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Journal of Clinical Medicine Research

Review

Volume 9, Number 1, January 2017, pages 1-9

Effects of N-3 Polyunsaturated Fatty Acids on Dementia

It has been considered that n-3 polyunsaturated fatty acids (PUFAs) including α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-atherosclerotic and anti-inflammatory effects and also neuronal protective functions and may benefit prevention of dementia; however, the epidemiological evidence is limited. Furthermore, there is a lack of consensus on the benefits of EPA and DHA supplementations on cognition in dementia and/or Alzheimer’s disease (AD) elderly. An National Institutes of Health (NIH) State of the Science Conference panel concluded in 2010 that insufficient evidence is available to recommend the use of any primary prevention therapy for AD or cognitive decline with age [1]. Therefore, the literatures were reviewed to find whether serum n-3 PUFAs are associated with risk of dementia.

The literature about the association between n-3 PUFA and dementia was searched, by using Pubmed. Eighty-nine, 206 and 398 articles were found by using “EPA and dementia”, “DHA and dementia” and “n-3 PUFA and dementia and human or omega-3 PUFA and dementia and human” as the keywords, respectively. After the review of the literatures, articles were divided into “observational studies”, “intervention studies” and “the underlying mechanisms for n-3 PUFA-mediated improvement or prevention of dementia”.

The observational studies which assessed the association between n-3 PUFA and dementia are shown in Table 1 [2-21]. Recently, Yamagishi et al performed an intra-cohort case-control study nested in a community-based cohort, involving 7,586 Japanese individuals aged 40 - 74 years. Serum ALA, EPA, and DHA were measured in 315 cases of incident disabling dementia.

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Table 1. The Observational Studies Which Assessed the Association Between N-3 PUFA and Dementia

Serum ALA level was inversely associated with risk of disabling dementia. However, associations of EPA and DHA with disabling dementia were not statistically significant [2]. ALA, but not EPA and DHA, was also associated with reduction of the risk for mild dementia among the Korean elderly [3]. In the Invecchiare in Chianti study where plasma fatty acids (FAs) were measured by gas chromatography in 935 community-dwelling older persons from the population of two towns near Florence, Italy, dementia is associated with low plasma n-3 PUFA relative concentrations, especially low plasma ALA concentrations [4]. Recent studies demonstrated a significant association of ALA with dementia.

In the Mayo Clinic Study of Aging, the odds ratio of mild cognitive impairment (MCI) decreased with increasing n-3 PUFA intake [5]. The top quartile of plasma phosphatidylcholine DHA level was associated with a significant 47% reduction in the risk of developing all-cause dementia in the Framingham Heart Study [6]. In the Cardiovascular Health Cognition Study, consumption of fatty fish was associated with a reduced risk of dementia and AD for those without the APOE epsilon4 (APOEε4) allele [7]. In the prospective study conducted from 1993 through 2000, dietary intake of n-3 PUFA and weekly consumption of fish were associated with reduction of the risk of incident AD [8]. In cross-sectional analyses, moderate seafood consumption was correlated with lesser AD neuropathology [9]. An ongoing longitudinal, community-based epidemiological study of aging and dementia suggested protective relations of one meal per week of seafood and n-3 PUFA against decline in multiple cognitive domains [10].

In the case-cohort study, plasma and dietary DHA were associated with protection against dementia [11]. The case-control study showed that serum cholesteryl ester-DHA levels were progressively reduced with severity of clinical dementia and were the important determinants of mini-mental state examination (MMSE) score [12]. Plasma phospholipid, phosphatidylcholine and phosphatidylethanolamine levels of DHA, total n-3 PUFA, and the n-3/n-6 ratio were lower in the AD, other dementias, and cognitive impairment no dementia (CIND) groups [13]. In an observational follow-up study, total n-3 PUFA and DHA concentrations were associated with benefits for cognition at approximately 64 years old [14]. After adjustment for sex, APOEε4 status, and intelligence quotient at 11 years old, the effects associated with total n-3 PUFA remained significant.

In the cross-sectional study using the data from the Keys to Optimal Cognitive Aging (KOCOA) study, an ongoing cohort of relatively healthy volunteers aged over 80 years old, living in Okinawa, Japan, higher serum EPA and DHA + EPA levels were independently associated with better scores on global cognitive function among the oldest old, free from dementia [15]. In the retrospective cohort study, an association between red blood cell (RBC) DHA + EPA levels and age-associated cognitive decline was not observed in a cohort of older, dementia-free women [16]. The study which investigated differences in dietary intake and blood plasma content of EPA and DHA in individuals with CIND, AD and healthy volunteers (HVs), showed the possibility that n-3 PUFA has an impact on cognitive decline [17]. Higher adherence to a Mediterranean diet (MeDi) and n-3 PUFA may contribute to decreased dementia risk. In the study which investigated the relationship between plasma FA and MeDi adherence suggested that the protective effect of the MeDi on cognitive functions might be mediated by higher plasma DHA and lower n-6/n-3 PUFA ratio [18].

In a cohort study of a representative sample of persons aged ≥ 65 years, conducted from 1991 to 2002, no associations between n-3 PUFA and dementia or AD were found [19]. Devore et al studied the dietary consumption of fish and n-3 PUFA in relation to long-term (an average follow-up of 9.6 years) dementia risk, by using 5,395 participants aged ≥ 55 years in the Rotterdam Study who were free of dementia and reported dietary information at baseline. In this Dutch cohort, a moderate consumption of fish and n-3 PUFA do not appear to be associated with long-term dementia risk [20]. Of 1,214 non-demented participants in the Three-City Study from Bordeaux (France) who were followed up for 4 years, 65 participants developed dementia. The association between the proportion of plasma FA at baseline and the risk of incident dementia was assessed by multivariate proportional hazard models, taking into account depressive status. A high plasma EPA concentration may decrease the risk of dementia, whereas high ratios of n-6 to n-3 PUFA and of arachidonic acid (AA) to DHA may increase the risk of dementia, especially in depressed older persons [21].

In the analyses of observational studies, three studies reported a significant association between ALA and dementia. N-3 PUFA, DHA, DHA + EPA, and EPA have been reported to be significantly associated with dementia, in two, five, two, and one studies, respectively; however, the association between DHA + EPA and dementia was denied by one study. Fish or seafood intake was beneficially associated with dementia in four studies; however, one article challenged such association.

The intervention studies which assessed the association between n-3 PUFA and dementia are shown in Table 2 [22-34]. In a randomized, double-blind, placebo-controlled trial (RCT), healthy older adults with subjective memory impairment were allocated to fish oil group or placebo group for 24 weeks. EPA and DHA supplementation increases RBC n-3 PUFA content, working memory performance, and blood oxygen level-dependent signal in the posterior cingulate cortex during greater working memory load in older adults with subjective memory impairment [22]. However, another RCT confirmed an overall negligible benefit of n-3 PUFA supplementation for individuals with CIND or AD [23]. Eriksdotter et al demonstrated the dose-response relationships between plasma levels of n-3 PUFA and preservation of cognition [24]. The large intervention study showed no effect of dietary doses of n-3 PUFA on global cognitive decline in coronary heart disease patients [25].

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Table 2. The Intervention Studies Which Assessed the Association Between N-3 PUFA and Dementia

A 6-month RCT showed that increased intakes of DHA and EPA benefited mental health in older people with MCI, and increasing n-3 PUFA intakes may reduce depressive symptoms and the risk of progressing to dementia [26]. In RCT, patients with AD received 1.7 g of DHA and 0.6 g of EPA or placebo 0.6 g of linoleic acid per day for 6 months. After 6 months, all patients received DHA and EPA for another 6 months. A DHA-enriched n-3 PUFA supplement may positively affect weight and appetite in patients with mild to moderate AD. Not carrying the APOEε4 allele and high DHA were independently associated with weight gain [27].

An RCT involving 302 cognitively healthy (MMSE score > 21) individuals aged 65 years or older was performed to investigate the effect of EPA and DHA supplementation on cognitive performance. Participants were randomly assigned to 1,800 mg/day EPA-DHA, 400 mg/day EPA-DHA, or placebo capsules for 26 weeks. No overall effect of 26 weeks of EPA and DHA supplementation on cognitive performance was observed [28].

In an RCT where 204 AD patients (74 ± 9 years) with acetylcholine esterase inhibitor treatment and an MMSE > 15 points were randomized to daily intake of 1.7 g DHA and 0.6 g EPA or placebo for 6 months. Supplementation with n-3 PUFA in patients with mild to moderate AD did not result in marked effects on neuropsychiatric symptoms except for possible positive effects on depressive symptoms in non-APOEε4 carriers and agitation symptoms in APOEε4 carriers [29].

Recall of object locations was significantly better after n-3 PUFA (2,200 mg/day) supplementation compared with placebo [30]. A 24-week n-3 PUFA (1.8 g/day) treatment showed a significant improvement in AD assessment scale compared to the placebo group in participants with MCI, which was not observed in those with AD [31].

In Japan, participants in elderly care facilities and nursing homes were randomized in active and placebo groups [32]. This study suggested that DHA-enriched meals protect against age-related cognitive decline, and also improve apathy and caregiver burden for the oldest-elderly Japanese with cognitive impairment. The 24-week supplementation with 900 mg/day DHA improved learning and memory function in age-related cognitive decline [33]. However, supplementation with algal DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate AD [34].

In the analyses of intervention studies, n-3 PUFAs have been reported to improve dementia in three studies. EPA + DHA supplementation was beneficially associated with dementia in three studies; however, four studies reported the negligible effects of EPA + DHA for dementia. DHA was favorably associated with dementia in two studies, however, which was challenged by one article.

The accumulation of neurotoxic amyloid-β peptide (Aβ) is a pathologically profound characteristic of AD [35-40]. Aβ is derived from amyloid precursor protein (APP) [41]. APP is cleaved by α-secretases within the Aβ domain to produce α-secretase-cleaved soluble APP (sAPPα). sAPPα is neurotrophic and neuroprotective and enhancing APP processing by α-secretases [42, 43]. EPA and DHA are able to increase membrane fluidity and lead to increase in sAPPα secretion [44]. Transthyretin (TTR) binds Aβ and may reduce brain Aβ. N-3 PUFA treatment appeared to increase plasma-TTR in patients with AD [45]. N-3 PUFA is associated with enhancing clearance of Aβ.

Hjorth et al reported that DHA and EPA can be beneficial in AD by enhancing removal of Aβ, increasing neurotrophin production, and decreasing pro-inflammatory cytokine production [46].

AD is associated with brain inflammation and reduced levels of specialized proresolving mediators (SPMs) which are derivatives of n-3 and n-6 PUFA and induce resolution of inflammation. Supplementation with n-3 PUFA for 6 months prevented a reduction in SPMs released from peripheral blood mononuclear cells (PBMCs) of AD patients [47]. Serini et al treated in vitro phytohemagglutinin (PHA)- or lipopolysaccharide (LPS)-stimulated PBMC from AD patients and age-matched healthy controls with EPA or DHA. The addition of both EPA and DHA markedly reduced the cytokine release [48].

Prostaglandin F-2α release from LPS-stimulated PBMC from AD patients was significantly diminished by a DHA-rich fish oil as compared with placebo. Prostaglandin F-2α changes were correlated inversely with changes in plasma DHA and EPA. Decreased IL-6 and IL-1β levels correlated with decreased prostaglandin F-2α levels [49].

Isoform-specific protein kinase C (PKC) activators may be useful as therapeutic agents for the treatment of AD. Three new epsilon-specific PKC activators (AA-CP4, EPA-CP5, and DHA-CP6), made by cyclopropanation (CP) of PUFA, have been developed. DHA-CP6 reduced the intracellular and secreted levels of Aβ by 60-70% [50]. AD patients treated with DHA-rich n-3 PUFA supplementation increased their plasma concentrations of DHA (and EPA), which were associated with reduced release of IL-1β, IL-6, and granulocyte colony-stimulating factor from PBMC [51].

N-3 PUFA may improve AD by increasing clearance of Aβ, neurotrophic and neuroprotective factors, and by anti-inflammatory effects.

Only one database (Pubmed) was searched for articles to be reviewed.

Characteristics of patients whose dementia can be improved or prevented by n-3 PUFA are shown in Table 3. Patients with mild memory and/or cognitive impairment can be treated by a long-term and higher intake of n-3 PUFA.

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Table 3. Characteristics of Patients Whose Dementia Can Be Improved or Prevented by N-3 PUFA

Conflicts of Interest

The author declares that he has no conflicts of interest concerning this article.

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