Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank
Open accessAbstract
Background The three main alleles of the APOE gene (ε4, ε3 and ε2) carry differential risks for conditions including Alzheimer's disease (AD) and cardiovascular disease. Due to their clinical significance, we explored disease associations of the APOE genotypes using a hypothesis-free, data-driven, phenome-wide association study (PheWAS) approach. Methods We used data from the UK Biobank to screen for associations between APOE genotypes and over 950 disease outcomes using genotype ε3ε3 as a reference. Data was restricted to 337,484 white British participants (aged 37–73 years). Findings After correction for multiple testing, PheWAS analyses identified associations with 37 outcomes, representing 18 distinct diseases. As expected, ε3ε4 and ε4ε4 genotypes associated with increased odds of AD (p ≤ 7.6 × 10 −46 ), hypercholesterolaemia (p ≤ 7.1 × 10 −17 ) and ischaemic heart disease (p ≤ 2.3 × 10 −4 ), while ε2ε3 provided protection for the latter two conditions (p ≤ 3.7 × 10 −10 ) compared to ε3ε3. In contrast, ε4-associated disease protection was seen against obesity, chronic airway obstruction, type 2 diabetes, gallbladder disease, and liver disease (all p ≤ 5.2 × 10 −4 ) while ε2ε2 homozygosity increased risks of peripheral vascular disease, thromboembolism, arterial aneurysm, peptic ulcer, cervical disorders, and hallux valgus (all p ≤ 6.1 × 10 −4 ). Sensitivity analyses using brain neuroimaging, blood biochemistry, anthropometric, and spirometric biomarkers supported the PheWAS findings on APOE associations with respective disease outcomes. Interpretation PheWAS confirms strong associations between APOE and AD, hypercholesterolaemia, and ischaemic heart disease, and suggests potential ε4-associated disease protection and harmful effects of the ε2ε2 genotype, for several conditions. Funding National Health and Medical Research Council of Australia.
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In the same registries, APOEε2 has been associated with lower LDL cholesterol levels, increased triglyceride levels and increased risk of peripheral vascular disease.
“By contrast, in the same registries, APOEε2 has been associated with lower LDL cholesterol levels, increased triglyceride levels and increased risk of peripheral vascular disease87,88.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [88]
The Results (Sensitivity analyses of disease biomarkers) report low LDL and very high triglycerides for ε2ε2 compared with ε3ε3; the Results (Genotype PheWAS analyses) also report elevated odds of peripheral vascular disease for ε2ε2. The claim omits the important homozygosity qualifier: the paper does not establish that increased triglycerides and peripheral vascular disease apply to APOE ε2 carriers generally. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBesides AD, APOE has been associated with at least eighteen other diseases, including heart disease and high cholesterol.
“Besides AD43, APOE has been associated with at least eighteen other diseases, including heart disease and high cholesterol44.”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [44]
The Abstract (Findings) reports APOE associations with 18 distinct diseases, including Alzheimer’s disease, hypercholesterolaemia and ischaemic heart disease. It does not support the claim of at least 18 diseases besides Alzheimer’s disease; the reported total is 18 including it. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAPOE genotype was determined using SNP data at rs429358 and rs7412, defining the three major APOE isoforms, consistent with prior UK Biobank studies.
“APOE genotype was determined using SNP data at rs429358 and rs7412, which define the three major APOE isoforms (ε2, ε3, and ε4) based on established haplotypes. Genotypes were assigned according to allele combinations, consistent with prior UK Biobank studies,79”
From TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice (2025) · cites this paper as [79]
The risk increase for PAD in ε22 genotype was also recently reported cross-sectionally in the UK Biobank.
“a risk increase also recently reported cross-sectionally in the UK Biobank [42]”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [42]
In large health registries such as the UK BioBank, the APOEε4 allele has been associated with higher LDL cholesterol and triglycerides levels, lower HDL cholesterol levels and an increased risk of coronary artery disease.
“In large health registries such as the UK BioBank, the APOEε4 allele has been associated with higher LDL cholesterol and triglycerides levels, lower HDL cholesterol levels and an increased risk of coronary artery disease.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [88]
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Apolipoprotein E in lipid metabolism and neurodegenerative disease
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APOE ε4 carriers share immune-related proteomic changes across neurodegenerative diseases
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Marais, A. D. (2021) · Current Atherosclerosis Reports · doi:10.1007/s11883-021-00933-4 · Cited by 48 · see citing works
Elevated C-reactive protein mediates the liver-brain axis: a preliminary study
Jiang, R., Wu, J., Rosenblatt, M., Dai, W., Rodriguez, R. X., Sui, J., Qi, S., Liang, Q., Xu, B., Meng, Q., et al. (2023) · eBioMedicine · doi:10.1016/j.ebiom.2023.104679 · Cited by 46 · see citing works
Dong, C., Zhou, C., Fu, C., Hao, W., Ozaki, A., Shrestha, N., Virani, S. S., Mishra, S. R., & Zhu, D. (2022) · Biology of Sex Differences · doi:10.1186/s13293-022-00431-5 · Cited by 43 · see citing works
COVID-19 enters the expanding network of apolipoprotein E4-related pathologies
Gkouskou, K. K., Vasilogiannakopoulou, T., Andreakos, E., Davanos, N., Gazouli, M., Sanoudou, D., & Eliopoulos, A. G. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101938 · Cited by 41 · see citing works
“A recent phenome-wide association study of APOE genotypes with 950 disease outcomes registered in the UK biobank confirmed the elevated risk of cardiovascular diseases, AD and hypercholesterolaemia associated with ε 4 ( ε 3/ ε 4 or ε 4/ ε 4) compared to the ε 3/ ε 3 genotype [23].”
Neuroimmunometabolism: A New Pathological Nexus Underlying Neurodegenerative Disorders
Mitra, S., Banik, A., Saurabh, S., Maulik, M., & Khatri, S. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.0998-21.2022 · Cited by 44 · see citing works
“The APOE « 4 allele is one of the most investigated genetic risk factors for AD with a 15-fold increased risk for AD in people homozygous for this allele (Mosconi, 2013; Lumsden et al., 2020).”
COVID-19 as a Risk Factor for Alzheimer’s Disease
Golzari-Sorkheh, M., Weaver, D. F., & Reed, M. A. (2023) · Journal of Alzheimer's Disease · doi:10.3233/jad-220800 · Cited by 39 · see citing works
Rasmussen, K. L., Tybjærg-Hansen, A., Nordestgaard, B. G., & Frikke-Schmidt, R. (2023) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2022.4602 · Cited by 40 · see citing works
Mulligan, M. D., Murphy, R., Reddin, C., Judge, C. S., Ferguson, J. P., Alvarez‐Iglesias, A., McGrath, E. R., & O'Donnell, M. J. (2023) · EClinicalMedicine · doi:10.1016/j.eclinm.2023.102012 · Cited by 38 · see citing works
Nguyen, T. N. M., Chen, L., Trares, K., Stocker, H. R., Holleczek, B., Beyreuther, K. T., Brenner, H., & Schöttker, B. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01017-4 · Cited by 36 · see citing works
“Genomewide genetic data were available for 488,377 participants, of whom 49,950 were genotyped on the UK BiLEVE Axiom array while the remaining were run on the UK Biobank Axiom array [25].”
BackgroundThe Impact of Apolipoprotein E (APOE) Epigenetics on Aging and Sporadic Alzheimer’s Disease
Lozupone, M., Dibello, V., Sardone, R., Castellana, F., Zupo, R., Lampignano, L., Bortone, I., Daniele, A., Bellomo, A., Solfrizzi, V., et al. (2023) · Biology · doi:10.3390/biology12121529 · Cited by 36 · see citing works
“Biology 2023 , 12 , 1529 5 Biology 2023 , 12 , x FOR PEER REVIEW 5 of 14 65 [66 In AD, the association between these polymorphic sites and the variability of sequence in the proximal promoter with ApoE protein levels are not clearly understood.”
BackgroundAssociation between liver fibrosis and incident dementia in the UK Biobank study
Parikh, N. S., Kamel, H., Zhang, C., Kumar, S. R., Rosenblatt, R. E., Spincemaille, P., Gupta, A. K., Cohen, D. E., de Leon, M. J., Gottesman, R. F., et al. (2022) · European Journal of Neurology · doi:10.1111/ene.15437 · Cited by 35 · see citing works
“The apolipoprotein gene was directly genotyped for UK Biobank participants, and we used standard definitions to assign genotypes based on rs429358 and rs7412 alleles [31, 32].”
MethodAcute Myocardial Infarction and Risk of Cognitive Impairment and Dementia: A Review
Thong, E. H., Quek, J. W. E., Loo, J. H., Yun, C.-Y., Teo, Y. N., Teo, Y. H., Leow, A. S., Li, T. Y., Sharma, V. K., Tan, B. Y., et al. (2023) · Biology · doi:10.3390/biology12081154 · Cited by 31 · see citing works
“It is also is a prevalent genetic risk factor of AD, being expressed in more than half of AD patients, and this may explain why patients with the ApoE epsilon-4 allele are at increased risk of both AMI and AD [220].”
BackgroundOnisiforou, A., Charalambous, E. G., & Zanos, P. (2025) · Microorganisms · doi:10.3390/microorganisms13010090 · Cited by 31 · see citing works
“The APOE genotype is the most significant genetic risk factor for AD [183].”
Neuron-level explainable AI for Alzheimer’s Disease assessment from fundus images
Yousefzadeh, N., Tran, C., Ramirez‐Zamora, A., Chen, J., Fang, R., & Thai, M. T. (2024) · Scientific Reports · doi:10.1038/s41598-024-58121-8 · Cited by 30 · see citing works
Li, M., Zhao, J. V., Kwok, M. K., & Schooling, C. M. (2021) · Scientific Reports · doi:10.1038/s41598-021-88256-x · Cited by 27 · see citing works
Parikh, N. S., Kamel, H., Zhang, C., Gupta, A. K., Cohen, D. E., de Leon, M. J., Gottesman, R. F., & Iadecola, C. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12795 · Cited by 27 · see citing works
Genetics of Gallstone Disease and Their Clinical Significance: A Narrative Review
Costa, C. J., Nguyen, M. T. T., Vaziri, H., & Wu, G. Y. (2024) · Journal of Clinical and Translational Hepatology · doi:10.14218/jcth.2023.00563 · Cited by 26 · see citing works
“38,39 In a meta-analysis of studies that reported genotypes and ultrasound examinations, researchers investigated the potential associations between E4 variants and GS disease.”
BackgroundGünaydin, C., Sondhi, D., Kaminsky, S. M., Lephart, H. C., Leopold, P. L., Hackett, N. R., Khanna, R., & Crystal, R. G. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.11.003 · Cited by 26 · see citing works
Lozupone, M., Imbimbo, B. P., Balducci, C., Vecchio, F. L., Bisceglia, P., Latino, R. R., Leone, M. A., Dibello, V., Solfrizzi, V., Greco, A., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12728 · Cited by 26 · see citing works
Complexity of Sex Differences and Their Impact on Alzheimer’s Disease
Kadlecová, M., Freude, K., & Haukedal, H. (2023) · Biomedicines · doi:10.3390/biomedicines11051261 · Cited by 26 · see citing works
Bhale, A. S., Meilhac, O., d’Hellencourt, C. L., Vijayalakshmi, M. A., & Venkataraman, K. (2024) · BioFactors · doi:10.1002/biof.2057 · Cited by 24 · see citing works
“221 The exact mechanisms by which ApoE isoforms contribute to disease pathology, including lipid metabolism, neuroinflammation, synaptic function, and amyloid-beta metabolism in the brain, are still under investigation.”
Innes, H. A., Nischalke, H. D., Guha, I. N., Weiss, K. H., Irving, W. L., Gotthardt, D. N., Barnes, E. J., Fischer, J., Ansari, M. A., Rosendahl, J., et al. (2021) · Hepatology Communications · doi:10.1002/hep4.1886 · Cited by 24 · see citing works
“(24,25) Previous studies have shown that rs429358:C is associated with a reduced risk of cirrhosis in HCV,(25) NAFLD,(8) and in mixed- etiology population cohorts.(26,27) Our results extend this narrative by demonstrating that rs429358:C is also associated with a reduced risk of HCC in HCV cirrhosis, alcohol- related…”
ResultVicente, M. C., Addo-Osafo, K., & Vossel, K. A. (2024) · Frontiers in Neurology · doi:10.3389/fneur.2024.1277613 · Cited by 25 · see citing works
Matatall, K. A., Wathan, T. K., Nguyen, M., Chen, H., McDonald, A., Qi, G., Belk, J. A., Florez, M. A., Le, D. T., Olarinde, T., et al. (2025) · Cell Stem Cell · doi:10.1016/j.stem.2025.06.006 · Cited by 23 · see citing works
Venkatesh, S. S., Ganjgahi, H., Palmer, D. S., Coley, K., Linchangco, G. V., Hui, Q., Wilson, P. W. F., Ho, Y.-L. A., Cho, K., Arumäe, K., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49998-0 · Cited by 23 · see citing works
“The precise pathway by which this variant affects weight change is dif fi cult to pinpoint, as APOE is a highly pleiotropic locus associated with hundreds of biomarkers and diseases 63 .”
McGeachan, R., Meftah, S., Taylor, L. W., Catterson, J. H., Negro, D., Bonthron, C., Holt, K., Tulloch, J., Rose, J., Gobbo, F., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58879-z · Cited by 14 · see citing works
Maturation and application of phenome-wide association studies
Liu, S., & Crawford, D. C. (2022) · Trends in Genetics · doi:10.1016/j.tig.2021.12.002 · Cited by 23 · see citing works
Lopes-Araújo, A., Arrifano, G. D. P., Macchi, B. D. M., Augusto‐Oliveira, M., Santos-Sacramento, L., Martín-Doimeadios, R. C. R., Jiménez-Moreno, M., Filho, A. J. M., Alvarez-Leite, J. I., Oriá, R. B., et al. (2023) · Environmental Research · doi:10.1016/j.envres.2023.115971 · Cited by 23 · see citing works
APOE and vascular disease: Sequencing and genotyping in general population cohorts
Rasmussen, K. L., Luo, J., Nordestgaard, B. G., Tybjærg-Hansen, A., & Frikke-Schmidt, R. (2023) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2023.117218 · Cited by 22 · see citing works
A microglia clonal inflammatory disorder in Alzheimer’s disease
Vicario, R., Fragkogianni, S., Weber, L., Lazarov, T., Hu, Y., Hayashi, S. Y., Craddock, B., Socci, N. D., Alberdi, A., Baako, A., et al. (2025) · eLife · doi:10.7554/elife.96519.3 · Cited by 21 · see citing works
“APOE risk allele frequency for patients and controls was comparable to published series ( Murrell et al., 2006 ; Sando et al., 2008 ; Lumsden et al., 2020 ; Figure 1—figure supplement 1A ), and analysis of germline mutations did not identify deleterious variants in the 140 genes associated with…”
Genetic influence on within-person longitudinal change in anthropometric traits in the UK Biobank
Kemper, K. E., Sidorenko, J., Wang, H., Hayes, B. J., Wray, N. R., Yengo, L., Keller, M. C., Goddard, M. E., & Visscher, P. M. (2024) · Nature Communications · doi:10.1038/s41467-024-47802-7 · Cited by 21 · see citing works
APOEε4 and risk of Alzheimer’s disease – time to move forward
Lefterov, I. M., Fitz, N. F., Lü, Y., & Koldamova, R. P. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1195724 · Cited by 23 · see citing works
Optimized prime editing of the Alzheimer’s disease-associated APOE4 mutation
Rottner, A. K., Lundin, A., Li, S., Firth, M. A., Maresca, M., & Sienski, G. (2024) · Stem Cell Reports · doi:10.1016/j.stemcr.2024.11.002 · Cited by 20 · see citing works
Murphy, K. B., Hu, D., Wolfs, L., Rohde, S. K., Fauró, G. L., Geric, I., Mancuso, R., De Strooper, B., & Marzi, S. J. (2025) · Nature Communications · doi:10.1038/s41467-025-60099-4 · Cited by 25 · see citing works
Qiao, S.-Y., Shang, K., Chu, Y., Yu, H., Chen, X., Qin, C., Pan, D., & Tian, D.-S. (2022) · Disease Markers · doi:10.1155/2022/1407183 · Cited by 20 · see citing works
“APOE polymorphisms and its risk associations with coronary artery disease [9], hypertension [10], diabetes [11], and carotid arterial atherosclerosis [12] are widely debated.”
BackgroundPitchika, A., Markus, M. R. P., Schipf, S., Teumer, A., der Auwera, S. V., Nauck, M. A., Dörr, M., Felix, S. B., Grabe, H. J., Völzke, H., et al. (2022) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2022.109778 · Cited by 21 · see citing works
Mulugeta, A., Navale, S. S., Lumsden, A. L., Llewellyn, D. J., & Hyppönen, E. (2022) · Nutrients · doi:10.3390/nu14193907 · Cited by 20 · see citing works
“Indeed, one of the key AD variants, APOE4, while increasing the risk in older age disease [31], is also associated with better episodic memory in young and healthy populations [32].”
BackgroundSelf-citationThe Effects of Estrogen on the Risk of Developing Dementia: A Cohort Study Using the UK Biobank Data
Park, H. K., Marston, L., & Mukadam, N. (2024) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2024.01.025 · Cited by 20 · see citing works
Xu, C., Garcia, D., Lu, Y., Ozuna, K., Adjeroh, D. A., Wang, K., & Initiative, O. B. O. T. A. D. N. (2021) · Cells · doi:10.3390/cells11010029 · Cited by 19 · see citing works
“The ApoE ε 3 allele is the most common allele, followed by ε 4 allele [2].”
InfluentialHu, H., Wan, S., Hu, Y., Wang, Q., Li, H., & Zhang, N. (2025) · Annals of Medicine · doi:10.1080/07853890.2024.2445194 · Cited by 19 · see citing works
“Notably, the combination of two non-synonymous single nucleotide polymorphisms (rs429358 and rs7412) in the fourth exon of the APOE gene leads to variations in the amino acids at positions 112 and 158 of the APOE protein [12,13].”
Stephen, T., Breningstall, B. M., Suresh, S., McGill, C. J., & Pike, C. J. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02650-4 · Cited by 17 · see citing works
“Specifically, we find that astrocytes in male E3FAD mice show greater astrocyte coverage, elevated plaque compaction, and lower levels of neurite injury; these effects are significantly diminished by female sex with both APOE3 and APOE4 genotypes.”
BackgroundInfluentialBraak, H., Mayer, B., Feldengut, S., Schön, M., & Tredici, K. D. (2025) · Acta Neuropathologica · doi:10.1007/s00401-025-02862-x · Cited by 20 · see citing works
Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult
Nunzio, G. D., Hellberg, S., Zhang, Y., Osman, A., Wang, J., Zhang, X., Björck, H. M., Chizh, V., Schipper, R., Aulin, H., et al. (2024) · Nature Cardiovascular Research · doi:10.1038/s44161-024-00448-6 · Cited by 17 · see citing works
“APOE also has additional properties beyond lipoprotein transport, including an anti-inflammatory function 18,36 and restraining germinal center formation 18,37 , and human alleles of APOE are implicated in the risk of developing multiple complex diseases, including cardiovascular disease 38 .”
Amyloid-beta metabolism in age-related neurocardiovascular diseases
Aivalioti, E., Georgiopoulos, G., Tual-Chalot, S., Bampatsias, D., Delialis, D., Sopova, K., Drakos, S., Stellos, K., & Stamatelopoulos, K. (2024) · European Heart Journal · doi:10.1093/eurheartj/ehae655 · Cited by 16 · see citing works
“121 Importantly, the observed association of CAD and late-onset AD (LOAD) is mediated by the ApoE locus, and this association vanished when the impact of the ApoE gene is excluded, suggesting that ApoE locus is the chief determinant of shared genetic architecture between CAD and LOAD.”
Taylor, H., Lewins, M., Foody, M. G. B., Gray, O. P., Bešević, J., Conroy, M. C., Collins, R., Lacey, B., Allen, N. E., & Burkitt-Gray, L. (2025) · Neurology Genetics · doi:10.1212/nxg.0000000000200226 · Cited by 18 · see citing works
Baichan, P., Naicker, P., Augustine, T. N., Smith, M., Candy, G. P., Devar, J. W., & Nweke, E. E. (2023) · Clinical Proteomics · doi:10.1186/s12014-023-09399-9 · Cited by 17 · see citing works
Butnariu, L. I., Gorduza, E. V., Țarcă, E., Pânzaru, M.-C., Popa, S., Stoleriu, S., Lupu, V. V., Lupu, A., Cojocaru, E., Trandafir, L. M., et al. (2023) · Diagnostics · doi:10.3390/diagnostics13142348 · Cited by 20 · see citing works
Pharmacogenomics of Dementia: Personalizing the Treatment of Cognitive and Neuropsychiatric Symptoms
Vuić, B., Milos, T., Tudor, L., Perković, M. N., Konjevod, M., Erjavec, G. N., Farkaš, V., Uzun, S., Mimica, N., & Štrac, D. Š. (2023) · Genes · doi:10.3390/genes14112048 · Cited by 17 · see citing works
Gene-Environment interactions and stochastic variations in the Gero-Exposome.
Finch, C., & Haghani, A. (2021) · The journals of gerontology. Series A, Biological sciences and medical sciences · doi:10.1093/gerona/glab045 · Cited by 15 · see citing works
Strafella, C., Caputo, V., Termine, A., Fabrizio, C., Ruffo, P., Potenza, S., Cusumano, A., Ricci, F., Caltagirone, C., Giardina, E., et al. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.626066 · Cited by 16 · see citing works
Heritable confounding of exposure and outcome in Mendelian randomization studiesPreprint
Sanderson, E. C. M., Rosoff, D. B., Vitt, N., Palmer, T., Tilling, K. M., Smith, G. D., & Hemani, G. (2024) · medRxiv · doi:10.1101/2024.09.05.24312293 · Cited by 16 · see citing works
Lower mortality risk in APOE4 carriers with normal cognitive ageing
Pirraglia, E., Glodzik, L., & Shao, Y. (2023) · Scientific Reports · doi:10.1038/s41598-023-41078-5 · Cited by 15 · see citing works
APOE Gene Variation’s Impact on Cardiovascular Health: A Case-Control Study
Ismail, A. B., Balcıoğlu, Ö., Özcem, B., & Ergören, M. Ç. (2024) · Biomedicines · doi:10.3390/biomedicines12030695 · Cited by 15 · see citing works
“In contrast to several preceding studies conducted by Boss et al., 2021 [12], Liu et al., 2019 [41], and Lumsden et al., 2020 [42], which reported a significant positive association between the expression of the ε 4 allele of the APOE gene and cardiovascular diseases.”
ResultInvestigating the Interplay between Cardiovascular and Neurodegenerative Disease
Cousineau, J., Dawe, A. M., & Alpaugh, M. (2024) · Biology · doi:10.3390/biology13100764 · Cited by 15 · see citing works
“For example, mutations in the prese-nilin genes PSEN1 and PSEN2 associated with early familial AD are also associated with dilated cardiomyopathy (CM) and HF [47], while the ApoE4 has also been associated with ischemic heart disease, myocardial infarction (MI), and AS [11,48].”
BackgroundSemaev, S., Шахтшнейдер, Е. В., Щербакова, Л. В., Иванощук, Д. Е., Orlov, P. S., Malyutina, S. K., Гафаров, В. В., Ragino, Y. I., & Voevoda, M. I. (2022) · Current Issues in Molecular Biology · doi:10.3390/cimb44040118 · Cited by 14 · see citing works
“Judging by the results of major global studies involving UK Biobank data, genotypes ε3/ε4 and ε4/ε4 are associated with hypercholesterolemia and coronary heart disease in contrast to the ε3/ε3 genotype, whereas the ε2/ε3 genotype has shown a protective effect ag inst these pathologi [6].”
BackgroundResultInfluentialApolipoprotein ε in Brain and Retinal Neurodegenerative Diseases
Abyadeh, M., Gupta, V., Paulo, J. A., Sheriff, S., Shadfar, S., Fitzhenry, M. J., Amirkhani, A., Gupta, V. B., Salekdeh, G. H., Haynes, P. A., et al. (2023) · Aging and Disease · doi:10.14336/ad.2023.0312-1 · Cited by 14 · see citing works
Williams, T., Bathe, T., Vo, Q., Sacilotto, P., McFarland, K. N., Ruiz, A. J., Hery, G. P., Sullivan, P. M., Borchelt, D., Prokop, S., et al. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01581-2 · Cited by 14 · see citing works
“On the other hand, the E2 allele is associated with increased longevity and protection from AD [3], though presence of E2 allele can often lead to hyperlipoproteinemia and metabolic pathologies [4, 5].”
BackgroundCholesterol metabolism: physiological versus pathological aspects in intracerebral hemorrhage
Huang, R., Pang, Q., Zheng, L., Lin, J., Li, H., Wan, L., & Wang, T. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-01462 · Cited by 18 · see citing works
“Furthermore, ApoE ε2 and ε4 are both risk factors for the occurrence of ICH in white populations (Lumsden et al., 2020).”
BackgroundInfluentialPhenome-wide association of APOE alleles in the All of Us Research Program
Khajouei, E., Ghisays, V., Piras, I. S., Martinez, K. L., Vicenti, A. T., Naymik, M., Ngo, P., Tran, T. C., Denny, J. C., Wheeler, T. J., et al. (2025) · EBioMedicine · doi:10.1016/j.ebiom.2025.105768 · Cited by 14 · see citing works
“4,20 In summary, we replicate extensive phenotypic associations with APOE alleles in a large, diverse cohort.”
InfluentialTitcomb, T. J., Richey, P. A., Casanova, R., Phillips, L. S., Liu, S., Karanth, S. D., Saquib, N., Nuño, T., Manson, J. E., Shadyab, A. H., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13416 · Cited by 13 · see citing works
Khaire, A. S., Wimberly, C. E., Semmes, E. C., Hurst, J. H., & Walsh, K. M. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.05.011 · Cited by 13 · see citing works
Cho, S. B. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25042211 · Cited by 12 · see citing works
Pitchika, A., Markus, M. R. P., Schipf, S., Teumer, A., der Auwera, S. V., Nauck, M. A., Dörr, M., Felix, S. B., Grabe, H. J., Völzke, H., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-09129-5 · Cited by 13 · see citing works
Wu, S., Liu, X., Yang, H., Ma, W., & Qin, Z. (2023) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2023.08.2194 · Cited by 12 · see citing works
“By contrast, the ε 2 allele was often found to be protective, while ε 3 seemed neutral in terms of AD incidence (Lumsden et al., 2020).”
BackgroundPietilä, E. M., Snellman, A., Tuisku, J., Helin, S., Viitanen, M. H., Jula, A., Rinne, J. O., & Ekblad, L. L. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106385 · Cited by 12 · see citing works
“APOE ε 4 genotype is also associated with vascular risk factors (Lumsden et al., 2020) which in turn, often associate with insulin resistance and are also associated with cognitive decline.”
BackgroundAPOE Gene Associated with Cholesterol-Related Traits in the Hispanic Population
Lozano, S., Padilla, V., Avila, M. L., Gil, M., Maestre, G. E., Wang, K., & Xu, C. D. (2021) · Genes · doi:10.3390/genes12111768 · Cited by 12 · see citing works
Affleck, A. J., Sachdev, P. S., & Halliday, G. M. (2023) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12922 · Cited by 11 · see citing works
Huang, X., Han, X., Chang, H., Yu, T., Dong, Y., Mao, M., Ding, J., Li, X., Liu, H., Tian, M., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03166-y · Cited by 11 · see citing works
“We conducted descriptive analyses to examine the characteristics of study participants by sex.”
Data-driven cluster analysis identifies distinct types of cardiovascular-kidney-metabolic syndrome
Yang, M., Su, C., Chang, X., Wang, G., & Liu, J. (2025) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwaf708 · Cited by 11 · see citing works
Wang, Q., Yuan, S., Wang, C., Huang, D., Zhang, M., Zhan, Y., Gao, F., Shi, J., Levey, A. I., & Shen, Y. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01644-z · Cited by 12 · see citing works
Neuropsychiatric symptoms and apolipoprotein E genotypes in neurocognitive disorders
Lozupone, M., Leccisotti, I., Mollica, A., Berardino, G., Moretti, M. C., Altamura, M., Bellomo, A., Daniele, A., Dibello, V., Solfrizzi, V., et al. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-01274 · Cited by 11 · see citing works
Chen, J., Chen, H., Wei, Q., Lu, Y., Wang, T., Pang, X., Xing, G., Chen, Z., Cao, X., & Yao, J. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02454-4 · Cited by 11 · see citing works
“The indoor temperature was maintained within a range of 20 – 26 °C, and the humidity was maintained within a range of 40 – 70%.”
Evaluating metabolome-wide causal effects on risk for psychiatric and neurodegenerative disorders
Gilchrist, L., Mutz, J., Hysi, P. G., Legido‐Quigley, C., Kõks, S., Lewis, C. M., & Proitsi, P. (2025) · BMC Medicine · doi:10.1186/s12916-025-04129-4 · Cited by 12 · see citing works
“The APOE region (chr19:45,020,859–45,844,508 (GRCh37)) was excluded from the AD GWAS due to known pleiotropic effects on relevant non-AD diseases such as heart disease and hypercholesterolaemia [54].”
Semaev, S., Шахтшнейдер, Е. В., Щербакова, Л. В., Orlov, P. S., Иванощук, Д. Е., Malyutina, S. K., Гафаров, В. В., Voevoda, M. I., & Ragino, Y. I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310908 · Cited by 11 · see citing works
“In our study, ε3 allele frequencies were consistent with data on the frequency of this allele worldwide [16,30,31].”
BackgroundResultInfluentialJung, J. H., Kong, N., & Lee, S. (2025) · The Journal of Prevention of Alzheimer s Disease · doi:10.1016/j.tjpad.2025.100363 · Cited by 10 · see citing works
“The apolipoprotein E ε 4 (APOE4) allele, a well-established genetic risk factor for AD, is associated with vascular damage as well as an increased risk of cardiovascular small vessel disease [16 – 18].”
Fernández‐de‐las‐Peñas, C., Arendt‐Nielsen, L., Díaz‐Gil, G., Gómez‐Esquer, F., Crujera, A. G., Gómez-Sanchez, S. M., Ambite‐Quesada, S., Palomar‐Gallego, M. A., Pellicer-Valero, Ó. J., & Giordano, R. (2023) · Genes · doi:10.3390/genes14071420 · Cited by 10 · see citing works
“observed that the ApoE ε4 genotype is associated with a higher risk of hypercholesterolemia and ischemic heart disease but also with a lower risk (protection effect) of obesity, chronic airway obstruction, and type 2 diabetes, among others [14].”
Background
- Authors
- Lumsden, A. L., Mulugeta, A., Zhou, A., & Hyppönen, E.
- Affiliations
- University of South Australia (AU)
- Corresponding author
- Hyppönen, Elina
- Venue
- eBioMedicine
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 59
- Pages
- 102954
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC7452404
- OpenAlex
- W3069395596
- Cited by
- 317
- References
- 31
- Citations by year
- 2026: 54 · 2025: 72 · 2024: 82 · 2023: 59 · 2022: 33 · 2021: 17
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- UniSA Research Outputs Repository (University of South Australia) (submittedVersion, other-oa)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- UK Biobank (GNT1123603)
- National Health and Medical Research Council (GNT1157281)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- apolipoprotein E, APOE genotype, APOE ε4, APOE ε2, Alzheimer's disease, hypercholesterolemia, ischemic heart disease, phenome-wide association study, disease risk, obesity, type 2 diabetes, peripheral vascular disease, thromboembolism, arterial aneurysm, peptic ulcer, hallux valgus, cardiovascular disease, genetic risk factors
- MeSH terms
- Adult, Aged, Alleles, Apolipoproteins E, Female, Genotype, United Kingdom, Humans, Male, Middle Aged, Phenotype, Population Surveillance, Registries, Risk Factors, Case-Control Studies, Biological Specimen Banks, Risk Assessment, Genetic Predisposition to Disease, Genetic Association Studies
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.
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