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. Author manuscript; available in PMC: 2023 Mar 1.
Published in final edited form as: Clin Nutr. 2022 Feb 3;41(3):731–736. doi: 10.1016/j.clnu.2022.01.019

Use of fish oil supplements is differently related to incidence of all-cause and vascular dementia among people with the distinct APOE ε4 dosage

Hao Ma a, Tao Zhou a, Xiang Li a, Yoriko Heianza a, Lu Qi a,b,c
PMCID: PMC8897253  NIHMSID: NIHMS1778923  PMID: 35172255

Abstract

Backgrounds &Aims:

Previous studies have shown that marine omega-3 PUFAs (fish oil) supplements was associated with improved cognitive function, whereas the association between use of fish oil supplements and risk of incident dementia was still unclear. We aimed to prospectively assess the relations between use of fish oil supplements and risks of all-cause and disease-specific dementia according to the apolipoprotein E (APOE) ε4 dosage.

Methods:

A total of 445,961 participants from UK biobank, who were free of dementia at baseline and completed data on supplement use and genetic information were analyzed in this study. Cox proportional hazards models were used to calculate the hazard ratios (HRs) comparing incident dementia rates in participants who did and did not use fish oil.

Results:

During a median of 12.2 years of follow-up, a total of 5,795 incident cases of dementia were documented, including 1,266 cases of vascular dementia and 2,382 cases of AD. After adjustment for covariates, use of fish oil supplements was significantly associated with lower risks of all-cause dementia (Hazard ratios, HR, 95 % CI, 0.90, 0.85–0.96) and vascular dementia (HR, 0.85; 95 % CI, 0.75–0.97), but not AD (HR, 0.99; 95 % CI, 0.91–1.09). For all-cause dementia and vascular dementia, we found that the protective associations appeared to be attenuated by the increasing APOE ε4 dosage (P-interaction=0.002 and 0.002, respectively). Notably, the use of fish oil supplements was significantly associated with an 86.0 % higher risk of vascular dementia in participants with two APOE-ε4 alleles (HR, 1.86, 95%CI, 1.23–2.80).

Conclusions:

Our results indicate that use of fish oil supplements is differently associated with risks of all-cause dementia and vascular dementia according to the APOE ε4 dosage.

Keywords: fish oil supplements, genetic, dementia

Introduction

Dementia is a set of symptoms that may include memory loss, difficulties with thinking, problem-solving or language[1]. Globally, around 47 million people had dementia in 2015, and this number is expected to triple by 2050[1]. To date, the accurate etiology of dementia has not been clearly understood, while both genetic and environmental factors have been implicated in the development of the disease. The allelic variation in the apolipoprotein E (APOE) gene is a major risk determinant of all-cause dementia and the subtypes of dementia, such as Alzheimer’ disease (AD) and vascular dementia [2, 3]. It has been estimated that almost 50% of AD patients and more than 40% of vascular dementia patients carry the APOE ε4 genotype[4, 5].

Omega-3 polyunsaturated fatty acids (PUFAs) are essential constituents of neuronal cell membranes and play a critical role in the formation of neuronal synapses and membrane fluidity. Oily fish and fish oil supplements are rich source of marine omega-3 PUFAs. Observational epidemiological studies have shown that high intakes of oily fish were associated with a lower risk of AD and improved cognitive function[6–9]. Owing to such results from observational studies and the potential safety concern for fish, taking marine omega-3 PUFAs supplements (fish oil supplements) has become a potentially effective way in the prevention of dementia. However, direct evidence relating the use of marine omega-3 PUFAs supplements with incident dementia is lacking, and previous randomized clinical trials using the cognitive function as outcome have yielded inconsistent results[10–12]. Of note, emerging evidence suggests that the relations between levels of marine omega-3 PUFAs and cognitive function or AD may be modified by the APOE genotype [13]. The previous studies, however, are largely limited by small sample size, failure in assessing APOE ε4 dosage, and only addressed AD but no other subtypes such as vascular dementia [13]. On the other side, results from a recent clinical trial indicate that APOE ε4 carriers may require higher doses of omega-3 PUFAs supplements to prevent dementia compared to non-APOE ε4 carriers[14]. In addition, a recent genome-wide study has identified several novel genetic variations associated with cognitive disorders and AD, which enable us to evaluate the overall genetic risk profile for dementia[2]. No study has assessed whether the overall genetic susceptibility might modify the relations between use of fish oil supplements and dementia.

In this study, we took advantage of the large sample size of UK biobank to evaluate the association between use of fish oil supplements and risks of all cause dementia and the major subtypes of dementia (AD and vascular dementia). We particularly analyzed the modification effects of the APOE ε4 dosage and overall genetic susceptibility on the associations between habitual use of fish oil supplements and risks of all-cause dementia and the subtypes of dementia.

Methods

Study population

The UK Biobank is a large population-based cohort study comprising more than half a million participants aged 37–73 years living in the United Kingdom. The details of the study design have been described in previously studies[15]. All participants provided written informed consent and the study was approved by the NHS National Research Ethics Service. The current analyses were restricted to white participants who have completed data on the use of fish oil supplements, APOE ε4 information and free of dementia at baseline. A total of 445,961 participants were included in the final analysis (Supplementary Figure 1).

Exposure Assessment

Information on consumption of fish oil supplements was collected through the baseline touch-screen questionnaire. Participants were asked “Do you regularly take any of the following?”. Participants selected more than one answer from a list of supplements through the touch-screen questionnaire. Fish oil user was defined as follows: 0, no; 1, yes. The validity of information on the fish oil supplements use were well demonstrated in two repeated surveys (Supplemental methods).

We determined the genetic risk profiles using two approaches: (1) APOE ε4 dosage; (2) polygenic risk score (PRS); APOE ε4 genotype was determined by APOE single nucleotide polymorphisms (SNPs): rs7412 and rs429358. The APOE ε4 dosage was coded as 0 (ε2/ε2, ε2/ε3, ε3/ε3), 1 (ε3/ε4) and 2 (ε4/ε4) respectively[16]. Because the ε2/ε4 genotype have a combination of potentially protective and risk alleles, we did not include this genotype in the main analysis[16–18]. PRS (without the AOPE genotype) was calculated by 25 single nucleotide polymorphisms (SNPs), which passed quality control, based on the previous study[2] (Supplementary table 1). A weighted method was used to calculate the PRS[19]; higher scores indicating a higher genetic predisposition to AD and cognitive disorder. Further detailed information on genotyping, imputation and quality control in the UK Biobank study has been described previously[20].

Ascertainment of the Outcomes

We used the dementia variables provided by UK Biobank, which were created by combining different data sources. Information on the diagnosis of dementia was collected through medical history and linkage to data on hospital admissions, questionnaire and the death register data. Prevalent dementia was defined as if the diagnosis time was prior to date of baseline (2006–2010) assessment or having a self-reported diagnosis at recruitment. Incident dementia was defined by the International Classification of Diseases, 10th Revision (ICD-10). End of follow-up for each participant was recorded as the date of end of follow-up (May 23, 2021) or the date of lose to follow-up or the date of death, whichever came first. A high agreement of dementia cases ascertainment with primary care records have been demonstrated in a recent study[21]. Detailed information on the ascertainment of dementia has have been described previously. (https://biobank.ctsu.ox.ac.uk/showcase/showcase/docs/alg_outcome_dementia.pdf).

Statistical Analysis

After checking proportional hazards assumption (The Kaplan-Meier method and the Schoenfeld residuals method), Cox proportional hazards models were used to calculate the hazard ratios (HRs) comparing incident dementia rates in participants who did and did not use fish oil. Several potential confounders were adjusted in these models, including age (years), sex, assessment centers, education level[22], BMI (kg/m2), Townsend deprivation index (TDI, quintiles), smoking status (current, past, never), moderate physical activity (≥600 MET/week or <600MET/week), moderate drinking (yes or no), healthy diet (yes or no), hypertension (yes or no), high cholesterol (yes or no), other supplements use (yes or no), frequency of depression, social isolation status (yes or no), hearing problem (yes or no). Detailed information on covariates were also fully described in the Supplemental Methods. For analyses about genetic data, we also adjusted for the first 10 genetic principal components and relatedness. Because the missing rates for all covariates were low (all covariates missing <5.5%) in the current study, multivariate imputation by chained equations was used to impute missing covariate values. To evaluate interactions between fish oil use and genetic factors (APOE ε4 dosage and PRS) or other confounding factors, multiplicative interaction was assessed by adding interaction terms to the Cox models.

All statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc) and SPSS 22.0. All statistical tests were two sided, and we considered P<0.05 to be statistically significant.

Results

Baseline characteristics of participants according to use of fish oil supplements

Baseline characteristics of study participants according to the fish oil use are shown in the Table 1. Overall, 31.6 % of the participants reported regular use of fish oil. Compared with participants who did not regularly use fish oil supplements, users of fish oil supplements were more likely to be older, females, and have lower prevalence of high education level and higher socioeconomic levels. In addition, fish oil users have a healthier lifestyle, less depressive symptoms, less social isolation symptoms and lower prevalence of diabetes, but higher prevalence of hearing problem, hypertension and high cholesterol as compared with non-fish oil users. Of note, users of fish oil supplements also tended to take more other supplements.

Table 1.

Basic Characteristics of Participants by Use of Fish oil in the UK Biobank Cohort.

Fish oil Non-user Fish oil User
N (%) 304,872 (68.4) 141,089 (31.6)
Age, years (SD) 55.8 (8.1) 58.9 (7.3)
Female 162,654 (53.4) 79,618 (56.4)
High education level a 148,697 (48.8) 63,168 (44.8)
Townsend deprivation index −1.4 (3.0) −1.7 (2.9)
BMI, kg/m2 27.5 (4.9) 27.2 (4.5)
MET ≥600 min/week 238,208 (78.1) 116,032 (82.2)
Current smoker 35,191 (11.5) 11,284 (8.0)
Moderate drinker 138,548 (45.4) 66,812 (47.4)
Healthy diet 211,452 (69.4) 111,933 (79.3)
Depressive symptoms 69,954 (23.0) 28,682 (20.3)
Social isolation 28,091 (9.2) 11,319 (8.0)
Hearing problem 74,423 (24.4) 37,309(26.4)
Diabetes 15,286 (5.0) 6,204 (4.4)
Hypertension 165,408 (54.3) 82,809 (58.7)
High cholesterol 54,053 (17.7) 29,169 (20.7)
Cardiovascular disease 18,567 (6.1) 8,686 (6.2)
Healthy lifestyle score 2.8 (0.9) 3.0 (0.8)
Other supplements use 84,538 (27.7) 103,276(73.2)
APOE ε4 dosage
 0 223,662 (73.4) 103,353 (73.3)
 1 73,879 (24.2) 34,267 (24.3)
 2 7,331 (2.4) 3,469 (2.5)
Polygenetic risk score (without APOE) 26.7 (3.0) 26.7 (3.0)
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Data are n (%) unless otherwise indicated.

Abbreviations: BMI, body mass index, MET, metabolic equivalents of task, SD standard deviation.

a

High education level include college or university degree and NVQ or NHD or HNC or equivalent.

The association between use of fish oil supplements and risk of dementia

After a median of 12.2 years of follow-up period (Interquartile range: 11.5–12.9), a total of 5,795 incident cases of dementia were documented in this study, including 1,266 cases of vascular dementia and 2,382 cases of AD. Habitual use of fish oil supplements was significantly associated with a 10.0 % lower risk of all-cause dementia (HR, 95 % CI, 0.90, 0.85–0.96) after adjustment for potential confounders (Table 2). For the subtypes of dementia, use of fish oil supplements was significantly associated with a lower risk of vascular dementia (adjusted HR, 0.85; 95 % CI, 0.75–0.97), but not AD (adjusted HR, 0.99; 95 % CI, 0.91–1.09). The results remained similar after further adjustment for the genetic risk factors (APOE ε4 dosage or PRS).

Table 2.

Associations of fish oil use with risk of dementia.

Non-users Fish oil-users
All-cause dementia P-value
 Cases, N (%) 3,654 (1.2) 2,141 (0.6)
 Model 1 a 1(reference) 0.90 (0.85–0.96) 0.001
 Model 1+ APOE ε4 dosage b 1(reference) 0.91 (0.86–0.96) 0.001
 Model 1+ PRS (without APOE) b 1(reference) 0.90 (0.85–0.96) 0.001
Alzheimer's disease Non-users Fish oil-users P-value
 Cases, N (%) 1,413 (0.5) 969 (0.7)
 Model 1 a 1(reference) 0.99(0.91–1.09) 0.901
 Model 1+ APOE ε4 dosage b 1(reference) 1.00 (0.92–1.10) 0.983
 Model 1+ PRS (without APOE)b 1(reference) 1.00 (0.91–1.09) 0.948
Vascular dementia Non-users Fish oil-users P-value
 Cases, N (%) 834 (0.3) 432 (0.3)
 Model 1 a 1(reference) 0.85 (0.75–0.97) 0.013
 Model 1+ APOE ε4 dosage b 1(reference) 0.85 (0.75–0.97) 0.016
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a

Model 1: Cox proportional hazards regression adjusted for age, sex, assessment centers, Townsend index, education, BMI, physical activity, healthy diet, smoking, moderate drinking, frequency of depression, social isolation, hearing problems, other supplements use and history of diabetes, history of high cholesterol, history of hypertension and history of cardiovascular disease.

b

Further adjustment for the first 10 genetic principal components and relatedness.

To evaluate whether the observed inverse associations might be due to an overall healthier lifestyle, higher socioeconomic level, lower prevalence of depression, social isolation or diabetes in the fish oil users as compared with non-users, we further conducted a series of stratified analyses according to these factors and oily fish intake. We did not find any potential confounders to significantly modify the associations between use of fish oil supplements and risk of all-cause dementia, vascular dementia or AD (Supplementary table 2). Interestingly, we found that the inverse associations of the use of fish oil supplements with risks of all-cause dementia and vascular dementia appeared to be stronger in participants with high oily-fish intake than those with low oily-fish intake (P-interaction<0.001 for all-cause dementia; P-interaction=0.002 for vascular dementia). (Supplementary table 2).

Associations between use of fish oil supplements and risk of dementia according to the genetic risk profiles.

As excepted, both greater APOE ε4 dosage and higher levels of PRS (without APOE) were significantly associated with higher risks of all-cause dementia, vascular dementia and AD (Supplementary Table 3).

We further analyzed the associations between use of fish oil supplements and risks of all-cause dementia and subtypes of dementia by different genetic risk profiles. We found that the use of fish oil supplements was differently related to risks of all-cause dementia and vascular dementia among participants with different APOE ε4 dosages (p-interaction=0.002 and 0.002, respectively). In participants without APOE ε4 allele, use of fish oil supplements was significantly associated with an 14.0 % lower risk of all-cause dementia (HR, 0.86; 95 % CI, 0.79–0.94); In participants with one APOE ε4 allele one or two APOE ε4 allele, use of fish oil supplements was not associated with risk of all-cause dementia (HR, 95%CI; 0.92, 0.84–1.01 and 1.07, 0.90–1.28, respectively) (Figure 1A). Notably, for vascular dementia, the use of fish oil supplements was associated with 22 % (HR, 95%CI; 0.78, 0.65–0.93) and 19 % (0.81, 0.65–0.99) lower risk of vascular dementia in participants with zero and one APOE ε4 allele; whereas the use of fish oil supplements was significantly associated with an 86% higher risk of vascular dementia in participants with two APOE ε4 alleles (Figure 1B). No significant interaction was observed for AD (p-interaction=0.17) (Figure 1B). Such results did not change after further adjustment for genetic risk from other genotype [PRS (without APOE)] (Supplementary Figure 2). Similar results were also observed after excluding participants who developed dementia within the first two years of follow-up (for all-cause dementia: p-interaction=0.005; for vascular dementia: p-interaction=0.002). (Supplementary Figure 3)

Figure 1.

Figure 1.

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Associations between use of fish oil and risk of dementia according to genetic risk profiles.

Results were adjusted for age, sex, assessment centers, Townsend index, education, BMI, physical activity, healthy diet, smoking, moderate drinking, frequency of depression, social isolation, hearing problems, other supplements use and history of diabetes, history of high cholesterol, history of hypertension and history of cardiovascular disease, the first 10 genetic principal components and relatedness.

We did not find significant interaction between use of fish oil supplements and PRS (without the APOE) in relation to risk of all-cause dementia or AD (p-interaction=0.642 and p-interaction=0.343, respectively) (Supplementary Figure 4). Because the current PRS was developed on the basis of AD and cognitive disorder, we did not evaluate the interaction between fish oil supplement and PRS in relation to risk of vascular dementia.

Discussion

In this study, we observed that use of fish oil supplements was associated with lower risks of incident all-cause dementia and vascular dementia, independent of traditional risk factors and genetic risk factors. In addition, we found that the associations between use of fish oil supplements and risks of all-cause dementia and vascular dementia significantly differed according to the APOE ε4 dosage.

A novel finding in this study was that we found that use of fish oil supplements was significantly associated with a lower risk of vascular dementia but not AD. To the best of our knowledge, no previous study has directly investigated the association between use of fish oil supplements and incident AD or incident vascular dementia. The lack of significant association between use of fish oil supplements and AD risk were supported by several previous studies evaluating the associations of fish intake or levels of marine omega-3 PUFAs with risk of AD[23–25], although the conflicting results were also reported[26, 27]. In the Cardiovascular Health Cognition Study, after an averaged 5.4 years of follow-up period, fatty fish intake at baseline was not associated with risk of AD or all-cause dementia after adjusting education level, income and other confounders[23]. In the three-city cohort study, after an averaged 3.5 years of follow-up period, higher fish consumption at baseline was not significantly associated with lower risk of AD[24]. No previous study has investigated the association between levels of marine omega-3 PUFAs with risk of vascular dementia due to its inadequate number of cases. Our findings of the significant inverse association between use of fish oil supplements and risk of vascular dementia are biologically plausible. Compelling evidence has implicated fish oil supplements in improving cardiovascular function[28]. Although vascular dementia and AD share many common pathological mechanisms, the development of vascular dementia is mainly due to cardiovascular dysfunction [3, 29], while AD is mainly caused by β-amyloid (Aβ) accumulation and the relation between vascular risk factors and AD is weak [30, 31]. Our data suggest that the significant association between use of fish oil supplements and all-cause dementia in our study is likely to be mainly driven by vascular dementia.

The dementia is a multifactorial disease with a substantial genetic component (60–80%), thus the next question is that whether habitual use of fish oil supplements can attenuate the increased genetic risk, especially the APOE gene. Our and others previous results have been suggested that participants with high genetic risk may be more vulnerable to environmental factors[32, 33], whereas such results might not apply for the effects of the fish oil supplements on the participants with high APOE genetic risk. Previous evidence has shown that omega-3 PUFAs metabolism is disturbed by the APOE ε4 allele[34, 35], and several clinical trials have demonstrated that the increment in plasma omega-3 PUFAs levels in response to marine omega-3 PUFAs supplementation was much lower in the APOE ε4 carriers as compared with the APOE ε4 non-carriers[36–38]. In addition, the APOE ε4 carriers, especially the participants with two alleles[39, 40], might already have developed APOE-related brain changes earlier in their lives, and such adverse effects of APOE ε4 on neuronal system were irreversible[41]. Therefore, the potential benefits of fish oil for the APOE ε4 carriers may be limited. Our results supported such hypothesis and showed that the strength of the protective association between use of fish oil supplements and risk of all-cause dementia appeared to be attenuated by the increasing APOE ε4 dosage.

No study has directly investigated the modification effects of the APOE ε4 dosage on the association between use of marine omega-3 PUFAs supplements and risk of incidence dementia, whereas previous studies using cognitive decline as the outcome have generated highly inconsistent results[13]. Several studies reported that the beneficial associations of marine omega-3 PUFAs supplements with the cognitive function were only restricted to the APOE ε4 carriers[12, 42, 43], whereas the opposite-direction results were reported in other studies[6, 10, 23, 44]. The potential misclassification due to failure to consider the dosage of APOE ε4 in the previous studies may partly account for such inconsistent results. Notably, in the APOE ε4 carriers (with one or two ε4 alleles), participants with two ε4 alleles might have much higher risk of dementia than those with one ε4 allele (compared with non-APOE ε4 carriers; participants with one ε4 allele have a 3 to 4-fold higher risk of dementia, whereas those with two ε4 alleles have a 12-fold higher risk of dementia)[45]. Therefore, the relations between the marine omega-3 PUFAs supplements and dementia may differ according to the ε4 dosage. Our results supported this hypothesis and showed that habitual use of fish oil supplements was marginally associated with a lower risk of all-cause dementia in participants with one APOE ε4 allele but associated with a non-significant higher risk of all-cause dementia in participants with two APOE ε4 alleles.

Notably, for the vascular dementia, we found that habitual use of fish oil supplements was significantly associated with a 22.0 % lower risk vascular dementia in participants without APOE-ε4 allele, whereas the use of fish oil supplements was significantly associated with an 86.0 % higher risk of vascular dementia in participants with two APOE-ε4 alleles. Although we cannot rule out that the unexcepted higher risk for vascular dementia in fish oil users was due to chance, these results deserve particular attention in future studies. Two random clinical trials indicated that the APOE ε4 genotype significantly modified the effects of marine omega-3 PUFAs supplements on the lipid profile, in which the significant benefits of marine omega-3 PUFAs supplements on the lipid profile were observed in the non-APOE ε4 carriers, whereas the adverse effects on LDL and TC were observed in APOE ε4 carriers[46, 47]. The APOE genotype specific changes in lipid profiles might differently affect cardiovascular conditions, which are closely related to vascular dementia but weakly related to AD[30, 31], and therefore partly account for the distinct modification effects of APOE ε4 dosage on AD and vascular dementia.

The major strengths of this study include the large sample size and the wealth of information of lifestyle, clinical measures, and other covariates. However, several potential limitations of this study need to be addressed. First, a major limitation was that the detailed information on use of fish oil supplements, such as the dose was not collected in this study. Notably, a well-designed clinical trial showed that using omega-3 doses of equal or less than 1 g per day may have reduced brain effects, and especially for APOE ε4 carriers, indicating that a higher dose of omega-3 PUFAs may be needed for APOE ε4 carriers[14]. Further studies are needed to explore the appropriate dosing of fish oil supplements among APOE ε4 carriers and non- APOE ε4 carriers. Second, use of fish oil supplements might be a marker for a healthier lifestyle. Nevertheless, in this study, we have carefully controlled for the potential confounders. Third, although this study has a large sample size and long follow-up period, the incidences of dementia are still relatively low, which might be that the incident dementia cases were ascertained through death registry and hospital inpatient records only. However, the accuracy of this method for ascertainment of incident dementia was well demonstrated in a recent study[21]. Fourth, several previous studies indicated that middle age might be a particularly critical period for use of fish oil supplements in the prevention of dementia[6, 13]. In this study, the majority of participants in this study are middle-aged white adults, thus the generalizability of our findings should be evaluated in other populations.

In conclusion, our findings indicate that use of fish oil supplements is associated with lower risks of all-cause dementia and vascular dementia, and the protective associations is attenuated by the increasing APOE ε4 dosage. Our findings highlight the importance of considering the genetic risk profile when using fish oil supplements to prevent dementia.

Supplementary Material

1

Acknowledgements:

This study has been conducted using the UK Biobank Resource, approved project number 29256.

Funding/Support:

Lu Qi was supported by grants from the National Heart, Lung, and Blood Institute (HL071981, HL034594, HL126024), the National Institute of Diabetes and Digestive and Kidney Diseases (DK115679, DK091718, DK100383, DK078616).

Footnotes

Competing interests: All the authors have indicated they have no potential conflicts of interest to disclose.

Ethical approval: The study was approved by the NHS National Research Ethics Service. The present analysis was approved by the Tulane University (New Orleans, Louisiana) Institutional Review Board.

Data sharing: The genetic and phenotypic UK Biobank data are available on application to the UK Biobank (www.ukbiobank.ac.uk/)

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