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

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% (P_linear < 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: AD; biomarker; cognitive decline; dementia; dietary; omega-3 fatty acid.

FIGURE 1

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.

FIGURE 2

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

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% (P_linear = 0.0005) or 9.9% (P_linear = 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.

FIGURE 4

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.