Circulating polyunsaturated fatty acids, fish oil supplementation, and risk of incident dementia: a prospective cohort study of 440,750 participants

Abstract

Cohort studies report inconsistent associations between omega-3 polyunsaturated fatty acids (n-3 PUFA) or fish oil and dementia risk. Furthermore, evidence relating omega-6 polyunsaturated fatty acids (n-6 PUFA) with dementia is scarce. Here, we included 440,750 dementia-free participants from UK Biobank to comprehensively investigate the associations between plasma levels of different types of PUFA, fish oil supplementation, and dementia risk. During a median follow-up of 9.25 years, 7768 incident dementia events occurred. Higher plasma levels of five PUFA measures showed consistent associations with lower dementia risk (hazard ratios [95% confidence intervals] for per standard deviation increment of plasma concentrations 0.85 [0.81-0.89] for total PUFAs; 0.90 [0.86-0.95] for omega-3 PUFAs; 0.92 [0.87-0.96] for docosahexaenoic acid (DHA); 0.86 [0.82-0.90] for omega-6 PUFAs; 0.86 [0.82-0.90] for linoleic acid (LA); all p < 0.001). Compared with non-users, fish oil supplement users had a 7% decreased risk of developing all-cause dementia (0.93 [0.89-0.97], p = 0.002), and the relationship was partially mediated by plasma n-3 PUFA levels (omega-3 PUFAs: proportion of mediation = 57.99%; DHA: proportion of mediation = 56.95%). Furthermore, we observed significant associations of plasma n-3 PUFA levels and fish oil supplementation with peripheral immune markers that were related to dementia risk, as well as the positive associations of plasma PUFA levels with brain gray matter volumes and white matter microstructural integrity, suggesting they may affect dementia risk by affecting peripheral immunity and brain structure. Taken together, higher plasma PUFA levels and fish oil supplementation were associated with lower risk of incident dementia. This study may support the value of interventions to target PUFAs (specifically n-3 PUFAs) to prevent dementia.

Keywords: Dementia; Fish oil; Omega-3; Omega-6; Polyunsaturated fatty acids; UK Biobank.

Fig. 1

Flow chart of study design. PUFA, polyunsaturated fatty acid

Fig. 2

Associations of plasma PUFA levels and fish oil supplementation with dementia risk. Plasma PUFA concentrations and proportions were standardized to Z values. Results were adjusted for age, sex, education, and APOE ε4 status (model 1). For plasma PUFA proportions, results were further adjusted for absolute concentration of total fatty acids. PUFA, polyunsaturated fatty acids; CI, confidence interval

Fig. 3

Mediation analysis of the relationship between fish oil supplementation and dementia. The relationship between fish oil supplementation and dementia was partially mediated by plasma concentrations of omega-3 PUFAs, docosahexaenoic acid, total PUFAs, and omega-6 PUFAs. Results were adjusted for age, sex, education, and APOE ε4 status. PUFA, polyunsaturated fatty acids; IE, indirect effect

Fig. 4

Associations between plasma PUFA levels and brain structure. A The volumes of cortical and subcortical regions were positively correlated with plasma proportions of total PUFAs, omega-6 PUFAs. and linoleic acid. B Top panel, the heatmap shows the Bonferroni-corrected p values for the associations between plasma PUFA levels and FA values of white matter tracts. Bottom panel, the heatmap shows the Bonferroni-corrected p values for the associations between plasma PUFA levels and MD values of white matter tracts. PUFA, polyunsaturated fatty acids; FA, fractional anisotropy; MD, mean diffusivity