Trends Sci. 2025; 22(8): 9754

Apolipoprotein E (ApoE) Gene Polymorphism and Cardiovascular Risk in Type 2 Diabetic Patients: A Systematic Review

Thahira A.¹, Thirumal Kumar D.², Dinesh Roy³, Swetapadma Pradhan⁴,

Yatindra Kumar⁵, Niyati Tandon⁶, Arghadip Das⁷, Ajit Panvalkar⁸,

Lalitha Soumya Johnson⁹, Harshad S.¹⁰, Akshay V. P.^11,* and Delna N. Saraswathy¹²

¹Meenakshi Academy of Higher Education and Research, MAHER-Deemed to be University,

Tamil Nadu, India

²Faculty of Allied Health Sciences-Meenakshi Academy of Higher Education and Research,

MAHER-Deemed to be University, Tamil Nadu, India
³Genetika-Centre for Advanced Genetic Studies, Kerala, India

⁴Faculty of Medicine, European University, Tbilisi, Georgia

⁵Department of Life Science and Biotechnology, Chhatrapati Shivaji Maharaj University, Maharashtra, India

⁶Department of Food Science and Nutrition, G. B. Pant University of Agriculture and Technology,

Uttarakhand, India

⁷Nilratan Sircar Medical College and Hospital, West Bengal, India

⁸Dr. D. Y. Patil Medical College, Hospital & Research Centre, Maharashtra, India

⁹Department of Biotechnology and Microbiology, Dr. Janaki Ammal Campus, Kannur University,

Kerala, India

¹⁰Department of Biochemistry, AKG Co-Operative Institute of Health Sciences, Kerala, India

¹¹Department of Biotechnology, Mansarovar Global University, Pradesh, India

¹²Department of Research and Training, BioDeskINDIA Labs, Madhya Pradesh, India

(^*Corresponding author’s e-mail: [email protected])

Received: 11 January 2025, Revised: 28 January 2025, Accepted: 4 February 2025, Published: 15 June 2025

Abstract

Background: Apolipoprotein E gene (ApoE) polymorphism has been extensively studied in the context of lipid metabolism and cardiovascular disease (CVD) risk. Its association with Type 2 Diabetes Mellitus (T2DM) patients presents a unique subset of cardiovascular risk due to underlying metabolic changes. This systematic review aims to summarize and critically evaluate the available evidence on the impact of ApoE gene polymorphism on cardiovascular risk among T2DM patients. Methods: We used the PEO (Population, Exposure and Outcome) framework to develop our protocol, which is publicly available in the Open Science Framework (OSF) registries. Following this protocol, a systematic search was conducted in PubMed, SCOPUS, and Google Scholar to identify studies focusing on adult individuals (≥ 18 years old) diagnosed with Type 2 Diabetes Mellitus (T2DM) that reported on ApoE gene polymorphisms. Only studies published in English between 2014 and 2024 were included. Three authors independently assessed the quality of the eligible studies using the Newcastle-Ottawa Scale (NOS) for case-control, cohort, and cross-sectional designs and the qualified studies were selected for full-text screening and data extraction. Results: 16 studies satisfied the quality assessment using the Newcastle-Ottawa Scale (NOS) with satisfying NOS scores included in the final review, which comprised 1 cohort study, 2 cross-sectional studies, and 13 case-control studies. Across the studies, E3/E3 is the dominant genotype in both control and T2DM populations. E3/E4 and E4/E4 genotypes are found to be significantly elevated in T2DM cases with cardiovascular risk factors compared to controls. The Ɛ3 allele is the most common across all populations, in most studies. The Ɛ4 allele is consistently strongly associated with elevated levels of low-density lipoprotein (LDL-C), total cholesterol, and triglycerides. Conclusion: Apolipoprotein E gene polymorphism is an evident risk factor for cardiovascular complications and ApoE genotyping will be a valuable tool for stratifying T2DM patients based on cardiovascular risk.

Keywords: ApoE gene polymorphism, Cardiovascular diseases, Type 2 diabetes mellitus, Systematic review

Introduction

In recent times, shifts in lifestyle have led to a transformation in disease trends, moving away from infectious and nutrition-related illnesses toward degenerative conditions such as cardiovascular disease (CVD) [1]. Mortality due to cardiovascular disease (CVD) is rising globally, from less than 10 % of total deaths at the start of the century to nearly 30 % by the end, with diabetes mellitus, particularly Type 2 diabetes mellitus (T2DM), emerging as a major risk factor [1,2]. Several observational studies have shown that patients with T2DM are at an increased risk of developing atherosclerotic cardiovascular diseases, including coronary artery disease, stroke, and peripheral artery disease [3]. The association between diabetes and cardiovascular complications is multifactorial, involving metabolic disturbances, hyperglycemia, dyslipidemia, and endothelial dysfunction. However, genetic factors also play a pivotal role in modulating the risk of CVD in individuals with T2DM [4].

Among the genetic factors linked to cardiovascular risk in T2DM, the ApoE gene is of particular interest [5]. Apolipoprotein E is a critical component in lipid transport and a primary ligand for low-density lipoprotein (LDL) receptors, influencing cholesterol metabolism and its influence in cardiovascular diseases. Specifically, ApoE2 and ApoE4 isoforms have been associated with an increased risk of heart disease [6,7]. ApoE2 elevates atherogenic lipoprotein levels due to its reduced affinity for LDL receptors, while ApoE4 raises LDL levels as it preferentially binds to triglyceride-rich, very low-density lipoproteins, leading to the downregulation of LDL receptors. This ApoE4 variant also heightens the susceptibility to cardiovascular diseases by influencing LDL levels. Therefore, the structural features and functional differences among ApoE isoforms, play a

critical role in shaping the landscape of cardiovascular diseases and associated risks. In diabetic patients, ApoE can undergo various changes and may play a role in the development and progression of cardiovascular diseases [6,7].

This systematic review aims to attempt a qualitative synthesis of the observational evidence regarding the association between ApoE gene polymorphisms and cardiovascular risk in individuals with Type 2 diabetes and will attempt to validate the predictive value of ApoE genotyping in evaluating cardiovascular risk among diabetic patients.

Materials and methods

We followed the updated 2020 “Preferred Reporting Items for Systematic Reviews” (PRISMA) guidelines for reporting the findings in this systematic review. A full version of the protocol is registered as a public record in the Open Science Framework (OSF) registry along with all supplementary files related to this review. (See protocol and supplementary files: https://doi.org/10.17605/OSF.IO/R36TS) [8,9].

Inclusion and exclusion criteria

We used the PEO (Population, Exposure and Outcome) framework to create the research questions and develop the protocol.

Inclusion criteria

Studies focused on adults (≥ 18 years old) diagnosed with T2DM and reported on ApoE gene polymorphisms, specifically the E2, E3, and E4 alleles. The studies evaluated cardiovascular outcomes, including primary outcomes such as myocardial infarction, stroke, and coronary artery disease, as well as secondary outcomes like changes in lipid profiles, markers of atherosclerosis, blood pressure, BMI, and HbA1c levels. The eligible study designs included cohort studies, case-control studies, cross-sectional studies, clinical trials, and genetic association studies that assessed cardiovascular outcomes in relation to ApoE polymorphisms in T2DM patients. Only studies published in the English language and published between 2014 and 2024 were included.

Exclusion criteria

Studies involving non-human subjects, animal models, or cell-based studies, as well as studies focusing on patients who were not diagnosed with Type 2 Diabetes Mellitus or who had other forms of diabetes (such as Type 1 Diabetes), were excluded. Studies that did not assess ApoE gene polymorphisms or those that focused on genes unrelated to ApoE, were also excluded. Additionally, studies that did not report on cardiovascular outcomes or relevant cardiovascular risk factors (e.g., studies solely focusing on neurodegenerative diseases or non-cardiovascular outcomes) were excluded. Reviews, editorials, commentaries, conference abstracts, and case reports without original data, or studies lacking a clear comparison group or control relevant to ApoE genotypes, were also not considered for inclusion.

Flowchart 1 PRISMA 2020 flow diagram of the identification, selection and screening stages of the systematic reviews process.

Table 1 Data extraction form of case-control studies.

Table 2 Data extraction form of cross-sectional studies.

Table 3 Data extraction form of cohort studies.

Search strategy

To obtain all potentially relevant sources to review we conducted a systematic search across scholarly databases including PubMed, SCOPUS and Google Scholar. For each database, a unique search strategy needs to be applied. A model search string for PubMed with MeSH terms and boolean operators: (“Apolipoprotein E” OR “ApoE” OR “ApoE polymorphism” OR “ApoE gene” OR “ApoE E2” OR “ApoE E3” OR “ApoE E4”) AND (“Type 2 Diabetes Mellitus” OR “T2DM” OR “Diabetes Mellitus, Type 2” [MeSH]) AND (“Cardiovascular Disease” OR “CVD” OR “cardiovascular risk” OR “myocardial infarction” OR “stroke” OR “coronary artery disease” OR “atherosclerosis” OR “lipid profile” OR “LDL-C” OR “HDL-C” OR “triglycerides”) AND ((“cohort study” OR “case-control study” OR “cross-sectional study” OR “clinical trial” OR “genetic association study”) OR (“cohort studies” [MeSH Terms] OR “case-control studies” (MeSH Terms) OR “cross-sectional studies” (MeSH Terms) OR “clinical trials as topic” (MeSH Terms))).

Data management

A transparent and organized data management process was ensured and the sources obtained, screening decisions, and data extraction files were stored in the OSF database according to ethical guidelines and repository policies.

Quality assessment

The quality of the selected studies was independently assessed by 3 reviewers using the Newcastle-Ottawa Scale (NOS) for case-control, cohort, and cross-sectional studies. The NOS for case-control and cohort studies evaluated criteria such as the adequacy of the case definition, representativeness of cases, selection and definition of controls, comparability of cases and controls, ascertainment of exposure, and non-response rate. For cross-sectional studies, the NOS quality evaluation assessed the representativeness of the sample, sample size, selection of study subjects, comparability between groups, assessment of outcome, and description of statistical tests.

Table 4 NOS scale quality assessment for cross-sectional studies.

Table 5 NOS scale quality assessment for Cohort studies.

Table 6 NOS scale quality assessment for case-control studies.

Results

The PRISMA flow diagram (Flowchart 1) illustrates the entire review process. A systematic search was conducted according to the strategy outlined in the protocol, resulting in an initial retrieval of 20,600 studies from databases. From this initial pool, 468 records were selected for screening. After the screening process, 56 studies were chosen for quality assessment using the Newcastle-Ottawa Scale (NOS) and 16 studies with satisfying NOS scores were included in the final review, which comprised 1 cohort study, 2 cross-sectional studies, and 13 case-control studies. These 16 studies were selected for full-text reading and data extraction (Tables 4 - 6).

All the selected studies examined the distribution of ApoE gene polymorphisms (genotypes and alleles) in T2DM populations and their direct association with cardiovascular risk or risk factors such as coronary artery disease (CAD), stroke, dyslipidemia, and obesity.

Prevalence of genotypes in T2DM and cardiovascular risk

Across the studies, E3/E3 is the dominant genotype in both control and T2DM populations, but the distribution of other genotypes varied according to the cases and their complications. Such as E3/E4 and E4/E4 genotypes are found to be significantly elevated in T2DM cases with cardiovascular risk factors compared to controls. On the other hand, E2/E3 shows mixed results, in some studies it is associated with a protective effect against dyslipidaemia and obesity, which are risk factors for CVD. However, in others, it is linked to elevated CVD risk in T2DM, particularly when combined with obesity or stroke cases. These evidences strengthen the predictive utility of ApoE gene polymorphisms for cardiovascular risk in T2DM. It is clear that analyzing gene polymorphisms will aid in healthcare decision-making and in categorizing patients into different risk groups.

Allelic distribution

The Ɛ3 allele is the most common across all populations, in most studies. The Ɛ4 allele consistently showed a strong association with elevated levels of LDL-C, TC, and triglycerides. Whereas the Ɛ2 allele demonstrates dual effects, where in some studies they are protective in reducing LDL-C and CVD risk in some populations, and in some studies, they are linked to dyslipidaemia and obesity. These observations indicate that analyzing the ApoE gene polymorphism can provide an early understanding of atherosclerotic status and predict cardiovascular risk in individuals with T2DM.

Graph 1 Graphical representation of the genotypic and allelic distribution of the ApoE gene among different groups of studies.

Discussion

Apolipoprotein E is a key structural and functional protein involved in lipoprotein metabolism, mediating the binding and clearance of chylomicrons, very-low-density lipoproteins (VLDL), and their remnants in the liver. The 3 main alleles - ApoE2, ApoE3, and ApoE4 - arise from single-nucleotide polymorphisms in the APOE gene and lead to amino acid substitutions in the ApoE protein. These isoforms differ in their affinity for lipoprotein receptors, which ultimately influence plasma lipid levels, including LDL-C and triglycerides, both critical contributors to atherosclerosis [25].

The elevated risk of CVD complications in T2DM patients can be attributed to several factors and the results of the studies in this systematic review suggest ApoE gene polymorphism is one of the critical risk factors and this elevated risk is conferred through mechanisms involving insulin resistance, inflammation, and dyslipidemia [25].

The APOE gene is located on chromosome 19 and encodes the ApoE protein, which is integral to the transport and clearance of cholesterol-rich lipoproteins such as chylomicrons, very-low-density lipoproteins (VLDL), and their remnants. Three major alleles ε2, ε3, and ε4 arise from single-nucleotide polymorphisms that translate into amino acid substitutions in the protein. From these alleles, 6 common genotypes emerge (E2/E2, E2/E3, E2/E4, E3/E3, E3/E4 and E4/E4) [26].

All the reviewed studies conducted a comprehensive genetic analysis of the ApoE genotype distribution and across the studies, ε3 allele and E3/E3 was the dominant genotype in both control and T2DM populations. The majority of the studies observed a relationship between ApoE gene polymorphisms and cardiovascular risk in T2DM subjects. The Ɛ4 allele, E3/E4 and E4/E4 genotypes were found to be significantly elevated in T2DM cases with cardiovascular risk factors compared to controls [10-12]. Whereas the Ɛ2 allele and E2/E3 genotypes shows a mixed effect where in some studies it was associated with a protective effect against dyslipidaemia and in some the very reverse [19,24].

The distribution of these alleles exhibits substantial variability among different ethnic groups and geographic regions. For instance, the ε4 allele is more prevalent in certain African and Northern European populations, whereas ε2 may be slightly more common in parts of Southeast Asia. Several factors may be accountable for this diverse distribution, such as genetic drift, founder effects, migration patterns, and natural selection, moreover, lifestyle and dietary habits are very influential. Such as high saturated fat intake in Western countries to predominantly plant-based diets in some regions of Asian countries [12,21,22,27]. Insulin resistance is the hallmark feature in T2DM which contributes to a distinct pattern of dyslipidaemia characterised by elevated triglycerides, reduced HDL, and variably elevated LDL, in all the studies that reported ApoE gene polymorphisms as a risk marker for CVD, presented APOE polymorphisms as an additional layer influencing the extent of lipid abnormalities and leading to subsequent atherosclerotic risk [28].

The synthesized qualitative evidence suggests that ApoE gene polymorphisms play a critical role in cardiovascular complications in T2DM through mechanisms such as lipid metabolism abnormalities, insulin resistance, dyslipidemia, and inflammatory and atherosclerotic processes [10,23]. However, caution is warranted when interpreting these findings, as some studies directly associate ApoE polymorphisms with cardiovascular disease (CVD), while others highlight that the phenotypic characteristics, such as lipid metabolism abnormalities, and inflammatory mechanisms may arise as a consequence of long-standing diabetes rather than solely due to ApoE gene variations.

The relationship between ApoE polymorphisms and cardiovascular risk is complex and influenced by multiple confounding factors, including age, sex, ethnicity, genetic background, lifestyle and behavioral factors, metabolic and clinical conditions, as well as medication and treatment regimens [22-24]. To accurately quantitatively synthesize the association between ApoE gene polymorphisms and cardiovascular risk, future studies should account for and adjust for these key confounding variables.

Despite the well-documented associations between these polymorphisms and CVD in T2DM, the magnitude of this effect is not uniform across all studies, and some studies were observed to fail to detect a significant relationship between ApoE gene polymorphism and CVD [14, 24]. Moreover, in this study, we have attempted a qualitative summary of current evidence on the predictive role of ApoE gene polymorphism in cardiovascular risk in T2DM. The findings of this study will serve as valuable qualitative evidence for future research efforts aimed at establishing ApoE gene genotyping as a routine marker. As an extension of the current study, a quantitative analysis of the current qualitative summary can be pursued in the future.

Although routine ApoE genotyping is not yet standard in clinical practice, it is clear that it holds value as a risk marker in T2DM patient subsets, guiding targeted lipid-lowering and lifestyle interventions. Future research with large-scale, multiethnic studies, is required to clarify the complexities of gene-by-environment interactions and to verify the usefulness of introducing ApoE genotyping into clinical practice.

Conclusions

Apolipoprotein E gene polymorphisms exert significant influences on lipid metabolism and cardiovascular risk among T2DM patients and the distribution of these alleles and genotypes varies considerably among study populations. All the reviewed empirical studies support the role of the Ɛ4 allele and E3/E4, E4/E4 genotypes in increasing cardiovascular risk in T2DM patients and E2/E3 and the Ɛ2 allele are occasionally protective but have mixed effects, particularly in populations predisposed to obesity and dyslipidaemia. Future research with large-scale, multiethnic studies is required to generalize these findings and to introduce ApoE genotyping in standard clinical practice.

Acknowledgements

We would like to express our sincere gratitude to Sai Shashank Gudla from GIET School of Pharmacy in Rajamahendravaram, India Andhra Pradesh, and Dr. Mayukh Pandit, Scientist and Co-investigator at North East Cancer Hospital and Research Institute in Assam, India for their invaluable support and assistance in this study.

References

[1] T Gaziano, KS Reddy, F Paccaud, S Horton and V Chaturvedi. Cardiovascular disease. In: D Jamison, JG Breman, AR Measham, G Alleyne, M Claeson, DB Evans, P Jha, A Mills and P Musgrove (Eds.). Disease control priorities in developing countries. World Bank, Washington DC, 2006, p.645-662.

[2] World Health Organization, Available at: https://iris.who.int/handle/10665/42510, accessed December 2024.

[3] N Sattar, J McMurray, J Borén, A Rawshani, E Omerovic, N Berg, J Halminen, K Skoglund, B Eliasson, HC Gerstein, DK McGuire, D Bhatt and A Rawshani. Twenty years of cardiovascular complications and risk factors in patients with type 2 diabetes: A nationwide swedish cohort study. Circulation: Journal of the American Heart Association 2023; 147(25), 1872-1886.

[4] S Rosa, B Arcidiacono, E Chiefari, A Brunetti, C Indolfi and DP Foti. Type 2 diabetes mellitus and cardiovascular disease: Genetic and epigenetic links. Frontiers in Endocrinology 2018. https://doi.org/10.3389/fendo.2018.00002

[5] Y Zeng, S Wen, L Huan, L Xiong, B Zhong and P Wang. Association of ApoE gene polymorphisms with serum lipid levels and the risk of type 2 diabetes mellitus in the Chinese Han population of central China. PeerJ: The Journal of Life and Environmental Sciences 2023; 11, 15226.

[6] P Abondio, M Sazzini, P Garagnani, A Boattini, D Monti, C Franceschi, D Luiselli and C Giuliani. The genetic variability of APOE in different human populations and its implications for longevity. Genes 2019; 10(3), 222.

[7] DA Raichlen and GE Alexander. Exercise, APOE genotype and the evolution of the human lifespan. Trends in neurosciences 2014; 37(5), 247-255.

[8] A Thahira, DT Kumar, D Roy, S Pradhan, Y Kumar, N Tandon, A Das, A Panvalkar and VP Akshay. ApoE gene polymorphism and cardiovascular risk in type 2 diabetic patients: A systematic review. MetaArXiv 2024. https://doi.org/10.17605/OSF.IO/R36TS

[9] MJ Page, JE McKenzie, PM Bossuyt, I Boutron, TC Hoffmann, CD Mulrow, L Shamseer, JM Tetzlaff, EA Akl, SE Brennan, R Chou, J Glanville, JM Grimshaw, A Hróbjartsson, MM Lalu, T Li, EW Loder, E Mayo-Wilson, S McDonald, LA McGuinness and D Moher. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Revista Española de Cardiología (English Edition) 2021; 74(9), 790-799.

[10] S Nadeem, T Maqbool, JA Qureshi, A Altaf, S Naz, MM Azhar, I Ullah, TA Shah, MU Qamar and AM Salamatullah. Apolipoprotein E gene variation in Pakistani subjects with type 2 diabetes with and without cardiovascular complications. Medicina (Published in Kaunas, Lithuania) 2024; 60(6), 961.

[11] D El-Lebedy, HM Raslan and AM Mohammed. Apolipoprotein E gene polymorphism and risk of type 2 diabetes and cardiovascular disease. Cardiovascular Diabetology 2016. https://doi.org/10.1186/s12933-016-0329-1

[12] AA Galal, AA Abd Elmajeed, RA Elbaz, AM Wafa and RM Elshazli. Association of apolipoprotein E gene polymorphism with the risk of T2DM and obesity among Egyptian subjects. Gene 2021; 769, 145223.

[13] W Chen, B Li, H Wang, G Wei, K Chen, W Wang, S Wang and Y Liu. Apolipoprotein E E3/E4 genotype is associated with an increased risk of type 2 diabetes mellitus complicated with coronary artery disease. BMC Cardiovascular Disorders 2024; 24(1), 160.

[14] B Sapkota, A Subramanian, G Priamvada, H Finely, PR Blackett, CE Aston and D Sanghera. Association of APOE polymorphisms with diabetes and cardiometabolic risk factors and the role of APOE genotypes in response to anti-diabetic therapy: Results from the AIDHS/SDS on a South Asian population. Journal of Diabetes and its Complications 2015; 29(8), 1191-1197.

[15] N Wang, Q Liu, H Liu, X Cong, H Yang, Y Yu, Y Cao and L Ma. Association of apolipoprotein E polymorphisms and risks of ischemic stroke in Chinese patients with type 2 diabetes mellitus. Journal of Diabetes Research 2021; 2021, 8816996.

[16] C Srirojnopkun, K Kietrungwilaikul, K Boonsong, J Thongpoonkaew and N Jeenduang. Association of APOE and CETP TaqIB polymorphisms with type 2 diabetes mellitus. Archives of Medical Research 2018; 49(7), 479-485.

[17] JY Seo, BJ Youn, HS Cheong and HD Shin. Association of APOE genotype with lipid profiles and type 2 diabetes mellitus in a Korean population. Genes & Genomics 2021; 43(7), 725-735.

[18] S Ereqat, S Cauchi, K Eweidat, M Elqadi, M Ghatass, A Sabarneh and A Nasereddin. Association of DNA methylation and genetic variations of the APOE gene with the risk of diabetic dyslipidemia. Biomedical Reports 2022; 17(1), 61.

[19] M Touré, FD Agne, A Dieng, RN Diallo, L Gueye and A Samb. Roles of the apolipoprotein E Gene and its polymorphisms in the etiopathophysiology of type 2 diabetes mellitus and its atherosclerotic complication in senegalese females. Journal of Diabetes Mellitus 2023; 13(4), 300-324.

[20] X Liu, H Zhou, X Li, R Zhang, C Zhao, Y Zhou and S Xu. Correlation between ApoE gene polymorphism and LEAD in patients with T2DM that are of Han nationality in Northern China. Clinical and Applied Thrombosis/Hemostasis: Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis 2022; 28, 10760296221092405.

[21] K Gonzalez-Aldaco, S Roman, LA Torres-Reyes and A Panduro. Association of apolipoprotein e2 allele with insulin resistance and risk of type 2 diabetes mellitus among an admixed population of Mexico. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2020; 13, 3527-3534.

[22] L Zhang, S He, Z Li, X Gan, S Li, X Cheng, N Yang and F Zheng. Apolipoprotein E polymorphisms contribute to statin response in Chinese ASCVD patients with dyslipidemia. Lipids in Health and Disease 2019; 18(1), 129.

[23] S Liu, J Liu, R Weng, X Gu and Z Zhong. Apolipoprotein E gene polymorphism and the risk of cardiovascular disease and type 2 diabetes. BMC Cardiovascular Disorders 2019; 19(1), 213.

[24] C Santos-Ferreira, R Baptista, M Oliveira-Santos, R Costa, J Pereira Moura and L Gonçalves. Apolipoprotein E2 genotype is associated with a 2-Fold increase in the incidence of type 2 Diabetes mellitus: Results from a long-term observational study. Journal of Lipids 2019; 2019(1), 1698610.

[25] AD Marais. Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease. Pathology 2019; 51(2), 165-176.

[26] D Seripa, G D’Onofrio, F Panza, L Cascavilla, C Masullo and A Pilotto. The genetics of the human APOE polymorphism. Rejuvenation Research 2011; 14(5), 491-500.

[27] AR Templeton. The theory of speciation VIA the founder principle, Genetics 1980; 94(4), 1011-1038.

[28] NB Ruderman, D Carling, M Prentki and JM Cacicedo. AMPK, insulin resistance and the metabolic syndrome. The Journal of Clinical Investigation 2013; 123(7), 2764-2772.