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The American Journal of Clinical Nutrition logoLink to The American Journal of Clinical Nutrition
. 2023 Apr 5;117(6):1096–1109. doi: 10.1016/j.ajcnut.2023.04.001

The Relationship of Omega-3 Fatty Acids with Dementia and Cognitive Decline: Evidence from Prospective Cohort Studies of Supplementation, Dietary Intake, and Blood Markers☆

Bao-Zhen Wei 1,2,†, Lin Li 3,†, Cheng-Wen Dong 2, Chen-Chen Tan 1; for the Alzheimer’s Disease Neuroimaging Initiative, Wei Xu 1,∗
PMCID: PMC10447496  PMID: 37028557

Abstract

Previous data have linked omega-3 fatty acids with risk of dementia. We aimed to assess the longitudinal relationships of omega-3 polyunsaturated fatty acid intake as well as blood biomarkers with risk of Alzheimer’s disease (AD), dementia, or cognitive decline. Longitudinal data were derived from 1135 participants without dementia (mean age = 73 y) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort to evaluate the associations of omega-3 fatty acid supplementation and blood biomarkers with incident AD during the 6-y follow-up. A meta-analysis of published cohort studies was further conducted to test the longitudinal relationships of dietary intake of omega-3 and its peripheral markers with all-cause dementia or cognitive decline. Causal dose–response analyses were conducted using the robust error meta-regression model. In the ADNI cohort, long-term users of omega-3 fatty acid supplements exhibited a 64% reduced risk of AD (hazard ratio: 0.36, 95% confidence interval: 0.18, 0.72; P = 0.004). After incorporating 48 longitudinal studies involving 103,651 participants, a moderate-to-high level of evidence suggested that dietary intake of omega-3 fatty acids could lower risk of all-cause dementia or cognitive decline by ∼20%, especially for docosahexaenoic acid (DHA) intake (relative risk [RR]: 0.82, I2 = 63.6%, P = 0.001) and for studies that were adjusted for apolipoprotein APOE ε4 status (RR: 0.83, I2 = 65%, P = 0.006). Each increment of 0.1 g/d of DHA or eicosapentaenoic acid (EPA) intake was associated with an 8% ∼ 9.9% (Plinear < 0.0005) lower risk of cognitive decline. Moderate-to-high levels of evidence indicated that elevated levels of plasma EPA (RR: 0.88, I2 = 38.1%) and erythrocyte membrane DHA (RR: 0.94, I2 = 0.4%) were associated with a lower risk of cognitive decline. Dietary intake or long-term supplementation of omega-3 fatty acids may help reduce risk of AD or cognitive decline.

Keywords: omega-3 fatty acid, dementia, AD, cognitive decline, dietary, biomarker

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder with a high prevalence among aging populations [1]. Given the lack of effective therapeutic strategies and the high disease burden, it is imperative to identify modifiable risk factors to prevent or postpone the onset of AD. Interest has raised recently in the role of omega-3 fatty acid dietary intake and blood concentrations in the prevention of dementia. Omega-3 fatty acids are a heterogeneous group of fatty acids with a double bond at the ω−3 carbon atom, mainly including DHA (22:6n-3), EPA (20:5n-3), and ALA (18:3n-3). Omega-3 fatty acids are primarily obtained through dietary intake, and fish is the primary dietary source of EPA and DHA in humans [2]. Plant-derived ALA is the most abundant omega-3 fatty acid in the diets of people who do not regularly consume fish [3].

Omega-3 fatty acids are nootropic agents that are beneficial for brain development, anti-inflammation, and cognitive preservation [4]. DHA is an essential fatty acid that maintains brain function and integrity, and its derivatives can modulate glial cell activity and improve cognition in the early stages of AD [5]. However, evidence from observational studies and clinical trials has produced unclear conclusions regarding the efficacy of omega-3 fatty acid supplementation for prevention of cognitive decline, dementia, or AD. Prospective studies have suggested that individuals who consume higher amounts of omega-3 fatty acids are less likely to develop AD [6], and erythrocyte DHA levels are inversely associated with risk of AD and all-cause dementia [7]. Compared with cognitively healthy individuals, patients with AD have been found to have lower concentrations of omega-3 fatty acids, especially DHA, in the serum, plasma phospholipids, and erythrocyte membranes [8,9]. In contrast, randomized clinical trials have shown limited efficacy of omega-3 fatty acid supplementation in reducing cognitive decline and probable AD [10]. Further, apolipoprotein ε4 (APOE ε4) genotype might modify the association between omega-3 fatty acid supplementation and cognitive decline [11], dementia, or AD [12]. The APOE ε4 allele, the major genetic risk factor for AD, could mediate AD-associated pathology, including inducing abnormal cholesterol metabolism [13]. It remains unclear how APOE ε4 interacts with omega-3 fatty acids to affect risk of dementia and cognitive decline. A study has found an association between a higher intake of omega-3 fatty acids and slower rates of cognitive decline among APOE ε4 carriers but not among APOE ε4 noncarriers [11]. Other studies have reported opposite results, showing that omega-3 fatty acids are only beneficial for APOE ε4 noncarriers [9,14]. The underlying mechanism may involve the reduced delivery of DHA and EPA into the brain caused by APOE ε4 [15].

To assess the longitudinal relationships between the intake of omega-3 polyunsaturated fatty acids and blood biomarkers and risk of AD, dementia, or cognitive decline, we analyzed data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) and conducted a systematic review and meta-analysis of newly published studies.

Methods

ADNI cohort study

Participants

Data were derived from the ADNI cohort (http://adni.loni.usc.edu/). As a multicenter study, the ADNI is designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of AD. The studied population are nondemented adults aged 55 y to 90 y at baseline. Participants underwent standardized neuropsychological assessments, in-person interviews for detailed medical history, and cognitive evaluation at study entry and follow-up (Figure 1A). The ADNI was approved by the institutional review boards of all participating institutions, and written informed consent was obtained from all participants according to the Declaration of Helsinki.

FIGURE 1.

FIGURE 1

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Flowchart for the overall selection process and summary characteristics of included studies. (A) Flowchart of the participants included in the ADNI cohort study. (B) Overall selection process in the meta-analysis of published longitudinal studies. (C) Most studies reported cognitive decline but not dementia (n = 27) followed by dementia (n = 16) or AD (n = 14), and only a few reported MCI (n = 4) or VD (n = 2). Of all 48 studies included in systematic review, most studies reported omega-3 fatty acid dietary intake (n = 31), followed by plasma (n = 14) and erythrocyte membrane (n = 6). (D) All 31 studies included in the meta-analysis; 18 reported dietary omega-3 including DHA (n = 13), EPA (n = 9), and ALA (n = 8). AD, Alzheimer’s disease; MCI, mild cognitive impairment; VD, vascular dementia.

Supplementation and blood measurement of omega-3 fatty acids

Dietary supplement use information was collected at the initial screening visit as a part of the medication-taking questionnaire. The question was open-ended, and participants provided the information about all prescribed and over-the-counter medications as well as any oral supplement they are taking, including the name and the time from initiation of use to discontinuation. Omega-3 fatty acid supplements are defined as fish oil, omega-3 fatty acid, PUFA, DHA, EPA, or ALA. Self-reported omega-3 fatty acid supplementation information was recorded at the initial screening visit with participants and their partners. Duration of omega-3 fatty acid supplementation was calculated as the time from initiation of use to discontinuation. Participants who used omega-3 fatty acid supplements for over 1 y were defined as the “exposed group” and others as “nonexposed group.” The “exposed” subjects were further divided into “medium-term users (1 ∼ 9 y)” group and “long-term users (≥10 y).”

Plasma samples for each subject were obtained in the morning following an overnight fast. The time from collection to freezing was mostly within 2 h. Lab technicians were blinded to the clinical information of samples. Fatty acid composition was quantified using Nightingale Health’s nuclear magnetic resonance (NMR) metabolomics platform. The samples were processed following the automated standard protocol provided by Nightingale’s technology, and blood metabolites were quantified in absolute concentrations and percentages using NMR spectroscopy [16].

Ascertainment of AD

AD was diagnosed by neurologists according to brain structure scans, cognitive score, and independent living ability, based on the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association (NINCDS-ADRDA) for definite, probable, or possible AD [17].

Covariate measurements

The covariates included age (continuous variable), sex (female =1, male = 0), education (continuous variable), cognitive status (mild cognitive impairment =1, normal cognition = 0), and APOE ε4 status (“44/34/24” = 1, “33/22/23” = 0). rs7412 and rs429358 were used to define the APOE ε2/ε3/ε4 isoforms [18]. Other potential covariates were obtained from baseline medical history, including dichotomous variables (hyperlipidemia, hypertension, diabetes, stroke history, insomnia, depression, anxiety, current smoking status, coronary artery disease, alcohol intake, multivitamin, vitamin B12, and folate supplementation, anti-hypertensive drugs, and anti-diabetic drugs) and continuous variable (BMI).

Evidence evaluation via meta-analysis

Search strategy and selection criteria

We registered the protocol on PROSPERO in advance (CRD42021238393). Meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines (PRISMA) statement [19]. PubMed, EMBASE, and Cochrane Library were searched using the strategy: ((fish) OR (fish oil) OR (omega-3) OR (omega) OR (polyunsaturated fatty acid) OR (PUFA) OR (docosahexaenoic acid) OR (DHA) OR (eicosapentaenoic acid) or (EPA) OR (Alpha linolenic acid) OR (ALA)) AND ((cognitive) OR (dementia) OR (Alzheimer)) until March 17, 2022. Reference lists of articles identified through database searches were manually screened to locate additional relevant studies. The inclusion criteria were as follows: 1) the relationships of omega-3 fatty acid intake and its peripheral biomarkers with risk of AD, all-cause dementia, or cognitive decline were investigated; 2) study designs were cohort studies or nested case-control studies; 3) risk estimates or the raw data that can be used to calculate these numbers were available; 4) publication type was original article. No restriction was imposed on language. Studies were excluded if they did not meet the inclusion criteria mentioned above.

Data extraction

A pre-designed template was used to extract the data (Supplementary Table 1). For data unavailable in the article, we attempted to obtain them by contacting the corresponding authors. Literature selection and data extraction were performed by 2 experienced investigators (B-ZW and C-WD), and a third reviewer (WX) occasionally participated in the negotiation to solve any discrepancies.

Identification of AD, dementia, and cognitive decline

Cognitive decline is a common outcome of aging and may lead to dementia, and AD is the primary kind of dementia. Participants underwent cognitive assessments at baseline and during follow-up, and a decline in scores on the Mini-Mental State Examination scale was considered as cognitive decline. AD and dementia were diagnosed by the consensus of physicians according to the NINCDS-ADRDA and the Diagnostic and Statistical Manual of Mental Disorders 4th/5th Edition (DSM-IV/DSM-V), respectively.

Assessment of study quality and credibility of meta-analyses

An evolving Newcastle- Ottawa Quality Assessment Scale for observational cohort studies [20] was employed to evaluate the quality of eligible studies (Supplementary Table 2). The evidence robustness of the meta-analysis was assessed by summing scores from 5 domains: risk of bias, heterogeneity, publication bias, effect size, and imprecision. Scores were ranked in descending order; the top third was categorized into high level (H), the middle third was moderate level (M), and the bottom third was low level (L) (Supplementary Table 3). To better utilize the whole body of evidence and avoid missing important research unsuitable for meta-analysis, we developed a semiquantitative index named “index S” [21] (Supplementary Table 4).

Statistical analyses

In the ADNI, the statistical differences on baseline variables (see “Covariate measurements”) between participants who developed AD and those who were free of dementia during follow-up was compared by Pearson chi-squared test or independent samples t-test. Cox proportional hazards models with age as the time metric were used to assess the influence of omega-3 fatty acid at baseline on AD incidence. Risk estimate was expressed as hazard ratio (HR) and 95% CI. The proportional hazards assumption was checked using Schoenfeld’s global test. No variable was statistically significant, suggesting that the proportional hazards assumption was not violated (P > 0.05). To examine the potential stratification or interaction effect, stratified analyses were performed according to sex, age, APOE ε4 status, and baseline cognitive diagnosis. Sensitivity analyses were conducted by excluding those who progressed to dementia within 1 y follow-up.

As for meta-analyses, data were analyzed using the ‘metagen,’ ‘metabias,’ and ‘trimfill’ packages in R V.3.4.3 software (https://www.r-project.org). All statistical tests were 2-sided and used a significance level of P < 0.05. The pooled risk estimates were first calculated based on the comparison of the highest versus the lowest category of exposure. For studies wherein the reference group was not the lowest category, we recalculated the effect size using the method of Orsini [22]. For studies reporting odd ratios (ORs), we transformed ORs to RRs using the following algorithm: RRadjusted = ORadjusted/[(1 − P0) + (P0× ORadjusted)] where P0 indicates the incidence of the endpoint (AD, dementia, or cognitive decline) in the nonexposed group of the cohort. When P0 was not available, the incidence rate of total participants was used as a proxy [23]. The multivariable-adjusted risk estimates and 95% CIs were log-transformed and pooled using random models (DerSimonian–Laird method) [24]. Heterogeneity was examined using the I2 statistic, and the source of heterogeneity was explored via sensitivity analyses, meta-regression (if n ≥ 10), and subgroup analyses according to multiple variables, including study design, region, sex, sample size, cognitive status at baseline, age stage (late life [mean age ≥ 65 y] or midlife), follow-up duration, whether APOE ε4 status was adjusted, type of outcome, effect estimate, and quality score. Publication bias was assessed by determining the symmetry of the funnel plot by Egger’s test and enhanced-contour funnel plots after the trim-and-fill method. Dose–response meta-analyses were conducted using the inverse variance weighted least squares regression with cluster robust error variances (random effects meta-regression model) [25,26]. The midpoint of the lower and upper bounds was regarded as the dose of each category if the study only reported the range. For studies with an open-ended boundary, we multiplied or divided the reported boundary by 1.25.

Results

ADNI cohort study

Baseline characteristics of the study population

In the ADNI cohort for incident AD, a total of 1135 participants (46.2% females, aged 73.36 ± 7.22 y) were included, with a mean follow-up time of 2.81 ± 1.60 y (range, 1–6 y) (Figure 1A). Compared with participants free of dementia, those who developed AD tended to be APOE ε4 carriers, have a lower BMI, were more likely to have a history of depression, and less likely to have a history of insomnia (Table 1).

TABLE 1.

Population characteristics at baseline in ADNI cohort

Variable Total Participants free of AD Participants who developed AD P
n 1,135 828 307
Age, y, mean ± SD 73.36 ± 7.22 73.11 ± 7.26 72.02 ± 7.05 0.057
Female, % 524 (46.2%) 400 (48.3%) 124 (40.4%) 0.017
Education, y 16.16 ± 2.69 16.24 ± 2.66 15.94 ± 2.78 0.101
MCI, % 711 (62.6%) 417 (50.4%) 294 (95.8%) <0.001
APOE ε4 carriers, % 513 (45.2%) 314 (37.9%) 199 (64.8%) <0.001
Omega-3 supplementation
 Exposure (yes or no) 272 (24.0%) 213 (25.7%) 59 (19.2%) 0.023
 Medium-term exposure (1∼9 y) 204 (18.0%) 153 (18.5%) 51 (16.6%) 0.397
 long-term exposure (≥10 y) 68 (6.0%) 60 (7.2%) 8 (2.6%) 0.030
Blood markers (N-867)
 Omega-3 0.43 ± 0.12 0.43 ± 0.12 0.42 ± 0.12 0.420
 DHA 0.13 ± 0.04 0.13 ± 0.04 0.13 ± 0.04 0.692
 ALA 0.41 ± 0.06 0.41 ± 0.06 0.41 ± 0.06 0.786
Insomnia, % 82 (7.2%) 71 (8.6%) 11 (3.9%) 0.004
Depression, % 247 (21.8%) 163 (19.7%) 84 (27.4%) 0.005
Anxiety, % 76 (6.7%) 52 (6.3%) 24 (7.8%) 0.357
Hypertension, % 528 (46.5%) 383 (46.3%) 145 (47.2%) 0.770
BMI (kg/m2) 27.04 ± 4.86 27.31 ± 4.95 26.33 ± 4.54 0.002
Diabetes, % 102 (9.0%) 75 (9.1%) 27 (8.8%) 0.891
Hyperlipidemia, % 225 (19.8%) 162 (19.6%) 63 (20.5%) 0.720
Stroke, % 41 (3.6%) 22 (2.7%) 19 (6.2%) 0.005
CAD, % 92 (8.1%) 65 (7.9%) 27 (8.8%) 0.605
Current smoker, % 166 (14.6%) 122 (14.7%) 44 (14.3%) 0.865
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Abbreviations: AD, Alzheimer’s disease; ADNI, Alzheimer’s Disease Neuroimaging Initiative; MCI, mild cognitive impairment.

Association of omega-3 fatty acid supplementation use with AD risk

In the unadjusted analysis (Model 1), omega-3 fatty acid supplementation was significantly associated with a lower risk of AD (HR: 0.73, 95% CI: 0.55, 0.97; P = 0.029) compared with that of omega-3 fatty acid nonusers. Moreover, long-term users had a 64% lower AD risk (HR: 0.36, 95% CI: 0.18, 0.72; P = 0.004) compared with nonusers. The results were similar in Models 2 and 3, which included more confounders (Table 2). Separate analyses by subgroup indicated that compared with no consumption, long-term use of omega-3 dietary supplements was significantly associated with risk of incident AD for males, those of advanced age, APOE ε4 carriers, and patients with mild cognitive impairment (MCI) (Table 3). Similar results were obtained in the sensitivity analyses after removing cases diagnosed in the first year (Supplementary Table 5).

TABLE 2.

Cox proportional hazards regression analysis of omega-3 supplementation use and its blood biomarkers for AD risk in ADNI cohort

AD cases/total Model 1
 P
 Model 2
 P
 Model 3
 P
HR (95%CI) HR (95%CI) HR (95%CI)
Omega-3 supplementation
 non-exposure 248/863 1 (reference) 1 (reference) 1 (reference)
 exposure 59/272 0.73 (0.55-0.97) 0.029 0.71 (0.53-0.94) 0.018 0.72 (0.54-0.97) 0.031
 medium-term exposure 51/204 0.87 (0.64-1.18) 0.370 0.84 (0.62-1.14) 0.262 0.85 (0.62-1.16) 0.304
 long-term exposure 8/68 0.36 (0.18-0.72) 0.004 0.35 (0.17-0.71) 0.004 0.37 (0.18-0.75) 0.006
Blood markers
 omega-3 287/867 0.91 (0.52-1.61) 0.752 1.15 (0.65-2.03) 0.640 1.28 (0.71-2.30) 0.407
 DHA 287/867 0.86 (0.57-1.30) 0.485 1.05 (0.70-1.57) 0.832 1.13 (0.74-1.71) 0.571
 ALA 287/867 1.08 (0.64-1.83) 0.781 1.23 (0.74-2.05) 0.428 1.27 (0.75-2.17) 0.374
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Model 1: crude HR with no covariates adjusted;

Model 2: HR adjusted for age, sex, education, clinical diagnosis, and APOE ε4;

Model 3: HR adjusted for Model 2 plus insomnia, depression, anxiety, hypertension, diabetes mellitus, hyperlipidemia, smoking, BMI, stroke, and coronary artery disease, alcohol intake, multivitamins, vitamin B12, folate, anti-hypertensive drugs and antidiabetic drugs.

TABLE 3.

Hazard ratios with corresponding 95% CIs of the association of omega-3 supplementation use and its blood biomarkers with risk of AD according to strata of age, sex, APOE ε4 status and cognitive status in the ADNI cohort

Omega-3 supplementation
 Blood markers
Non-exposure Exposure Medium-term exposure Long-term exposure Omega-3 DHA ALA
Sex Male 1 (reference) 0.80 (0.56-1.15) 0.10 (0.68-1.46) 0.33 (0.13-0.82) 1.04 (0.50-2.18) 1.02 (0.61-1.72) 1.11 (0.57-2.17)
Female 1 (reference) 0.62 (0.38-1.02) 0.65 (0.38-1.11) 0.50 (0.16-1.61) 1.84 (0.67-5.04) 1.40 (0.67-2.92) 1.85 (0.75-4.61)
Age Midlife <65 y 1 (reference) 0.87 (0.33-2.35) 0.94 (0.35-2.53) 0.78 (0.00-∞) 0.91 (0.12-6.70) 0.79 (0.18-3.44) 4.09(0.76-22.00)
Late life ≥65 y 1 (reference) 0.69 (0.47-0.88) 0.75 (0.54-1.05) 0.35 (0.17-0.73) 1.29 (0.71-2.37) 1.15 (0.75-1.76) 1.18 (0.68-2.06)
APOE ε4 APOE ε4 (+) 1 (reference) 0.75 (0.52-1.08) 0.90 (0.61-1.32) 0.29 (0.11-0.83) 2.03 (0.98-4.23) 1.60 (0.94-2.71) 1.11 (0.58-2.14)
APOE ε4 (-) 1 (reference) 0.71 (0.44-1.14) 0.81 (0.48-1.35) 0.45 (0.16-1.25) 0.49 (0.17-1.38) 0.57 (0.28-1.18) 1.72 (0.65-4.57)
Cognitive status CN 1 (reference) 0.27 (0.03-2.36) 0.44 (0.05-3.84) 0.45 (0.00-∞) 0.10 (0.00-2.42) 0.20 (0.02-2.13) 0.44 (0.03-6.94)
MCI 1 (reference) 0.75 (0.56-1.00) 0.87 (0.63-1.18) 0.40 (0.20-0.82) 1.36 (0.75-2.48) 1.17 (0.77-1.80) 1.41 (0.82-2.43)
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A separate Cox regression model was conducted for each stratum of the covariate

Abbreviations: CN, cognitively normal; MCI, mild cognitive impairment.

Association of blood omega-3 fatty acid and its components with AD risk

Plasma omega-3 fatty acid and its components were not significantly associated with AD risk (Table 2). Similar results were obtained when performing sensitivity analyses after removing cases diagnosed in the first year. (Supplementary Table 5).

Meta-analysis

Searching results and characteristics of studies

We initially identified 18,230 articles after de-duplication. After scanning the titles and abstracts, 709 articles were considered potentially eligible. Following detailed assessments, 48 longitudinal studies met the inclusion criteria, of which 31 were included in the meta-analysis, with a total of 103,651 participants (Figure 1B). The detailed characteristics of the studies included in this meta-analysis are presented in Table 4. Most studies reported omega-3 fatty acid dietary intake (n = 31), followed by plasma (n = 14), and erythrocyte membrane (n = 6).

TABLE 4.

Characteristics of 48 studies included in the systematic review and meta-analysis

N First author, y Design, Cohort name, Country Follow-up duration (mean) Age at baseline (mean) Female (%) Participants Cases Outcome Categories Exposure measurement Study quality
1 Li 2021 RC; ADNI; Canada, Unites States 2.8y 73y 46% 11351/867 2 3071/2872 AD 1 omega-3 2 omega-3, DHA, ALA FFQ 6
2 Melo van Lent 2021 [27] PC; AgeCoDe; Germany 7y 84y 64% 1264 233 AD 2 omega-3; DHA; EPA; ALA Blood sample 7
3 Koch 2021 [28] PNCC; GEMS; Unites States 4.8y 78y 47% 1252 498/334 Dementia; AD 2 omega-3; DHA; EPA; ALA Blood sample 6.5
4 Nozaki 2021 [29] PC; JPHC; Japan 15y 73y 69% 1127 380/54 Dementia; MCI 1 PUFA; omega-3; EPA; DHA FFQ 5.5
5 Thomas 2020 [30] PC; 3C; France 174y 74y NA 1279 271 Dementia 2 EPA; DHA Blood sample 7.5
6 Jiang et al. [31] 2020 PC; SCHS; Singapore 20y 45-74y NA 16736 2397 CD 1 PUFA; omega-3; ALA FFQ 8
7 Gustafson et al. [32] 2020 PC; WHICAP; Unites States 4.9y 76y 67% 2612 380 AD 1 PUFA; omega-3; DHA; EPA FFQ 7
8 Mao 2019 [33] PC; CARDIA; Unites States 25y 25y 56% 3231 NA CD 1 omega-3; DHA; EPA CARDI questionnaire 7.5
9 Bigornia 2018 [34] PC; BPRHS; Unites States 2y 45-75y 73% 1032 151 CD 1 and 3 ALA; EPA; DHA FFQ and blood sample 6.5
10 Haution-bitker 2018 [35] PNCC; GERIOX; France 11.55m 80y 65% 1402/703 44 CD 2 and 3 omega-3; EPA; DHA; ALA Blood sample 3
11 Nooyens 2018 [36] PC; DS; Netherlands 5y 43-70y 51% 2612 NA CD 1 PUFA; omega-3; DHA; ALA; EPA FFQ 7
12 Ammann 2017 [37] PC; WHIMS-ECHO; Unites States 9.85y 70y 100% 6706 587/671 Dementia; MCI 3 omega-3; DHA; EPA Blood sample 7.5
13 Yamagishi 2017 [38] PNCC; CIRCS; Japan 12.5y 64y 66% 7586 315 Dementia 2 DHA; EPA; ALA Blood sample (serum) 7.5
14 Vanderest 2016 [39] PC; MAP; Unites States 4.9y 81y 75% 915 NA CD 1 omega3; ALA FFQ 7
15 Otsuka 2014 [40] PC; NILS-LSA; Japan 10.2y 67y 46% 430 36 CD 2 DHA; EPA Blood sample 7
16 Bowman 2013 [41] PC; OBAS; Unites States 3.9y 86y 62% 86 NA CD 2 omega-3 Blood sample 6.5
17 Titova 2013 [42] PC; PIVUS; Sweden 5y 70y 48% 252 NA CD 1 omega-3 7-d food protocol 6.5
18 Ammann 2013 [43] PC; WHISCA; Unites States 5.95y 73y 100% 2157 NA CD 3 omega-3 Blood sample 6
19 Okereke 2012 [44] PC; WHS; Unites States 44y 66y 100% 6183 NA CD 1 PUFA FFQ 5
20 Ronnemaa 2012 [45] PC; ULSAM; Sweden 354y 50y 0% 2009 213/91 Dementia; AD 2 DHA; EPA; ALA Blood sample 6.5
21 Lopez 2011 [46] PC; RBS; Unites States 3y 80y 44% 2421/2662 42/30 Dementia; AD 1 and 2 DHA FFQ 6
22 Kesse-guyot 2011 [47] PC; SUVIMAX 2; France 13y 51y 46% 3294 NA CD 1 omega-3; DHA; EPA Repeated 24-h dietary records 6
23 Gao 2011 [48] PC; SLAS; Singapore 1.55y 66y 66% 1475 NA CD 1 omega-3 A self-reported single question 5.5
24 Samieri 2011 [49] PC; 3C; France 74y 74y 61% 1228 NA CD 2 DHA; EPA Blood sample 7.5
25 Vercambre 2010 [50] PC; WACS; Unites States 5.44y 72y 100% 2551 NA CD 1 PUFA Willett FFQ 5
26 Vercambre 2009 [51] PC; E3N; France 134y 78y 100% 4809 598 CD 1 PUFA; omega-3; ALA FFQ 5.5
27 Devore 2009 [52] PC; RS; Netherlands 9.6y 68y 59% 5395 465 Dementia; 1 omega-3; DHA; EPA SFFQ 7.5
28 Devore 2009(2) [53] PC; NHS; Unites States 4.2y 74y 100% 1486 NA CD 1 PUFA Willett FFQ 6
29 Kroger 2009 [54] PC; CSHA; Canada 4.95y 81y 66% 663 149/105 Dementia; AD 3 omega-3; DHA; EPA Blood sample 7
30 Vanderest 2009 [55] PC; NAS; Unites States 6y 68y 0% 1025 NA CD 1 omega-3; Willett FFQ 4
31 Samieri 2008 [56] PC; 3C; France 4y4 74y 62% 1214 65 Dementia 2 PUFA; omega-3; DHA; EPA;ALA Blood sample 6.5
32 Eskelinen 2008 [57] PC; CAIDE; Finland 21y 50y 62% 1449 82 MCI 1 PUFA FFQ 6.5
33 Velho 2008 [58] PC; NA; Portugal 8.5m 70y 71% 187 NA CD 1 omega-3 3- d food dietary record 5
34 Whalley 2008 [59] PC; SCRE; Scotland, United Kingdom 44y 64y 60% 120 NA CD 3 omega-3; DHA; EPA Blood sample 5
35 Barberger-Gateau 2007 [60] PC; 3C; France 3.5y ≥65y NA 8085 281/183 Dementia; AD 1 omega-3 FFQ 7
36 Beydoun et al. [14] 2007 PC; ARIC; Unites States 6y 50-65y 55% 78141/22512 486/140 CD 1,2 omega-3; ALA Blood sample 5.5
37 Vangelder 2007 [61] PC; ZES ;Netherlands 5y 70-89y 51% 210 NA CD 1 omega-3 Cross-check dietary history method 6
38 Dullemeijer 2007 [62] PC;FACIT; Netherlands 3y 50-70y 0% 404 NA CD 2 PUFA; omega-3; DHA; EPA; ALA Blood sample 6.5
39 Solfrizzi 2006(2) [63] PC; ILSA; Italy 2.65y 65-84y 28% 278 18 MCI 1 PUFA FFQ 5.5
40 Schaefer 2006 [64] PC; FHS; Unites States 9.1y 76y 45% 4881/8992 79 AD 1 and 2 DHA FFQ 7
41 Laitinen 2006 [65] PC; CAIDE; Finland 21y 50y 64% 1341 117/76 Dementia; AD 1 PUFA FFQ 8.5
42 Solfrizzi 2006 [66] PC; ILSA; Italy 8.55y 73y 62% 278 NA CD 1PUFA FFQ 7
43 Morris 2005 [67] PC; CHAP; Unites States 64y 74y 45% 3718 NA CD 1 omega-3; DHA; EPA; ALA FFQ 6.5
44 Morris 2003 [68] PC; CHAP; Unites States 3.9y 65-94y 62% 815 131 AD 1 omega-3; DHA; EPA; ALA FFQ 6
45 Heude 2003 [69] PC; EVA; France 4y 63-74y 61% 246 27 CD 3 PUFA; omega-3; DHA; EPA Blood sample 5
46 Laurin 2003 [70] PC; CSHA; Canada 5y 77y 58% 174 11 Dementia 2 PUFA; omega-3; DHA; EPA Blood sample 7.5
47 Engelhart 2002 [71] PC; RS;Netherlands 6.0y 68y 66% 5395 197/146 /29 Dementia; AD; VD 1 PUFA; omega-3 FFQ 6.5
48 Kalmijn 1997 [72] PC; ZES; Netherlands 3y 69-89y 59% 342 51 CD 1PUFA; omega-3; DHA; EPA Cross-check dietary history method 4.5
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Abbreviations: AD, Alzheimer’s disease; ADNI, Alzheimer’s Disease Neuroimaging Initiative; AgeCoDe, German Study on Aging, Cognition, and Dementia; BPRHS, Boston Puerto Rican Health Study; CAIDE, Cardiovascular risk factors, Aging and Dementia study; CARDIA, Coronary Artery Risk Development in Young Adults; CD, cognitive decline; CIRCS, Circulatory Risk in Communities Study; CHAP, Chicago Health and Aging Project; CHCS, Cardiovascular Health Cognition Study; CHNS, China Health and Nutrition Survey; CLHLS, Chinese Longitudinal Health Longevity Study; CSHA, Canadian Study of Health and Aging; DS, Doetinchem Study; EVA, Etude du Vieillissement Artériel Study; E3N, Etude Epideámiologique de Femmes de la Mutuelle Geáneárale de l’Education Nationale study; FACIT, Folic Acid and Carotid Intima-media Thickness Trial; FHS, Framingham Heart Study; GEMS, Ginkgo Evaluation of Memory Study; ILSA, Italian Longitudinal Study on Aging; JPHC, Japan Public Health Center-based Prospective Study; MAP, Rush Memory and Aging Project; MCI, mild cognitive impairment; NA, not available; NAS, Normative Aging Study; NILS-LSA, National Institute for Longevity Sciences-Longitudinal Study for Aging; NHS, Nurses’ Health Study; OBAS, Oregon Brain Aging Study; Omega-3, omega-3 polyunsaturated fatty acid; PC, prospective cohort; PIVUS, Prospective Investigation of the Vasculature in Uppsala Seniors Cohort; PNCC, Prospective nested case-control study; PUFA, polyunsaturated fatty acid; RBS, Rancho Bernardo Study; RC, retrospective cohort; RS, Rotterdam Study; SCHS, Singapore Chinese Health Study; SCRE, Scottish Council for Research in Education; SLAS, Singapore Longitudinal Aging Study; SUVIMAX, Supplementation with Antioxidant Vitamins and Minerals; ULSAM, Uppsala Longitudinal Study of Adult Men cohort; VD, vascular dementia; WACS, Women’s Antioxidant Cardiovascular Study; WHICAP, Washington Heights-Hamilton Heights-Inwood Columbia Aging Project; WHISCA, Women's Health Initiative Study of Cognitive Aging; WHIMS-ECHO, Woman's Health Initiative Memory Study - Epidemiology of Cognitive Health Outcomes; WHS, Women's Health Study; ZES, Zutphen Elderly Study; 3C, Three-City Study.

1

dietary

2

plasma/serum

3

erythrocyte

4

max age

5

median age

Association of dietary intake of omega-3 fatty acid and its components with cognitive decline

A meta-analysis of 18 studies with 46,548 participants revealed a significant protective effect of dietary omega-3 fatty acid intake on lower risk of cognitive decline (RR: 0.91, 95% CI: 0.82, 1.00; I2 = 60.0%, Level M) (Figure 2). Meta-regression analysis revealed that no factor could explain the source of heterogeneity. The significantly protective effect was observed in the subgroup adjusting for APOE ε4 status (n = 8, RR: 0.83, 95% CI: 0.71, 0.97; I2 = 65.0%) (Supplementary Table 6). In addition, the dose–response analysis (27,161 participants and 3797 cases) revealed that risk of cognitive decline was reduced when the intake of omega-3 fatty acids exceeded 1.0 g/d. However, the decrease in risk was not significantly linear with the increase in dietary intake (Figure 3A).

FIGURE 2.

FIGURE 2

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Association of omega-3 and its peripheral biomarkers with risk of cognitive decline. Squares represent overall estimate effects and solid lines represent 95% CIs (Supplementary Table 6). The blue fan represents proportion of heterogeneity among studies. Green/red dots represent the number of studies/participants included, respectively. D-omega-3, dietary intake of omega-3 fatty acid; E-omega-3, erythrocyte omega-3 fatty acid; P-omega-3, plasma omega-3 fatty acid.

FIGURE 3.

FIGURE 3

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Dose–response relationships between dietary omega-3 and cognitive decline. The dose–response analyses revealed significantly linear associations between dietary intake of DHA (B) or EPA (C) and risk of cognitive decline. An increment of 0.1 g/d of DHA or EPA intake was associated with an 8.0% (Plinear = 0.0005) or 9.9% (Plinear = 0.0004) lower risk of cognitive decline, respectively. The dose–response analyses revealed a nonsignificant relationship between dietary intake of omega-3 (A), ALA (D) and risk of cognitive decline. AD, Alzheimer’s disease; RR, relative risk.

Regarding its components, the pooled estimate for dietary DHA from 13 studies was 0.82 (95% CI: 0.72, 0.93; I2 = 63.6%, Level H) (Figure 2). Dietary intake of DHA was associated with a 27% decreased risk of dementia and a 24% decreased risk of AD, whereas dietary intake of ALA (Level H) and EPA (Level L) did not have a significant protective effect on cognitive decline (Supplementary Figures 1–3). The dose–response analysis revealed that an increment of 0.1 g/d of DHA or EPA intake was associated with an 8.0% (Plinear = 0.0005) or 9.9% (Plinear = 0.0004) lower risk of cognitive decline, respectively (Figure 3B, C). No publication bias was identified.

Association of plasma omega-3 fatty acid and its components with cognitive decline

No significant association was found between higher levels of plasma DHA and a lower risk of cognitive decline (RR: 0.88, 95% CI: 0.76, 1.03; I2 = 63.6%, Level L), with publication bias (Egger’s P = 0.007, corrected RR: 0.99, 95% CI: 0.85, 1.14; I2 = 69%) (Figure 2). Meta-regression analysis indicated that the mean age could partly account for the heterogeneity (P = 0.02, tau2 = 0.002). Risk of cognitive decline in older participants (with an average baseline age ≥ 65 y) was significantly reduced by 23%, whereas in younger participants, no significant association was indicated for plasma levels of DHA (Supplementary Table 6). Higher levels of plasma EPA were significantly associated with lower risk of cognitive decline (RR: 0.88, 95% CI: 0.78, 0.995; I2 = 38.1%, Level M), and dementia (RR: 0.84, 95% CI: 0.73, 0.96; I2 = 0.0%, Level M). Plasma levels of omega-3 fatty acid (Level L) and ALA (Level L) did not have a significant protective effect on cognitive decline (Figure 2 and Supplementary Figures 4 and 5).

Association of erythrocyte membrane omega-3 fatty acid and its components with cognitive decline

Five longitudinal studies involving 14,940 participants explored the association between omega-3 fatty acid levels in erythrocyte membranes and risk of cognitive decline. No significant protective effect was revealed (RR: 0.96, 95% CI: 0.90, 1.02; I2 = 34.5%, Level M). However, higher levels of erythrocyte membrane DHA (RR: 0.94, 95% CI: 0.89, 0.98; I2 = 0.4%, Level H) and EPA (RR: 0.95, 95% CI: 0.89, 1.00; I2 = 0%, Level H) were associated with a lower risk of cognitive decline (Figure 2 and Supplementary Figures 6 and 7).

Summary of evidence credibility

The larger area of the pentagonal graph represents better evidence credibility, whereas Figures 4A–C represent omega-3 fatty acids in 3 states: dietary, plasma, and erythrocytes. The evidence credibility for dietary intake and erythrocytes was higher than that of plasma (Figure 4). A higher Index Sdifference indicates a stronger degree of consistency between the results of meta-analyses and the results of each individual cohort study included. Thus, the consistency of the results related to erythrocytes was greater than that of dietary intake and plasma. Overall, the evidence credibility, ranked from highest to lowest, was as follows: erythrocytes, diet, and plasma (Supplementary Table 4).

FIGURE 4.

FIGURE 4

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Evidence rating results. The credibility of each meta-analysis result was categorized into 3 levels: ‘High (H)’, ‘Moderate (M)’, and ‘Low (L)’ by summing the scores of 5 domains: risk of bias, heterogeneity, publication bias, effect size, and imprecision. Scores in each domain ranged from 0 to 10, and a score of 50 represents the highest level of evidence. (A) dietary; (B) plasma; (C) erythrocyte.

Discussion

In the present study, we found that supplemental omega-3 fatty acid use was significantly associated with a lower risk of AD, with a potential moderating effect by APOE ε4. Our meta-analysis findings strengthened the possible association between dietary omega-3 fatty acid intake and its peripheral biomarkers with AD, dementia, or cognitive decline. Compared with previous studies [[73], [74], [75]] (Supplementary Table 7), we included 27 new cohorts and provided the most comprehensive evidence of the relationship of omega-3 fatty acids and dementia.

APOE ε4 status may influence the association between omega-3 fatty acids and AD. APOE ε4 is the strongest genetic risk factor for AD [76]. The ADNI cohort revealed an inverse association between omega-3 fatty acid dietary supplements and AD only among APOE ε4 carriers, which is consistent with our previous finding [12]. Consistently, several studies concluded that omega-3 fatty acid supplementation could attenuate the effect of APOE ε4 on AD pathologic changes and that such protective effects existed in APOE ε4 carriers only [11,77]. However, plasma DHA levels showed few changes after omega-3 fatty acid supplementation among APOE ε4 carriers [78,79]. It has also been proposed that APOE ε4 carriers are more likely to exhibit blood–brain barrier dysfunction, which can impair DHA delivery to the brain. Thus, it is questionable whether APOE ε4 carriers can gain benefits from supplementing with omega-3 fatty acids. A compensatory mechanism hypothesis might help explain the dispute, such that DHA utilization and metabolic demands are increased in APOE ε4 carriers. Consistent with the hypothesis, a positron emission tomography imaging study discovered a higher increase in DHA incorporation in several brain regions in APOE ε4 carriers as compared to noncarriers [80]. Future studies should focus on populations with high genetic susceptibility (e.g., APOE ε4 genotype) to test the efficacy of omega-3 fatty acid supplementation.

Our findings support the hypothesis that the efficacy of omega-3 fatty acid supplementation is dose-dependent. We found that omega-3 fatty acid supplementation was significantly associated with a decreased risk of AD, particularly among long-term users. Regular intake of omega-3 fatty acids may help maintain stable blood concentrations, which can benefit the prevention of dementia. Although we did not observe a significant linear relationship between dietary omega-3 fatty acid intake and risk of cognitive decline, risk of cognitive decline decreased when the intake of omega-3 fatty acids exceeded 1.0 g/d. For this reason, we propose that 1.0 g/d may be the threshold dosage of omega-3 fatty acids for the prevention of cognitive decline. Appropriate dosing of omega-3 fatty acids is beneficial not only for preventative purposes in individuals with healthy cognition but also for the treatment of patients with cognitive impairment. Previous randomized controlled trials discussed the appropriate dosage of omega-3 fatty acids and found that high doses (0.9–1.8 g/d) of DHA/EPA intake improved cognitive function [[81], [82], [83]], whereas low doses (0.3–0.7 g/d) failed to exert benefits [84,85]. Since the optimal doses for the prevention and treatment are not well established, future studies should explore the efficacious dose range. Furthermore, the recommended dose may differ for specific populations, such as APOE ε4 carriers.

This evidence-based summary revealed the significant role of erythrocyte DHA in predicting risk of cognitive decline and a suggestive role of plasma and erythrocyte EPA (high-level evidence). Several mechanisms may explain the importance of omega-3 fatty acid biomarkers in predicting dementia. First, DHA is commonly considered beneficial for maintaining the integrity of brain neurons and expressing neuroprotection by inhibiting tau phosphorylation. Second, DHA could target AD-specific pathology pathways adversely affected in APOE ε4 carriers, including microglia and inflammatory pathways, astrocytes and lipid metabolism, and pericytes and blood–brain barrier integrity [86]. Third, although EPA is rarely found in the brain, it is important to balance inflammation and immune function associated with AD pathogenesis. Based on our moderate-to-high evidence levels, it is reasonable to conclude that blood tests for EPA and DHA concentration may be useful for AD risk evaluation. Specifically, erythrocyte membrane concentration is a relatively more stable indicator for clinical research. Erythrocyte concentrations may reflect with higher precision dietary intake over a longer term (estimated range of the past 60 to 90 d) than plasma concentrations (estimated range of the past 7 to 14 d). Future studies should further investigate the different biological effects of EPA and DHA so that the assessment of their concentrations via regular blood tests in high-risk populations may be useful for early risk detection and reduction of AD.

Future cohort studies should be refined as follows: 1) baseline measures for omega-3 fatty acids should include the dosage of daily intake and more detailed supplement information, 2) baseline evaluation of population characteristics should include certain genetic factors (e.g., APOE ε4 genotype), and cognitive level (e.g., cognitively intact/nondemented/MCI and preclinical dementia) should be thoroughly screened using objective rating scales rather than self-reported questionnaire; 3) special attention should be paid to the interaction of omega-3 fatty acids with other kinds of fatty acids because balanced blood levels of omega-3 fatty acids and other fatty acids are necessary for favorable cognitive outcomes. Some implications for practical use also apply as follows: 1) maintaining an adequate intake of omega-3 fatty acids provides a tool for the potential prevention of dementia, especially in APOE ε4 carriers; 2) particular attention should be paid to the regular examination of erythrocyte DHA in populations who are at increased risk of dementia, either based on the APOE ε4 genotype or other risk factors.

However, potential limitations of this study must be considered. First, although we adjusted for several relevant potential confounders, residual confounding from unmeasured confounders (such as dietary intake and physical activity) remains an issue. Second, the total duration of supplementation but not the accurate dose was used in the ADNI analyses, which might introduce certain risk of measurement bias. According to previous publications, the omega-3 supplement dose varied slightly from 0.6 to 1.3 g/d for the general population [31,32]. Third, all cohorts assessed omega-3 fatty acid exposure only at baseline, which may have resulted in misclassifications as the actual intake amount may change over time. Fourth, most cohort studies included in the meta-analysis assessed omega-3 fatty acid intake using FFQ, which are designed to measure the frequency of intake rather than exposure time, which was not verified in the meta-analysis. Fifth, due to too little data in the included studies, the associations between dementia subtypes and the role of omega-3 fatty acids in different APOE ε4 groups have not been thoroughly explored.

In conclusion, our findings suggest that 1) long-term omega-3 fatty acid supplementation may reduce risk of AD; 2) dietary omega-3 fatty acid intake, especially DHA, may lower risk of dementia or cognitive decline; and 3) peripheral biomarkers of omega-3 fatty acids may serve as predictors of cognitive decline. However, further investigation is needed to understand the gene–environment interactions involved in the intake of omega-3 fatty acids.

Funding

This study was supported by grants from the National Natural Science Foundation of China (82001136) and the Tai-Shan Scholar Project.

Acknowledgments

The authors’ responsibilities were as follows – WX: conceptualization and design of the study, revision of the manuscript; B-ZW: analysis of published longitudinal data, drafting and revision of the manuscript, and figure preparation; LL: analysis of ADNI cohort data, drafting and revision of the manuscript, and figure preparation; C-WD and C-CT: revision of the manuscript; and all authors: read and approved the final manuscript. The authors thank contributors, including the staff at Alzheimer’s Disease Centers who collected samples used in this study, patients, and their families whose help and participation made this work possible. Data collection and sharing for this project were funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). The ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Author disclosures

The authors report no conflicts of interest.

Data availability

All data are available upon reasonable request or can be obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu).

Footnotes

☆

The data used in preparation for this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-ontent/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajcnut.2023.04.001.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Multimedia component1
mmc1.pdf (832.7KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Multimedia component1
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Data Availability Statement

All data are available upon reasonable request or can be obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu).

Articles from The American Journal of Clinical Nutrition are provided here courtesy of American Society for Nutrition

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