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Systematic Review

A Review of Interaction Between Sleep Apnea and APOE e4 on the Risk of Dementia

by
Xiuhua Ding
1,*,
Carol Watwood
2,†,
Amit Patel
1,
Krupa Hegde
3,
Brooke Mahanna
1,
Lindsey Escudero
1 and
Jean Neils-Strunjas
4
1
Department of Public Health, Western Kentucky University, Bowling Green, KY 42101, USA
2
WKU Libraries, Western Kentucky University, Bowling Green, KY 42101, USA
3
Department of Cell Biology, Yale College, New Haven, CT 06520, USA
4
Department of Communication Sciences and Disorders, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
*
Author to whom correspondence should be addressed.
†
Retired.
J. Gerontol. Geriatr. 2026, 74(1), 4; https://doi.org/10.3390/jgg74010004
Submission received: 17 April 2025 / Revised: 29 January 2026 / Accepted: 19 February 2026 / Published: 2 March 2026
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Abstract

Dementia has a significant impact on individuals, families, communities, and the economy. Alzheimer’s disease (AD) accounts for 60–80% of dementia cases. The APOE e4 allele is well known as the primary genetic risk factor for AD and dementia. Studies have also shown that sleep apnea increases the risk of dementia. Some research further suggests a possible interaction between sleep apnea and the APOE in dementia development; however, this relationship remains unclear. The purpose of this study is to synthesize evidence from the existing literature and report findings on the relationship between APOE, sleep apnea, and dementia. A systematic search of multiple databases was conducted using selected keywords. Articles were screened and selected according to predefined inclusion criteria. Only original, peer-reviewed articles published between 2000 and 2021 in English were included. Data from the included studies were extracted and summarized descriptively, including information on population characteristics, study design, key findings, and other relevant variables. Of the 328 records identified, 3 studies met inclusion criteria and were included in the final analysis. Their findings suggest a potential interaction between sleep apnea and APOE that may influence dementia risk. This review highlights the need for further research to clarify the role of sleep apnea in the APOE pathway and its contribution to dementia.

1. Introduction

Dementia is one of the leading causes of death and disability in the U.S. and globally [1]. It is estimated that about 6.9 million people aged 65 and older in the United States are living with Alzheimer’s Disease-related dementia [2]. By 2060, this number is projected to reach 14 million people, with Black and Hispanic populations disproportionately affected [3]. Alzheimer’s disease accounts for 60–80% of all dementia cases. Caring for individuals with dementia places a substantial burden on family and caregivers and has both direct and indirect economic consequences [4]. As the worldwide population is aging, there is an urgent need to improve the diagnosis and treatment of dementia. In recent years, efforts to identify biomarkers for Alzheimer’s disease have intensified, with APOE being one of the most extensively studied candidates [5,6].
Apolipoprotein E (APOE) is a lipoprotein produced in the liver and brain that plays a critical role in cholesterol transport and deposition. APOE polymorphic alleles are the primary genetic risk factors for Alzheimer’s disease (AD) and dementia [7]. The three major APOE alleles—e2, e3, e4 [8]—are associated with different levels of risk for AD. The presence of one e4 allele increases the risk of AD by approximately 20%, while having two e4 alleles increases this risk by up to 90% [9]. Approximately 40% of individuals with AD carry at least one e4 allele [4]. Identifying factors that interact with genetic predispositions like APOE ɛ4 is essential for targeting clinical interventions.
Recent research has highlighted the role of sleep quality as a risk factor for Alzheimer’s disease [10,11]. Sleep apnea, a common age-associated sleep disorder, is characterized by symptoms such as loud snoring, breathing pauses (e.g., choking or gasping), morning headaches, insomnia, and excessive daytime sleepiness [12,13,14,15]. It affects 20–50% of older adults [13], and an estimated 17% of men and 9% of women aged 50–70 have moderate-to-severe sleep-disordered breathing (SDB) [16,17]. Sleep apnea and its associated risks, including obesity, have become critical public health concerns [12,13,18,19,20,21]. Sleep apnea has been linked to cognitive impairment and dementia in older populations [22,23]. Emerging evidence suggests a bidirectional relationship between sleep apnea and AD, with sleep apnea potentially serving as a modifiable risk factor for AD [24,25,26].
Although sleep apnea and the APOE e4 allele have each been identified as predictors of Alzheimer’s disease (AD)/dementia, the potential interaction between these two factors and their combined effect on AD/dementia risk has not been thoroughly investigated and remains unclear. The purpose of this study is to synthesize evidence from the existing literature and report findings on the relationship between sleep apnea, APOE, and risk of dementia.

2. Method

This study is a review that references the PRISMA guidelines to promote transparency in reporting (Supplementary Materials). While elements of PRISMA were used to guide the literature identification process, the review does not meet all criteria for a systematic review and, therefore, presents a narrative synthesis of the existing evidence.

2.1. Search Strategy

A literature search of PubMed/MEDLINE, Web of Science, and the Cochrane Library was conducted to identify studies published between 2000 and 2021 that examined the following question: In individuals with sleep apnea and varying APOE genotypes (P), how does the interaction between sleep apnea and APOE influence the risk of dementia (O) compared with individuals with sleep apnea or APOE alone (C)? Search terms were developed through a review of the current literature and in consultation with a medical librarian and a senior researcher. The search terms included: (APOE OR APOE4 OR APOE3 OR APOE2 OR APOE-E OR apolipoprotein OR apolipoproteins OR apoprotein OR apoproteins) AND (sleep apnea OR hypopnea OR hypersomnia OR SDB OR sleep-disordered breathing OR SHS OR sleep apnea syndromes OR OSA OR OSAH OR OSAHS OR apnea OR apnoea OR respiratory disturbance index OR hypoxia OR anoxia).
Each database was searched individually using the selected terms, and all identified studies were imported into EndNote X9. Additionally, a manual search of the reference lists of included articles was performed to identify relevant studies not captured by the automated search. Duplicate records were then removed in EndNote X9.

2.2. Selection Criteria

Eligible studies had to meet all the following criteria:
  • Original research examining the interaction between sleep apnea and APOE on cognition, cognitive decline, and dementia/AD.
  • Studies conducted with human adults.
  • Studies that used polysomnography or clinical diagnosis to identify sleep apnea.
Studies that only examined the association between sleep apnea and APOE without focusing on their interactive effect on the risk of dementia were excluded. Studies conducted in animals, as well as those that examined the association between sleep apnea and APOE without investigating their interaction on the risk of dementia, were excluded.

2.3. Reviewing Procedure, Data Extraction

Three authors (AP, BM, and LE) independently reviewed the titles and abstracts of all identified studies using EndNote X9. Disagreements regarding study inclusion were resolved by two additional authors (XD and CW). XD performed data extraction for each eligible study. Extracted information included authors, year of publication, study design, study population, age, sleep apnea measurement, APOE measurement, outcome assessment, statistical analysis methods, covariates, and main findings. Figure 1 illustrates the study selection process.

2.4. Quality Assessment and Analysis

The methodological quality of the included studies was evaluated using the Joanna Briggs Institute (JBI) Critical Appraisal Tools, which provide design-specific criteria for cohort and cross-sectional studies. For each study, key domains were assessed, including study design and setting, key strengths, and key limitations. Strengths across the studies included objective APOE measurement and standardized cognitive assessments, while limitations included potential residual confounding, variable assessment of sleep apnea, and limited generalizability for clinic-based samples. These quality assessments guided the interpretation of the evidence but did not influence study inclusion. Furthermore, given the limited number of studies included in this review (n = 3), a quantitative meta-analysis was not feasible. Instead, a narrative synthesis was conducted to summarize and interpret the findings. Key study characteristics—including study design, population, setting, APOE assessment, sleep apnea assessment, and dementia/cognitive outcomes—were extracted and compared across studies. The relationships between APOE, sleep apnea, and cognitive outcomes were evaluated by identifying patterns, consistencies, and discrepancies in the evidence.

3. Results

Figure 1 illustrates the study selection process. Initially, 328 studies were identified. After removing duplicate records, 237 studies remained for screening based on titles and abstracts. Following this screening, 57 full-text articles were retrieved for further evaluation. Ultimately, three studies met the inclusion and exclusion criteria outlined in the Section 2 and were selected for analysis.
Table 1 shows results for the quality assessment of three studies. The cohort study by Lim et al. allowed for temporal assessment of the relationship between APOE genotype, sleep apnea, and subsequent cognitive outcomes, while the cross-sectional studies provided snapshots of associations at a single time point. Overall, study quality was moderate across all studies. Strengths included objective APOE genotyping, standardized cognitive assessments, and, in some cases, polysomnography-based evaluation of sleep apnea. Limitations were primarily related to study design and setting: cross-sectional designs prevented causal inference, clinic-based sampling reduced generalizability, and some studies had incomplete adjustment for potential confounders, including cardiovascular risk factors. Overall, the findings suggest that sleep apnea interacts with APOE to influence the risk of AD or cognitive outcomes.
Table 2 presents the information extracted from eligible studies. Lim et al. reported that better sleep consolidation reduced the effect of the APOE e4 allele on AD risk. Specifically, the hazard ratio for AD among APOE e4 carriers compared with non-carriers decreased from 4.1 for poor sleep consolidation to 2.5 for median sleep consolidation and 1.8 for good sleep consolidation [27]. Nikodemova et al. found that sleep-disordered breathing—defined as increased resistance to airflow through the upper airway, loud snoring, reduced airflow (hypopnea), or complete cessation of breathing (apnea)—was associated with poorer performance on memory tests (Auditory Verbal Learning Test) and verbal fluency (Controlled Oral Word Association Test) among APOE e4 carriers, whereas no significant effects were observed in non-carrier [28]. Similarly, correlation analyses in O’Hara et al. indicated that the number of respiratory events was negatively associated with memory performance only in APOE e4 carriers [29].

4. Discussion

This study reviewed observational research conducted over the past two decades on the interaction between APOE and sleep apnea and their impact on cognition and the risk of mild cognitive impairment (MCI) or Alzheimer’s disease (AD) in adults. Evidence on this topic is limited, with only three studies identified during that period. Nonetheless, these studies indicate that APOE and sleep apnea may interact to influence cognitive function and the likelihood of MCI or AD. Another study by Ding et al. [30] concluded that baseline sleep apnea was associated with the development of dementia, but only in APOE-e4 non-carriers. However, since the sleep apnea measurement in this study was self-reported, it was excluded from this review. Interest in this topic has been increasing, with several recent studies focusing on the issue. Yiallourou et al. found no consistent association between sleep architecture and incident dementia after pooling five U.S. cohort studies and adjusting for APOE e4 [31]. Sun et al. reported that sleep EEG-based brain age index (BAI) was positively associated with the risk of incident dementia using pooled data from community-based longitudinal cohorts [32]. Fonseca et al. found that, among American Indians, midlife sleep characteristics were correlated with cognitive performance [33]. However, these studies did not investigate the interaction between sleep and APOE. Marchi et al. examined the moderating effect of APOE on the association between obstructive sleep apnea (OSA) and cognitive function. They concluded that severe OSA was associated with lower Stroop test performance among APOE e4 carriers, but not among non-carriers [34]. Similarly, Gara et al. found that APOE e4 carriers with moderate-to-severe OSA demonstrated worse episodic memory, whereas non-carriers did not [35]. Notably, both studies were cross-sectional and had small sample sizes, which limits the strength of their conclusions.
It is well-established that Apolipoprotein E (APOE) is one of the most important genetic risk factors for Alzheimer’s disease (AD), primarily through its influence on amyloid-beta (Aβ) pathology [9,36,37,38,39]. The association between sleep apnea and cognitive decline, as well as the development of mild cognitive impairment (MCI), AD, or dementia, has been widely investigated in observational studies [27,40,41,42,43,44,45]. There are three common APOE alleles—e2, e3, and e4. Individuals carrying one or more e4 alleles have an increased risk of developing LOAD. Evidence suggests that the APOE genotype may affect Aβ clearance and aggregation, leading to Aβ accumulation and deposition [7,46,47]. Human studies have shown that Aβ deposition is more likely in AD patients who are APOE e4-carriers than in those who are APOE e4 non-carriers [48,49,50].
Studies using transgenic mice to model Aβ deposition have provided evidence that APOE influences Aβ accumulation in terms of both amount and distribution. Bales et al. used APOE knockout mice and demonstrated that, in the absence of APOE, in vivo Aβ deposition was dramatically reduced [51]. Bubu et al. conducted a systematic review integrating findings from studies on sleep apnea, cognition, and AD over the past three decades. They concluded that the association between sleep apnea and cognitive function is more evident in younger adults than in older adults, independent of study design [52]. They also found that sleep apnea is associated with the development of MCI or AD in older adults. Duan et al. reported that taking a nap at noon affects the risk of MCI depending on APOE status [53]. Turner et al. conducted stratified analyses based on race and found that the interaction between OSA and APOE e4 was significantly associated with white matter hyperintensities (WMHs) and hippocampal volume in Black/African American participants, but not in White participants [54]. Furthermore, adjusting for confounders is essential in studies involving older populations to ensure accurate and meaningful results. Lim et al. found that the interaction between sleep and APOE remained unchanged after adjusting for vascular diseases, vascular risk factors, stroke, Parkinson’s disease (PD), and psychotropic medications [27]. Nikodemova et al. [28] assessed various covariates, including medical history, medication use, alcohol consumption, and CPAP treatment, and found that only sleep, APOE4 status, age, sex, education, and BMI had a significant effect on cognitive scores. However, no additional covariates were available in O’Hara’s study [29].
Several plausible mechanisms may explain these associations, including disrupted sleep, intermittent hypoxia, and reduced slow-wave sleep (SWS), all of which can affect amyloid-beta (Aβ) metabolism [55,56]. In humans, the sleep/wake cycle regulates Aβ levels. Sleep deprivation studies have shown that lack of sleep may increase Aβ production by approximately 30% overnight [44,57]. Increased wakefulness under sleep deprivation also reduces Aβ clearance via the glymphatic system, thereby increasing Aβ levels [58]. Observations of greater sleep disturbances in amyloid-positive versus amyloid-negative cognitively normal, late-middle-aged adults suggest that sleep disruption may contribute to Aβ accumulation even in the preclinical phase of AD [11,59]. Chronic intermittent hypoxia resulting from sleep apnea may further promote Aβ deposition, as oxidative stress increases Aβ production and accumulation [60,61,62,63]. Mouse studies have demonstrated that intermittent hypoxia is associated with increased Aβ production [64,65]. Reduced SWS is another potential mechanism linking sleep apnea to AD pathogenesis [66], as SWS has been shown to correlate with Aβ levels [67,68,69,70].
This review has several limitations. First, only three studies met the inclusion criteria, which limits the breadth of available evidence and prevents robust comparisons across study populations, methods, or outcomes. Second, the small number of studies precluded the use of meta-analysis and restricted the review to a narrative synthesis. Third, the included studies varied in design, setting, and measurement of sleep apnea, APOE genotype, and cognitive outcomes, which may introduce heterogeneity and limit the generalizability of findings. Finally, publication bias cannot be ruled out, as studies with null findings may be less likely to be published.

5. Conclusions

In conclusion, the available evidence suggests a potential interaction between sleep apnea and APOE ε4 status in relation to cognitive function and dementia, although findings remain limited and heterogeneous. This study suggests that limited research has explored the interaction between APOE and sleep in Alzheimer’s disease (AD), likely due to challenges in study design, the high cost of longitudinal studies, and data availability issues, as older sleep studies often lacked APOE testing. Publication bias may also play a role, as studies with negative or inconclusive results are less likely to be published. This review highlights a growing interest in this area, with more recent studies pooling data from multiple cohorts. However, future research should focus on understanding the underlying mechanisms, such as how sleep may influence APOE-related AD pathology. As AD-related changes, like amyloid-beta accumulation, can begin 15–20 years before dementia symptoms appear, alterations in sleep patterns at younger ages may serve as early biomarkers for AD prediction and intervention.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jgg74010004/s1, PRISMA 2020 Checklist.

Author Contributions

X.D. designed and oversaw the study. C.W. conducted a literature search, screened titles and abstracts for eligibility, and extracted data from the full-text articles. A.P., K.H., B.M. and L.E. screened literature titles and abstracts, and extracted the full articles. J.N.-S. reviewed the manuscript and provided critical feedback. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the WKU Research & Creative Activities Program (RCAP) and by grant P20GM103436-22 (KY INBRE) from the National Institute of General Medical Sciences at the National Institutes of Health.

Data Availability Statement

No new data were created in this study. However, data may be available upon reasonable request from the corresponding author, subject to ethical approval and privacy restrictions.

Conflicts of Interest

The authors have no conflicts of interest to declare.

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Jgg 74 00004 g001
Figure 1. Study procedure. Flowchart depicting the study selection process for the systematic review. Arrows indicate the progression from initial identification of studies through database searching (n = 328) to final inclusion (n = 3). The process includes removing duplicates, screening studies by title and abstract, assessing full-text articles for eligibility, and excluding studies based on various criteria (e.g., conference abstracts, not measuring OSA objectively).
Figure 1. Study procedure. Flowchart depicting the study selection process for the systematic review. Arrows indicate the progression from initial identification of studies through database searching (n = 328) to final inclusion (n = 3). The process includes removing duplicates, screening studies by title and abstract, assessing full-text articles for eligibility, and excluding studies based on various criteria (e.g., conference abstracts, not measuring OSA objectively).
Jgg 74 00004 g001
Table 1. Quality Assessment Table for the Three Studies.
Table 1. Quality Assessment Table for the Three Studies.
StudyDesign & SettingKey StrengthsKey LimitationsOverall Quality/Risk of Bias
Lim et al., 2013 [27]Cohort, community-basedProspective design allows temporal interpretation; Objective sleep apnea assessment (e.g., PSG); APOE genotyping clearly defined.Potential residual confounding; Attrition and follow-up details not fully reported.Moderate
Nikodemova et al., 2013 [28]Cross-sectional, clinic-basedLarge clinical sample; Detailed sleep apnea severity data; Laboratory-confirmed APOE genotyping Clinic-based samples reduce generalizability; Cross-sectional design limits causal inference; Dementia/cognitive impairment may be incompletely assessedModerate to High
O’Hara et al., 2005 [29]Cross-sectional, community-basedCommunity-based sampling increases representativeness; Standardized cognitive assessments likely used; APOE genotyping method describedSleep apnea assessment may rely on cross-sectional self-reports; Limited causal interpretation; Possible residual confounding.Moderate
Table 2. General characteristics of study participants for selected study and main findings.
Table 2. General characteristics of study participants for selected study and main findings.
StudyStudy Design
&
Study Setting		nAge in YearsGenderSleep ApneaAPOEOutcomeAdjusted VariablesKey Findings
Lim et al.,
2013 [27]		Cohort,
Community		69881.7536 Female; 162 MaleSleep consolidation KRA by actigraphye4carriersvs. e4 non-carriers Incident cases of ADAge, sex, educationBetter sleep consolidation attenuated the effect of the e4 allele on the risk of incident. For each allele corresponding to a 1 SD increase in sleep consolidation, the risk of AD decreases by 33%
Nikodemova et al.,
2013 [28]		Cross-sectional,
Clinic setting 		184353.9810 Female;
1033 Male		AHI < 5
5 ≤ AHI < 15
AHI ≥ 15		e4carriers vs. e4 non-carriersCognitive Test scoreAge, Sex, Education, BMINo significance in the full model, but some significant results in stratified analysis.
Moderate-to-severe disordered breathing while asleep was associated with poorer performance on memory and executive function for APOE-e4 positive individuals.
O’Hara et al.,
2005 [29]		Cross-sectional,
Community		3670.624 Female;
12 Male		AHI: the average number of apneas or hypopneas per hour of estimated sleepe4 carriers vs. e4 non-carriersCognitive test scoresN/AThe relationship between AHI and delayed recall and short-term recall is significantly different in e4 carriers vs. e4 non-carriers.
Notes: AHI = Apnea–Hypopnea Index; BMI = Body Mass Index; AD = Alzheimer’s Disease; SD = Standard Deviation.
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MDPI and ACS Style

Ding, X.; Watwood, C.; Patel, A.; Hegde, K.; Mahanna, B.; Escudero, L.; Neils-Strunjas, J. A Review of Interaction Between Sleep Apnea and APOE e4 on the Risk of Dementia. J. Gerontol. Geriatr. 2026, 74, 4. https://doi.org/10.3390/jgg74010004

AMA Style

Ding X, Watwood C, Patel A, Hegde K, Mahanna B, Escudero L, Neils-Strunjas J. A Review of Interaction Between Sleep Apnea and APOE e4 on the Risk of Dementia. Journal of Gerontology and Geriatrics. 2026; 74(1):4. https://doi.org/10.3390/jgg74010004

Chicago/Turabian Style

Ding, Xiuhua, Carol Watwood, Amit Patel, Krupa Hegde, Brooke Mahanna, Lindsey Escudero, and Jean Neils-Strunjas. 2026. "A Review of Interaction Between Sleep Apnea and APOE e4 on the Risk of Dementia" Journal of Gerontology and Geriatrics 74, no. 1: 4. https://doi.org/10.3390/jgg74010004

APA Style

Ding, X., Watwood, C., Patel, A., Hegde, K., Mahanna, B., Escudero, L., & Neils-Strunjas, J. (2026). A Review of Interaction Between Sleep Apnea and APOE e4 on the Risk of Dementia. Journal of Gerontology and Geriatrics, 74(1), 4. https://doi.org/10.3390/jgg74010004

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