Effects of Peroral Omega-3 Fatty Acid Supplementation on Cerebrospinal Fluid Biomarkers in Patients with Alzheimer's Disease: A Randomized Controlled Trial-The OmegAD Study.

BACKGROUND: Studies have suggested a connection between a decrease in the levels of polyunsaturated fatty acids (PUFAs) and Alzheimer's disease (AD). We aimed to assess the effect of supplementation with omega-3 fatty acids (n-3 FAs) on biomarkers analyzed in the cerebrospinal fluid (CSF) of patients diagnosed with AD. OBJECTIVE: To investigate the effects of daily supplementation with 2.3 g of PUFAs in AD patients on the biomarkers in CSF described below. We also explored the possible correlation between these biomarkers and the performance in the cognitive test Mini-Mental State Examination (MMSE). METHODS: Thirty-three patients diagnosed with AD were randomized to either treatment with a daily intake of 2.3 g of n-3 FAs (n  =  18) or placebo (n  =  15). CSF samples were collected at baseline and after six months of treatment, and the following biomarkers were analyzed: Aß 38, Aß 40, Aß 42, t-tau, p-tau, neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), soluble IL-1 receptor type II (sIL-1RII), and IL-6. RESULTS: There were no significant differences between the groups concerning the level of the different biomarkers in the CSF at baseline. Within the treatment group, there was a small but significant increase in both YKL-40 (p = 0.04) and NfL (p = 0.03), while the other CSF biomarkers remained stable. CONCLUSION: Supplementation with n-3 FAs had a statistically significant effect on NfL and YKL-40, resulting in an increase of both biomarkers, indicating a possible increase of inflammatory response and axonal damage. This increase in biomarkers did not correlate with MMSE score.

Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer's Disease: The OmegAD Study.

BACKGROUND: Trials of supplementation with omega-3 fatty acids (ω3-FAs) in patients with mild cognitive impairment or Alzheimer's disease (AD) have produced inconsistent effects on cognitive decline. There is evidence of an interaction between B vitamin status and ω3-FAs in relation to brain atrophy and cognitive decline. OBJECTIVE: We investigated whether baseline levels of plasma total homocysteine (tHcy), a marker of B vitamin status, modify the effects of ω3-FAs supplementation on cognitive performance in moderate AD. METHODS: This post hoc analysis of the OmegAD trial included 171 community-based patients with AD (MMSE≥15): 88 patients received daily doses of 1.7 g docosahexaenoic acid and 0.6 g eicosapentaenoic acid for 6 months. Treatment outcome on cognition was analyzed according to baseline levels of tHcy using a general linear model and ANCOVA. RESULTS: We found significant interactions between ω3-FA supplementation and tHcy on cognition and clinical stage assessed by MMSE (p = 0.040), global CDR (p = 0.059), and CDRsob (p = 0.023), but not on ADAS-cog (p = 0.649). In patients with tHcy levels <11.7µmol/L, ω3-FA supplementation improved cognitive performance as measured by MMSE (+7.1%, 95% CI: 0.59 to 13.7%, p = 0.033) and clinical status as measured by CDRsob (-22.3%, 95% CI: -5.8 to -38.7%, p = 0.009) compared with placebo. CONCLUSION: The effect of ω3-FA supplementation on MMSE and CDR appears to be influenced by baseline tHcy, suggesting that adequate B vitamin status is required to obtain beneficial effects of ω3-FA on cognition.

Does Fatty Acid Composition in Subcutaneous Adipose Tissue Differ between Patients with Alzheimer's Disease and Cohabiting Proxies?

Low tissue levels of the major marine ω3 fatty acids (FAs) DHA and EPA are found in Alzheimer's disease (AD). We investigated if healthy proxies to AD patients have higher levels of these ω3 FAs. We observed lower levels of EPA and DHA in subcutaneous adipose tissue biopsies from 64 AD patients compared with 16 cognitively healthy proxies. No significant difference was observed when pairwise comparisons were made between a subset of 16 AD patients and their co-habiting proxies. Larger studies are needed to replicate these findings and to determine if they could depend on FA intake or differences in metabolism.

DHA-rich n-3 fatty acid supplementation decreases DNA methylation in blood leukocytes: the OmegAD study.

Background: Dietary fish oils, rich in long-chain n-3 (ω-3) fatty acids (FAs) [e.g., docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3)], modulate inflammatory reactions through various mechanisms, including gene expression, which is measured as messenger RNA concentration. However, the effects of long-term treatment of humans with DHA and EPA on various epigenetic factors-such as DNA methylation, which controls messenger RNA generation-are poorly described.Objective: We wanted to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global DNA methylation of peripheral blood leukocytes (PBLs) and the relation to plasma EPA and DHA concentrations in Alzheimer disease (AD) patients.Design: In the present study, DNA methylation in four 5'-cytosine-phosphate-guanine-3' (CpG) sites of long interspersed nuclear element-1 repetitive sequences was assessed in a group of 63 patients (30 given the n-3 FA preparation and 33 given placebo) as an estimation of the global DNA methylation in blood cells. Patients originated from the randomized, double-blind, placebo-controlled OmegAD study, in which 174 AD patients received either 1.7 g DHA and 0.6 g EPA (the n-3 FA group) or placebo daily for 6 mo.Results: At 6 mo, the n-3 FA group displayed marked increases in DHA and EPA plasma concentrations (2.6- and 3.5-fold), as well as decreased methylation in 2 out of 4 CpG sites (P < 0.05 for all), respectively. This hypomethylation in CpG2 and CpG4 sites showed a reverse correlation to changes in plasma EPA concentration (r = -0.25, P = 0.045; and r = -0.26, P = 0.041, respectively), but not to changes in plasma DHA concentration, and were not related to apolipoprotein E-4 allele frequency.Conclusion: Supplementation with n-3 FA for 6 mo was associated with global DNA hypomethylation in PBLs. Our data may be of importance in measuring various effects of marine oils, including gene expression, in patients with AD and in other patients taking n-3 FA supplements. This trial was registered at clinicaltrials.gov as NCT00211159.

Plasma Fatty Acid Profiles in Relation to Cognition and Gender in Alzheimer's Disease Patients During Oral Omega-3 Fatty Acid Supplementation: The OmegAD Study.

BACKGROUND: ω3 fatty acids (ω3 FAs) may slow the rate of decline in cognitive performance in mild forms of cognitive impairment and Alzheimer's disease (AD). However, the relationship between changes of plasma ω3 FA levels and cognitive performance, as well as effects of gender, are poorly known. OBJECTIVE: To study the effect of 6-month administration of DHA-rich ω3 FA supplementation on plasma FA profiles in patients with mild to moderate AD in relation to cognitive performance and gender. This investigation is part of the OmegAD Study. METHODS: 174 AD patients (74 ± 9 years) were randomized to a daily intake of 2.3 g ω3 FA or placebo for 6 months; subsequently all received the ω3 FA preparation for the next 6 months. Baseline as well as changes in plasma levels of the main ω3 FAs in 165 patients, while receiving ω3 FA supplementation for 6 months, were analyzed for association to cognitive performance (assessed by ADAS-cog and MMSE scores) as well as to gender. RESULTS: Preservation of cognitive functioning, assessed by ADAS-cog or its sub-items (but not MMSE) scores, was significantly associated to increasing plasma ω3 FA levels over time. Thus, the higher ω3 FA plasma levels rose, the lower was the rate of cognitive deterioration. This effect was not related to gender; since although females displayed higher ω3 FA plasma levels than did males after 6 months of supplementation, this difference disappeared when adjusted for body weight. CONCLUSIONS: Since our study suggests dose-response relationships between plasma levels of ω3 FA and preservation of cognition, future ω3 FA trials in patients with mild AD should consider exploring graded (and body weight adjusted) doses of ω3 FA.

Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells: the OmegAD study.

Specialized proresolving mediators (SPMs) induce resolution of inflammation. SPMs are derivatives of n-3 and n-6 PUFAs and may mediate their beneficial effects. It is unknown whether supplementation with PUFAs influences the production of SPMs. Alzheimer's disease (AD) is associated with brain inflammation and reduced levels of SPMs. The OmegAD study is a randomized, double-blind, and placebo-controlled clinical trial on AD patients, in which placebo or a supplement of 1.7 g DHA and 0.6 g EPA was taken daily for 6 months. Plasma levels of arachidonic acid decreased, and DHA and EPA levels increased after 6 months of n-3 FA treatment. Peripheral blood mononuclear cells (PBMCs) were obtained before and after the trial. Analysis of the culture medium of PBMCs incubated with amyloid-ß 1-40 showed unchanged levels of the SPMs lipoxin A4 and resolvin D1 in the group supplemented with n-3 FAs, whereas a decrease was seen in the placebo group. The changes in SPMs showed correspondence to cognitive changes. Changes in the levels of SPMs were positively correlated to changes in transthyretin. We conclude that supplementation with n-3 PUFAs for 6 months prevented a reduction in SPMs released from PBMCs of AD patients, which was associated with changes in cognitive function.

Effects of supplementation with omega-3 fatty acids on oxidative stress and inflammation in patients with Alzheimer's disease: the OmegAD study.

BACKGROUND: Oxidative stress and inflammation are two key mechanisms suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Omega-3 fatty acids (ω-3 FAs) found in fish and fish oil have several biological properties that may be beneficial in AD. However, they may also auto-oxidize and induce in vivo lipid peroxidation. OBJECTIVE: The objective of this study was to evaluate systemic oxidative stress and inflammatory biomarkers following oral supplementation of dietary ω-3 FA. METHODS: Forty patients with moderate AD were randomized to receive 1.7 g DHA (22:6) and 0.6 g EPA (20:5) or placebo for 6 months. Urinary samples were collected before and after supplementation. The levels of the major F2-isoprostane, 8-iso-PGF2α, a consistent in vivo biomarker of oxidative stress, and 15-keto-dihydro-PGF2α, a major metabolite of PGF2α and biomarker of inflammatory response, were measured. RESULTS: F2-isoprostane in urine increased in the placebo group after 6 months, but there was no clear difference in treatment effect between supplemented and non-supplemented patients on the urinary levels of F2-isoprostanes and 15-keto-dihydro-PGF2α. At baseline, the levels of 15-keto-dihydro-PGF2α showed negative correlative relationships to ω-3 FAs, and a positive correlation to linoleic acid. 8-iso-PGF2α correlated negatively to the ω-6 FA arachidonic acid. CONCLUSION: The findings indicate that supplementation of ω-3 FAs to patients with AD for 6 months does not have a clear effect on free radical-mediated formation of F2-isoprostane or cyclooxygenase-mediated formation of prostaglandin F2α. The correlative relationships to FAs indicate a potential role of FAs in immunoregulation.

Omega-3 fatty acids enhance phagocytosis of Alzheimer's disease-related amyloid-ß42 by human microglia and decrease inflammatory markers.

The use of supplements with omega-3 (ω3) fatty acids (FAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is widespread due to proposed beneficial effects on the nervous and cardiovascular systems. Many effects of ω3 FAs are believed to be caused by down-regulation and resolution of inflammation. Alzheimer's disease (AD) is associated with inflammation mediated by microglia and astrocytes, and ω3 FAs have been proposed as potential treatments for AD. The focus of the present study is on the effects of DHA and EPA on microglial phagocytosis of the AD pathogen amyloid-ß (Aß), on secreted and cellular markers of immune activity, and on production of brain-derived neurotrophic factor (BDNF). Human CHME3 microglial cells were exposed to DHA or EPA, with or without the presence of Aß42. Phagocytosis of Aß42 was analyzed by flow cytometry in conjunction with immunocytochemistry using antibodies to cellular proteins. Secreted proteins were analyzed by ELISA. Both DHA and EPA were found to stimulate microglial phagocytosis of Aß42. Phagocytosis of Aß42 was performed by microglia with a predominance of M2 markers. EPA increased the levels of BDNF in the culture medium. The levels of TNF-α were decreased by DHA. Both DHA and EPA decreased the pro-inflammatory M1 markers CD40 and CD86, and DHA had a stimulatory effect on the anti-inflammatory M2 marker CD206. DHA and EPA can be beneficial in AD by enhancing removal of Aß42, increasing neurotrophin production, decreasing pro-inflammatory cytokine production, and by inducing a shift in phenotype away from pro-inflammatory M1 activation.