APOE and Alzheimer disease: a major gene with semi-dominant inheritance
Open accessAbstract
Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.
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Equivalent expression of E2 almost cancels out the deleterious effect of the E4 allele.
“and equivalent expression of E2 almost cancels out the deleterious effect of the E4 allele.6,14,15”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [6]
The Results (page unavailable) report an Alzheimer disease odds ratio of 2.64 for APOE 24 relative to APOE 33. Although the Introduction describes APOE 2 as protective, the elevated risk for people carrying both E2 and E4 contradicts the claim that E2 almost cancels E4’s deleterious effect. The paper does not assess equivalent expression of the two alleles. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredE2/E4 heterozygotes have only double the risk of E3/E3 homozygotes.
“E2/E4 heterozygotes have only double the risk of E3/E3 homozygotes”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [6]
The Results report higher Alzheimer disease odds for APOE E2/E4 (APOE 24) than for E3/E3 (APOE 33), but the pooled odds ratio is 2.64, not two. The paper also distinguishes odds ratios from lifetime risk, so this passage does not establish that E2/E4 carriers have exactly double the risk. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAPOE4 homozygotes have an earlier age of onset for developing Alzheimer's disease (approximately 5 years for each APOE4 allele compared to APOE3 homozygotes).
“as well as an earlier age of onset for developing the disease (approximately 5 years for each APOE4 allele compared to APOE3 homozygotes).6,9,10”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [6]
The Results (page not provided) compare APOE4 genotypes with APOE3 homozygotes across age-of-onset groups, and the paper says APOE4 is a risk factor for early-onset Alzheimer’s disease. It does not report an onset approximately five years earlier for each APOE4 allele. (LLM, conf=0.83)
Experimental — accuracy not yet measuredAPOE2 homozygotes are protected from late-onset AD.
“APOE2 homozygotes are protected from late-onset AD and, compared to E4 homozygotes, APOE2/E4 heterozygotes have a markedly reduced risk of developing AD.6,12,13”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [6]
The Introduction says APOE2 has a protective effect in Caucasian subjects. The Results report lower AD odds for APOE2/2 and APOE2/3 combined across age groups, but do not give a separate estimate for APOE2 homozygotes or specifically establish protection from late-onset AD for that genotype alone. (LLM, conf=0.84)
Experimental — accuracy not yet measuredConverting an APOE4 homozygote to an E4/E2 heterozygote would markedly decrease the risk for developing early-onset AD compared with E4 homozygotes.
“From epidemiologic studies, this would markedly decrease the risk for developing early-onset AD compared to E4 homozygotes.”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [6]
The Results (page unavailable) report much lower observed AD odds for APOE E2/E4 than for E4/E4, and stratify cases by age of onset. Those epidemiologic comparisons support a lower-risk prediction, but the paper does not test whether converting a person’s genotype would reduce their risk of early-onset AD. (LLM, conf=0.84)
Experimental — accuracy not yet measured
The APOE polymorphism is the most studied, successfully replicated, and well-established risk factor for Alzheimer's disease, with APOE*2 protective and APOE*4 risk compared to APOE*3.
“The APOE polymorphism is the most studied, successfully replicated, and well-established risk factor for AD where APOE*2 is the protective allele and APOE*4 is the risk allele as compared to APOE*3 [7–10].”
From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [10]
The Introduction reports higher Alzheimer’s disease odds for APOE 3/4 and 4/4 than for APOE 3/3, and a protective effect of APOE 2 in Caucasian subjects. The Results say the APOE 4/4 estimate is consistent with previous estimates, supporting a replicated association. The paper does not establish the comparative claim that APOE is the most studied risk factor. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe effect of APOE*4 on Alzheimer's disease risk is dose-dependent; one and two copies increase AD risk by 3.5- and 14.5-fold, respectively.
“The effect of APOE*4 is dose-dependent; one and two copies of E*4 increase the AD risk by 3.5- and 14.5-fold, respectively [10].”
From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [10]
The Results report an odds ratio of 14.49 for two APOE*4 copies relative to APOE 3/3, supporting the 14.5 figure and the dose-dependent association. The Introduction gives 3.2, not 3.5, for one copy and explicitly distinguishes odds ratios from an individual's actual disease risk. No page numbers are available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredApoE4 occurs in approximately two-thirds of all Alzheimer's disease cases.
“occurs in approximately two-thirds of all cases [1–3]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [3]
The Introduction reports that APOE4 is enriched among Alzheimer’s disease patients, and the Results say genotype frequencies were estimated for cases. Neither passage gives a two-thirds figure for cases; the Discussion’s 0.09–0.30 figure concerns allele frequency in human populations, not the proportion of patients carrying APOE4. Page numbers are unavailable in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredAPOE is estimated to account for 20% of the AD attributable risk.
“APOE is estimated to account for 20% of the AD attributable risk, and the APOE-associated risk is similar to those identified for major genes in other Mendelian diseases, such as BRCA1 in breast cancer [31].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [31]
The Discussion (page not available in our copy) compares APOE-associated lifetime risk with that of BRCA1 in breast cancer, supporting the second part of the citing sentence. The Results report genotype-specific lifetime risks, but neither those passages nor passages retrieved for attributable risk give an estimate that APOE accounts for 20% of AD attributable risk. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe major risk factor for Alzheimer's disease is inheritance of the E4 allele of apolipoprotein E (APOE).
“The major risk factor for AD is inheritance of the E4 allele of apolipoprotein E (APOE).5,6”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [6]
APOE4 homozygotes have a markedly increased risk of developing Alzheimer's disease (14.5-fold compared to APOE3 homozygotes).
“APOE4 homozygotes have a markedly increased risk of developing AD (14.5-fold compared to APOE3 homozygotes)”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [6]
Compared to E4 homozygotes, APOE2/E4 heterozygotes have a markedly reduced risk of developing AD.
“APOE2 homozygotes are protected from late-onset AD and, compared to E4 homozygotes, APOE2/E4 heterozygotes have a markedly reduced risk of developing AD.6,12,13”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [6]
Individuals who are APOE4 homozygotes have a markedly increased risk of developing AD.
“Individuals who are APOE4 homozygotes have a markedly increased risk of developing AD.”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [6]
APOE4 is the major genetic risk factor for sporadic, late-onset AD.
“APOE4 is the major genetic risk factor for sporadic, late-onset AD (199, 368, 580, 612).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [199]
Apolipoprotein E4 is the major genetic risk factor for Alzheimer's disease.
“Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s disease (AD)”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [3]
In humans, the APOE4 and APOE2 alleles are codominant.
“In humans, the APOE4 and APOE2 alleles are codominant”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [6]
The Introduction and Results discuss how APOE genotypes relate to Alzheimer disease risk, including a protective association for APOE2 and semi-dominant inheritance of disease risk. They do not address whether APOE4 and APOE2 are codominant alleles; semi-dominance of disease risk does not settle that separate claim. Searches for codominance and the APOE2/APOE4 combination found no decisive passage. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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“Consistent with accelerating APOE4 -dependent risk for AD and cognitive decline with older age [17], some studies have reported stronger effects of APOE4 on WM microstructure with age [3, 15, 18], whereas others observed no such interaction [8].”
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- Authors
- Genin, E., Hannequin, D., Wallon, D., Sleegers, K., Hiltunen, M., Combarros, O., Bullido, M. J., Engelborghs, S., De Deyn, P., Berr, C., Pasquier, F., Dubois, B., Tognoni, G., Fiévet, N., Brouwers, N., Bettens, K., Arosio, B., Coto, E., Del Zompo, M., Mateo, I., Epelbaum, J., Frank-Garcia, A., Helisalmi, S., Porcellini, E., Pilotto, A., Forti, P., Ferri, R., Scarpini, E., Siciliano, G., Solfrizzi, V, Sorbi, S., Spalletta, G., Valdivieso, F., Vepsäläinen, S., Alvarez, V, Bosco, P., Mancuso, M., Panza, F., Nacmias, B., Bossù, P., Hanon, O., Piccardi, P., Annoni, G., Seripa, D., Galimberti, D., Licastro, F., Soininen, H., Dartigues, J.-F., Kamboh, M. I., Van Broeckhoven, C., Lambert, J. C., Amouyel, P., & Campion, D.
- Affiliations
- Inserm (FR)
- University of Antwerp (BE)
- University of Eastern Finland (FI)
- Universidad de Cantabria (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Centre Hospitalier Universitaire de Lille (FR)
- Pitié-Salpêtrière Hospital (FR)
- University of Pisa (IT)
- University of Milan (IT)
- Hospital Universitario Central de Asturias (ES)
- University of Bologna (IT)
- Casa Sollievo della Sofferenza (IT)
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- Oasi Maria SS (IT)
- University of Bari Aldo Moro (IT)
- University of Florence (IT)
- Fondazione Santa Lucia (IT)
- Hôpital Broca (FR)
- University of Cagliari (IT)
- University of Milano-Bicocca (IT)
- University of Pittsburgh (US)
- Corresponding author
- Campion, D
- ORCID
- Hannequin, D
- Wallon, D
- Sleegers, K
- Hiltunen, M
- Bullido, M J
- Engelborghs, S
- Berr, C
- Pasquier, F
- Dubois, B
- Brouwers, N
- Arosio, B
- Coto, E
- Helisalmi, S
- Porcellini, E
- Pilotto, A
- Forti, P
- Ferri, R
- Scarpini, E
- Siciliano, G
- Solfrizzi, V
- Sorbi, S
- Spalletta, G
- Bosco, P
- Mancuso, M
- Panza, F
- Nacmias, B
- Bossù, P
- Hanon, O
- Seripa, D
- Galimberti, D
- Soininen, H
- Dartigues, J-F
- Kamboh, M I
- Lambert, J C
- Amouyel, P
- Campion, D
- Venue
- Molecular Psychiatry
- Published
- 2011-05-10
- Volume
- 16
- Issue
- 9
- Pages
- 903-907
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3162068
- OpenAlex
- W2107094473
- Cited by
- 714
- References
- 21
- Citations by year
- 2026: 43 · 2025: 65 · 2024: 67 · 2023: 42 · 2022: 68 · 2021: 58 · 2020: 60 · 2019: 43 · 2018: 40 · 2017: 31 · 2016: 51 · 2015: 34 · 2014: 35 · 2013: 37 · 2012: 35
- FWCI
- 24.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCrea (University of Cantabria) (acceptedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
- Florence Research (University of Florence) (submittedVersion)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- National Institute on Aging (AG-005133, P50AG005133, R01AG030653, AG 030653)
- 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 › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- apolipoprotein E, APOE ε4, Alzheimer's disease, lifetime risk, semidominant inheritance, major gene hypothesis, genetic risk, early-onset Alzheimer's disease, late-onset Alzheimer's disease, penetrance, age-stratified risk, PAQUID cohort
- MeSH terms
- Age Factors, Aged, Alleles, Alzheimer Disease, Female, France, Genotype, Humans, Male, Middle Aged, United States, Incidence, Odds Ratio, Case-Control Studies, Genetic Predisposition to Disease, Heredity, Apolipoprotein E3, Apolipoprotein E4
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