% in APOE ɛ4/- [26, 27] and a mean age at dementia onset of 73–74 years in APOE ɛ4/ɛ4 and 75–82 in APOE ɛ4/- [28, 29].”
Most rapid cognitive decline in APOE ε4 negative Alzheimer's disease with early onset
van der Vlies, A. E., Koedam, E., Pijnenburg, Y. A. L., Twisk, J. W. R., Scheltens, P., & van der Flier, W. M. (2009) · Psychological Medicine · doi:10.1017/s0033291709005492 · Cited by 107 · see citing works
“The apolipoprotein E gene (APOE) is an important risk factor for AD (Kuusisto et al. 1994 ; Strittmatter & Roses, 1995 ; Slooter et al. 1998 ; Petersen et al. 2005).”
BackgroundPrestroke Cognitive Performance, Incident Stroke, and Risk of Dementia
Reitz, C., Bos, M. J., Albert Hofman, D., Koudstaal, P. J., & Breteler, M. M. B. (2007) · Stroke · doi:10.1161/strokeaha.107.490334 · Cited by 106 · see citing works
Self-citationGenetics of Alzheimer disease in the pre- and post-GWAS era
Ertekin‐Taner, N. (2010) · Alzheimer s Research & Therapy · doi:10.1186/alzrt26 · Cited by 107 · see citing works
“PAR esti mates may have an upward bias in family-based studies and younger populations given that APOE has a stronger eff ect in younger ages (from younger than age 70 to eighties) and longitudinal studies may provide more accurate estimates of PAR of APOE where estimates of 20% were obtained [35,37,38].”
BackgroundAlzheimer’s Disease: Mechanism and Approach to Cell Therapy
Amemori, T., Jendelová, P., Růžička, J., Urdzíková, L. M., & Syková, E. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161125961 · Cited by 102 · see citing works
“[20,21]; however, in sporadic cases its estimated prevalence risk is only 10%–20% [22].”
BackgroundGenome-wide association analysis of age-at-onset in Alzheimer's disease
Kamboh, M. I., Barmada, M. M., Demirci, F. Y., Minster, R. L., Carrasquillo, M. M., Pankratz, V. S., Younkin, S. G., Saykin, A. J., Initiative, T. A. D. N., Sweet, R. A., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.135 · Cited by 100 · see citing works
The effect of APOE genotype on clinical phenotype in Alzheimer disease
van der Flier, W. M., Schoonenboom, S. N. M., Pijnenburg, Y. A. L., Fox, N. C., & Scheltens, P. (2006) · Neurology · doi:10.1212/01.wnl.0000228222.17111.2a · Cited by 98 · see citing works
“8 Amyloid (1-42) (A 42), total tau, and tau phosphorylated at threonine-181 (Ptau-181) were measured by sandwich ELISA (Innotest -amyloid[1-42], Innotest hTAU-Ag, and Innotest Phosphotau(181P); Innogenetics, Ghent, Belgium).”
MethodHolmquist, S., Nordström, A., & Nordström, P. (2020) · PLoS Medicine · doi:10.1371/journal.pmed.1003016 · Cited by 97 · see citing works
van der Willik, K. D., Fani, L., Rizopoulos, D., Licher, S., Fest, J., Schagen, S. B., Ikram, M. K., & Ikram, M. A. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1454-z · Cited by 96 · see citing works
Evidence for a Novel Late-Onset Alzheimer Disease Locus on Chromosome 19p13.2
Wijsman, E. M., Daw, E. W., Yu, C. E., Payami, H., Steinbart, E. J., Nochlin, D., Conlon, E. M., Bird, T. D., & Schellenberg, G. D. (2004) · The American Journal of Human Genetics · doi:10.1086/423393 · Cited by 95 · see citing works
Luck, T., Riedel-Heller, S. G., Luppa, M., Wiese, B., Köhler, M., Jessen, F., Bickel, H., Weyerer, S., Pentzek, M., König, H.-H., et al. (2014) · Psychological Medicine · doi:10.1017/s0033291713001918 · Cited by 93 · see citing works
“The ε4 allele of apolipoprotein E (APOE) is the most important currently known genetic risk factor for lateonset Alzheimer’s disease (AD) dementia (Paulson & Igo, 2011), and is thought to account for around 20–50% of the attributable total risk for dementia (Slooter et al. 1998; Ashford, 2004).”
BackgroundWhite Matter Microstructure in Relation to Education in Aging and Alzheimer's Disease1
Teipel, S. J., Meindl, T., Wagner, M., Kohl, T., Bürger, K., Reiser, M. F., Herpertz, S. C., Möller, H., & Hampel, H. J. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1077 · Cited by 92 · see citing works
“Important risk factors for AD that are not accessible to intervention include age, female gender, and apolipoprotein E4 (ApoE4) genotype [11,12].”
BackgroundGenetic susceptibility factors for Alzheimer's disease
Richard, F., & Amouyel, P. (2001) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00903-1 · Cited by 91 · see citing works
Dubal, D. B. (2020) · Handbook of clinical neurology · doi:10.1016/b978-0-444-64123-6.00018-7 · Cited by 88 · see citing works
Aerssens, J., Raeymaekers, P., Lilienfeld, S., Geerts, H., Konings, F., & Parys, W. (2001) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000051238 · Cited by 90 · see citing works
Emerging Link between Alzheimer’s Disease and Homeostatic Synaptic Plasticity
Jang, S.-S., & Chung, H. J. (2016) · Neural Plasticity · doi:10.1155/2016/7969272 · Cited by 89 · see citing works
Cognitive Resilience to Apolipoprotein E ε4
Kaup, A. R., Nettiksimmons, J., Harris, T. B., Sink, K. M., Satterfield, S., Metti, A. L., Ayonayon, H. N., & Yaffe, K. S. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2014.3978 · Cited by 88 · see citing works
“Future research might explore whether the following differ by race: (1) types of stressors experienced in aging, (2) older adults’ coping styles, and (3) the neurobiological effects of stress on the aging brain.”
Genetic Testing For Alzheimer’s And Long-Term Care Insurance
Taylor, D. H., Cook-Deegan, R. M., Hiraki, S. C., Roberts, J. S., Blazer, D. G., & Green, R. C. (2010) · Health Affairs · doi:10.1377/hlthaff.2009.0525 · Cited by 87 · see citing works
Transcriptional regulation of Alzheimer's disease genes: implications for susceptibility
Theuns, J. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.16.2383 · Cited by 86 · see citing works
Vascular factors in dementia: an overview
DeCarli, C. S. (2004) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2004.09.005 · Cited by 87 · see citing works
Apolipoprotein E ε4 Allele Differentiates the Clinical Response to Donepezil in Alzheimer’s Disease
Bizzarro, A., Marra, C., Acciarri, A., Valenza, A., Tiziano, F. D., Brahe, C., & Masullo, C. (2005) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000087371 · Cited by 85 · see citing works
“Apolipoprotein E (APOE) genotype has been demonstrated to be a definite genetic risk factor for Alzheimer’s disease (AD) and the e4 allele has a significantly higher frequency in AD patients compared with healthy subjects [”
BackgroundApolipoprotein E and Carotid Artery Atherosclerosis
Slooter, A. J. C., Bots, M. L., Havekes, L. M., del Sol, A. I., Cruts, M., Grobbee, D. E., Albert Hofman, D., Broeckhoven, C. V., Witteman, J. C. M., & van Duijn, C. M. (2001) · Stroke · doi:10.1161/hs0901.095377 · Cited by 79 · see citing works
Self-citation
- Authors
- Slooter, A. J. C., Cruts, M., Kalmijn, S., Hofman, A., Breteler, M. M. B., Van Broeckhoven, C., & van Duijn, C. M.
- Affiliations
- Erasmus MC (NL)
- University of Antwerp (BE)
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 1998-07-01
- Volume
- 55
- Issue
- 7
- Pages
- 964
- ISSN
- 0003-9942 (ISSN-L)
- OpenAlex
- W2134448489
- Cited by
- 399
- References
- 31
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 7 · 2023: 8 · 2022: 14 · 2021: 10 · 2020: 16 · 2019: 9 · 2018: 9 · 2017: 15 · 2016: 10 · 2015: 18 · 2014: 18 · 2013: 25 · 2012: 15
- FWCI
- 8.48
- Type
- journal article
- Language
- en
- Open access
- green
- pure.eur.nl
- Locations
- Archives of Neurology (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- 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 › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- dementia, Alzheimer's disease, apolipoprotein E, APOE ε4, genetic risk factors, dementia incidence, attributable fraction, family history of dementia, Rotterdam Study
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Dementia, Female, Genotype, Humans, Male, Middle Aged, Netherlands, Incidence, Odds Ratio, Case-Control Studies, Risk Assessment
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