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Association between apolipoprotein E ε4 status and the risk of Alzheimer’s disease: a meta-analysis

BMC Neuroscience volume 26, Article number: 5 (2025) Cite this article

Abstract

Background

The apolipoprotein E ε4 (APOE ε4) status has a controversial role in predicting Alzheimer’s disease (AD) factors. This meta-analysis assessed AD event risk in patients with APOE ε4 status.

Materials and methods

The relevant English-language articles were identified by searching the Cochrane Library, EMBASE, and PubMed databases. The prognostic significance of APOE ε4 status in AD patients was examined on the basis of pooled hazard ratios (HRs).

Results

A total of 22 studies published after 1987, including 571,800 patients, were included. Consequently, APOE ε4 status was a risk factor for disease-free survival (DFS, HR = 2.033; 95% confidence interval [CI] = 1.589–2.602; P = 0.000; I 2 = 93.1%) in patients with AD. Additionally, subgroup analysis suggested that the ROC curve was the main risk factor among patients with AD.

Conclusions

AD patients with different events are managed via different methods; however, the present meta-analysis suggests an increased risk of AD events in patients with different APOE ε4 statuses.

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Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects people over the age of 65 and commonly results in progressive self-care ability loss, gradual memory loss, behavioral cognitive dysfunction, and neuropsychiatric abnormalities. This greatly affects quality of life in patients with AD [1, 2]. Owing to the increasing aging of the global population, an increasing number of patients with AD are being diagnosed annually, with AD becoming a primary public health challenge, resulting in tremendous burdens on patients, their families, and society.

Neurodegenerative alterations, which ultimately lead to dementia owing to AD, occur about 20 years before the appearance of clinical symptoms [3]. Currently, AD-related dementia cannot be cured; therefore, research should focus on AD in the prodromal and preclinical stages [4]. About two-thirds of patients with dementia are diagnosed with AD, with the characteristic features of neurofibrillary tau tangles and amyloid-β plaque deposition in neurons, glial inflammatory activation, decreased synaptic activity, and neuronal loss [5]. These cerebral pathological alterations occur owing to lifestyle and genetic factors [6]. An extended prodromal stage occurs in patients with AD, as evidenced by amyloid-β deposition initiating 15 years before dementia symptom occurrence in some people [7]. Therefore, disease risk must be accurately predicted in individuals for successful prevention and treatment of this disease.

Apolipoprotein E (apoE), a 34-kDa glycoprotein, is generated by brain astrocytes [8] and primarily by hepatocytes (> 90%) in the periphery [9]. Different morphologies of the APOE gene are present in humans, with three primary variants, namely, ε2, ε3, and ε4 [9], and the ε3 variant is significantly more common than the other two variants [10]. This may be due to the protective variant (rs10423769) distributed on chromosome 19 [11]. In recent studies, ε4 ancestry (European in comparison with African local genetic ancestry) has been demonstrated to affect APOE ε4 levels within the brain; in addition, such genetic heterogeneity may be related to the different ε4-induced risks of AD among populations of diverse races/ethnicities [12]. Thus, an increased risk of AD is related to low apoE expression in plasma [13]; moreover, the APOE ε4 genotype may be associated with increased risk through its relationship with low apoE expression in plasma [14, 15]. Nonetheless, the APOE ε4 status associated with prospective AD risk is still ambiguous. The status of the APOE ε4 gene accounts for the prospective risk of AD in certain studies [16,17,18]; however, such a relationship has not been reported in other studies, such as that by Elin Dybjer et al. (2023) [19]. Consequently, this study focused on evaluating the relationship between APOE ε4 status and AD risk.

Materials and methods

Registration

This study was reported following the guidelines of preferred reporting items of the systematic review and meta-analysis [20]. Owing to the retrospective nature of the study, ethical approval or patient consent was not needed.

Study screening process and eligibility criteria

Search strategy

The keywords (“APOE” OR “Apolipoprotein E”) AND (“Alzheimer”) were used to comprehensively search the PubMed, Cochrane Library, and Embase databases (2001–2023). The databases were searched repeatedly until no new relevant articles were obtained. To identify more qualified studies, the references of eligible articles were examined. Finally, two researchers evaluated these articles in line with our eligibility criteria.

Study screening

First, keywords were used to retrieve relevant articles, and their titles and abstracts were assessed to eliminate irrelevant articles. Second, the remaining articles were assessed using the eligibility criteria. The studies included (a) patients pathologically diagnosed with AD and (b) available or calculable hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). The studies excluded were letters, meeting summaries, commentary articles, posters, and those with unavailable results and outcomes.

Data collection

Two researchers (ZR and HG) collected the data. Any discrepancy between them was settled by discussion or the opinion of a third researcher. The data extracted were as follows: first author, publication year, study design, study population origin, case number, follow-up period, and cutoff generation approach. The present meta-analysis primarily explored APOE ε4 gene risk among AD patients.

Data processing and statistical analysis

This study aimed to examine the association of APOE ε4 gene status with AD. HRs and 95% CIs were used on the basis of a previously described method [21]. The multivariable HRs and 95% CIs or relevant univariable HRs (in the absence of multivariable HRs) were collected from the included articles. Parmar et al.’s method [22] was applied to estimate HRs when univariable and multivariable HRs were unavailable. The relevant variance was determined using Kaplan-Meier analysis, and Engauge Digitizer (version 9.4) was used for visualization. HRs < 1 and > 1 indicated good and dismal patient prognoses, respectively. Statistical heterogeneity was measured via the I2 statistic and chi-square test. Prominent heterogeneity was represented by I2 > 50% and P < 0.05, and a random or fixed effects model was applied. Statistical analysis was completed using RevMan version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration) and STATA version 12.0 (STATA Corp., College Station, TX). STATA version 12.0 was adopted to assess bias by Egger’s and Begg’s tests. P < 0.05 indicated a significant difference.

Results

Study screening results

A total of 448, 1124, and 0 articles were identified using the PubMed, Embase, and Cochrane Library databases, respectively. Next, meeting summaries and duplicates were removed to obtain 91 eligible articles. Thereafter, 69 articles were excluded owing to their undesirable study design (n = 31), case reports (n = 14), irrelevance to AD (n = 13), and lack of credible data (n = 11). Finally, 22 eligible articles involving 571,800 cases published between 2001 and 2023 were included in the meta-analysis [16,17,18,19, 23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39] (Fig. 1).

Fig. 1
figure 1

Flow diagram of the study selection process

Full size image

Study characteristics

These articles were published between 1987 and 2017. Of these, seven studies were retrospective, whereas 15 were prospective. The sample size ranged from 75 to 495.942. Five studies were conducted in Asia (three in China, one in Japan, and three in Korea), four in Sweden, two in Germany, one in the UK, one in Australia, one in Spain, and five in the USA. Moreover, patients were followed up for 18 months to 23 years. Detailed information about each study, such as the study period, follow-up duration, age, and case number, was collected (Table 1).

Table 1 Enrolled study features
Full size table

Study quality evaluation

This study evaluated study quality using CRITICAL APPRAISAL OF PROGNOSTIC STUDIES (https://www.cebm.net/wpcontent/uploads/2018/11/Prognosis.pdf; Fig. 2). After each article was assessed cautiously, most high-quality articles were retrospective. There were two studies with a high risk and another two with an unclear risk of bias owing to their non-blinded or non-randomized study design. Moreover, since some information was lost, the above three studies had five unclear or three high-bias risks regarding objective measurement and outcome criteria. Another article showed a high bias risk owing to prognostic factors (measurement of the follow-up period). Most of these included articles were well-designed and reported adverse reactions objectively.

Fig. 2
figure 2

A graph exhibiting bias risk judgments on bias risk items through reviewers displaying percentages among all included studies. B Risk of bias summarization: The risk of biased item judgment by reviewers for all the included studies

Full size image

Primary outcome: DFS

Twenty-two studies reported the risk of AD with APOE ε4 status. The studies by Elin Dybjer et al., Chenjie Xu et al., Weili Xu et al., Shanna L. Burke et al., Wei-Li Xu et al., Tomoyuki Ohara et al., Pei-Ning Wang et al., and Christiane Reitz et al. were regarded as independent works since two datasets associated AD with APOE ε4 status were used. A fixed-effects model was used to analyze significance (HR = 1.840; 95% CI = 1.739–1.940; P = 0.000; I2 = 93.1%). Between-study heterogeneity was analyzed, and significant results were obtained via a random effects model (HR = 2.033; 95% CI = 1.589–2.602) (Fig. 3A). A sensitivity analysis was conducted to predict the influence of each study on pooled HRs. Consequently, the results did not significantly change when one article was eliminated (Supplementary Fig. 1A), suggesting that the results were stable. Furthermore, publication bias was not detected in the funnel plots (Fig. 3B). Egger’s test and Begg’s test revealed the absence of prominent publication bias (P = 0.338, P = 0.392) (Supplementary Fig. 1B). Subgroup analyses stratified by region, study design, and cutoff method were conducted (Table 2). The region-stratified subgroup analysis revealed 11 Asian articles with an HR of 2.18 (95% CI: 1.47–3.22; P = 0.000; I2 = 92.7%), 12 European studies presented significant associations (HR = 1.94; 95% CI = 1.33–2.83; P = 0.000; I2 = 90.9%), and seven USA articles presented obvious connections (HR = 2.00; 95% CI = 1.40–2.88, P = 0.000; I2 = 75.4%). All the cases were classified into two subgroups based on the study design: for the 22 prospective studies, the HR was 2.02 (95% CI = 1.46–2.78, I2 = 94.3%), whereas the HR was 2.13 (95% CI = 1.54–2.93, I2 = 83.1%) for eight retrospective studies. According to the ROC curve, in four studies that adopted the cutoff method, the HR was 3.07 (95% CI: 2.26–4.16; P = 0.661; I2 = 0.0%), whereas 26 articles that adopted the cutoff method had an HR of 1.95 (95% CI: 1.49–2.54; P = 0.000; I2 = 93.9%).

Fig. 3
figure 3

Forest plots showing hazard ratios (HRs) of disease-free survival (DFS) (A) and funnel plots on DFS (B). Heterogeneity was detected via the chi-square test, where P < 0.05 indicated distinct heterogeneity between studies. Horizontal lines = 95% confidence intervals (CIs). (Fixed: fixed-effects model; horizontal lines = 95% CI. Rhombuses = estimates with corresponding 95% CIs. Squares = individual study point estimates). DFS = disease-free survival, and OS = overall survival

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Table 2 Subgroup analysis of DFS
Full size table

Discussion

The relationship between neurodegenerative diseases and APOE ε4 gene status has been widely investigated. A potentially increased risk of AD has been demonstrated [40, 41]. AD demonstrates an extended prodromal stage, which is evidenced by the deposition of amyloid-β, which is initiated 15 years before dementia symptoms occur in some individuals [7, 42]. Therefore, disease risk must be accurately predicted to successfully prevent and treat AD, which is beneficial for patients once APOE ε4 status contributes to AD risk prediction. To the best of our knowledge, this meta-analysis is the first to illustrate the importance of APOE ε4 status for AD prediction. This meta-analysis included 22 qualified articles with a total of 131,987 articles that mentioned the association between APOE ε4 and AD. According to the pooled analysis, although AD might be influenced by various factors, the HR of AD development with respect to APOE ε4 status was significantly increased (HR = 2.033; 95% CI = 1.589–2.602), regardless of the high degree of between-study heterogeneity; however, our combined analyses with a random effects model enhanced the robustness of our results.

There was obvious heterogeneity in the ability of APOE ε4 status to predict AD risk (P = 0.000; I2 = 93.1%). Therefore, we conducted a sensitivity analysis to predict whether one study impacted our pooled HRs; consequently, the results did not change when one study was eliminated, indicating that our results were significant. In addition, Egger’s and Begg’s tests and funnel plots were used to analyze potential publication bias, and obvious publication bias was not detected. Nonetheless, the relationship between APOE ε4 status and AD might be affected by certain confounders. Thus, we conducted subgroup analyses on the basis of region, study design, and cutoff method for investigating the source of heterogeneity. On the basis of region stratification and study design—stratified analysis—the groups did not show a reduction in heterogeneity. According to the cutoff method-stratified subgroup analysis, only the ROC group demonstrated statistical significance (I2 = 0.0%, P = 0.661), with the absence of heterogeneity. Therefore, different cutoff methods are considered sources of heterogeneity in DFS.

Although our results revealed the causes of heterogeneity from a statistical point of view, although subgroup and sensitivity analyses were performed, the sources of heterogeneity remain unclear. However, clinically, AD can be affected by many factors, such as different ages [43], diagnostic criteria are not uniform, and treatment options vary widely [44, 45]. Different lifestyles, living environments, people in different regions [46], and genetic susceptibilities [47, 48] may affect heterogeneity. In addition, the research methods of the 22 studies included in this study are not exactly the same, which may be the cause of heterogeneity. In the future, more high-quality, large-sample randomized controlled trial (RCT) studies are needed to confirm our conclusions.

Additionally, the quality of the included studies must be considered since it was a limitation of the present study. First, the included studies were evaluated using the Cochrane risk bias tool to identify high-quality studies; however, some of these studies had incomplete patient data. In addition, most of these articles were retrospective. Thus, further prospective studies integrating AD with APOE ε4 status are warranted. Second, while funnel plots and formal statistical tests suggest no publication bias, while funnel plots and formal statistical tests suggest no publication bias, this study included patients with different events who received diverse treatments owing to AD heterogeneity; from a clinical point of view, we cannot fully explain the causes of heterogeneity, which might affect event occurrence. Third, only studies published in English were included, and the majority of the included studies were from Asian, European, and U.S. populations. Other populations are not fully addressed, which may cause bias. This could be an important factor, as genetic risk factors for AD may differ across populations. Future research should aim to include more diverse populations and published studies in different languages. Fourth, published studies that used databases were included, which might have caused publication bias. In the future, more high-quality studies with large samples are needed to prove our conclusions.

Conclusion

Different methods are used to evaluate AD patients with different events; the present meta-analysis suggests an increased risk of AD events in patients with different APOE ε4 statuses. More large and high-quality studies are needed for further verification.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

APOE ε4:

Apolipoprotein E ϵ4

AD:

Alzheimer’s disease

DFS:

Disease-free survival

CI:

Confidence interval

HRs:

Hazard ratios

P:

Prospective

R:

Retrospective

ROC:

Receiver operating characteristic

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Acknowledgements

Zijun Ren, Zhenting Guan, Hongjian Guan and Huiying Che contributed equally to this work. All authors have contributed significantly. All authors are in agreement with the content of the manuscript

Funding

This research was supported by the Jilin Province science and technology development plan project, China (NO.: YDZJ202201ZYTS225).

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Author notes

  1. Zijun Ren and Zhenting Guan contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Yanbian University hospital, City of Yanji, Jilin Province, China

    Zijun Ren & Hongjian Guan

  2. Department of Integrated Traditional Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China

    Zhenting Guan

  3. Department of Neurosurgery, City of Zhucheng, Zhucheng Hospital of Chinese Medicine, Zhucheng, Shandong Province, China

    Qingliang Guan

  4. Department of General Medicine, Yanbian University Hospital, City of Yanji, Jilin Province, China

    Hongjian Guan

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Contributions

Conceptualization- Zijun Ren, Zhenting Guan. Investigation- Zijun Ren, Zhenting Guan, Qingliang Guan. Methodology - Qingliang Guan, Hongjian Guan. Original draft- Zijun Ren, Hongjian Guan, Huiying Che. Review and editing- Zhenting Guan, Huiying Che. All authors have read and approved the final manuscript.

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Correspondence to Hongjian Guan or Hongjian Guan.

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Ren, Z., Guan, Z., Guan, Q. et al. Association between apolipoprotein E ε4 status and the risk of Alzheimer’s disease: a meta-analysis. BMC Neurosci 26, 5 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12868-024-00914-8

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BMC Neuroscience

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