There is considerable interest in the potential impact of several polyunsaturated fatty acids (PUFAs) in mitigating the significant morbidity and mortality caused by degenerative diseases of the cardiovascular system and brain. Despite this interest, confusion surrounds the extent of conversion in humans of the parent PUFA, linoleic acid or alpha-linolenic acid (ALA), to their respective long-chain PUFA products. As a result, there is uncertainty about the potential benefits of ALA versus eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). Some of the confusion arises because although mammals have the necessary enzymes to make the long-chain PUFA from the parent PUFA, in vivo studies in humans show that asymptotically equal to 5% of ALA is converted to EPA and <0.5% of ALA is converted to DHA. Because the capacity of this pathway is very low in healthy, nonvegetarian humans, even large amounts of dietary ALA have a negligible effect on plasma DHA, an effect paralleled in the omega6 PUFA by a negligible effect of dietary linoleic acid on plasma arachidonic acid. Despite this inefficient conversion, there are potential roles in human health for ALA and EPA that could be independent of their metabolism to DHA through the desaturation - chain elongation pathway.

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BackgroundHigher fish or higher docosahexaenoic acid (DHA) intake normally correlates positively with higher plasma DHA level, but recent evidence suggests that the positive relationship between intake and plasma levels of DHA is less clear in the elderly.MethodsWe compared the metabolism of 13C-DHA in six healthy elderly (mean - 77 y old) and six young adults (mean - 27 y old). All participants were given a single oral dose of 50 mg of uniformly labelled 13C-DHA. Tracer incorporation into fatty acids of plasma triglycerides, free fatty acids, cholesteryl esters and phospholipids, as well as apparent retroconversion and β-oxidation of 13C-DHA were evaluated 4 h, 24 h, 7d and 28d later.ResultsPlasma incorporation and β-oxidation of 13C-DHA reached a maximum within 4 h in both groups, but 13C-DHA was transiently higher in all plasma lipids of the elderly 4 h to 28d later. At 4 h post-dose, 13C-DHA β-oxidation was 1.9 times higher in the elderly, but over 7d, cumulative β-oxidation of 13C-DHA was not different in the two groups (35% in the elderly and 38% in the young). Apparent retroconversion of 13C-DHA was well below 10% of 13C-DHA recovered in plasma at all time points, and was 2.1 times higher in the elderly 24 h and 7d after tracer intake.ConclusionsWe conclude that 13C-DHA metabolism changes significantly during healthy aging. Since DHA is a potentially important molecule in neuro-protection, these changes may be relevant to the higher vulnerability of the elderly to cognitive decline.

Carrying the apoE e4 allele (E4þ ) is the most important genetic risk for Alzheimer's disease. Unlike non-carriers (E42 ), E4þ seem not to be protected against Alzheimer's disease when consuming fish. We hypothesised that this may be linked to a disturbance in n-3 DHA metabolism in E4þ. The aim of the present study was to evaluate [ 13 C]DHA metabolism over 28 d in E4þ v. E42. A total of forty participants (twenty-six women and fourteen men) received a single oral dose of 40 mg [ 13 C]DHA, and its metabolism was monitored in blood and breath over 28 d. Of the participants, six were E4þ and thirty-four were E42. In E4þ, mean plasma [ 13 C]DHA was 31 % lower than that in E42, and cumulative b-oxidation of [ 13 C]DHA was higher than that in E42 1-28 d post-dose (P#0·05). A genotype £ time interaction was detected for cumulative b-oxidation of [ 13 C]DHA (P#0·01). The whole-body half-life of [ 13 C]DHA was 77 % lower in E4þ compared with E42 (P#0·01). In E4þ and E42, the percentage dose of [ 13 C]DHA recovered/h as 13 CO 2 correlated with [ 13 C]DHA concentration in plasma, but the slope of linear regression was 117 % steeper in E4þ compared with E42 (P# 0·05). These results indicate that DHA metabolism is disturbed in E4þ, and may help explain why there is no association between DHA levels in plasma and cognition in E4þ. However, whether E4þ disturbs the metabolism of 13 C-labelled fatty acids other than DHA cannot be deduced from the present study.

Benefits on cognition from docosahexaenoic acid (DHA, 22 : 6 n-3) intake are absent in humans carrying apolipoprotein E e4 allele (APOE4), the most important genetic risk factor for Alzheimer's disease (AD). To test the hypothesis that carrying APOE4 impairs DHA distribution, we evaluated plasma and brain fatty acid profiles and uptake of [ 14 C]-DHA using in situ cerebral perfusion through the blood-brain barrier in 4-and 13-month-old male and female APOE-targeted replacement mice (APOE2, APOE3, and APOE4), fed with a DHA-depleted diet. Cortical and plasma DHA were 9% lower and 34% higher in APOE4 compared to APOE2 mice, respectively. Brain uptake of [ 14 C]-DHA was 24% lower in APOE4 versus APOE2 mice. A significant relationship was established between DHA and apoE concentrations in the cortex of mice (r 2 = 0.21) and AD patients (r 2 = 0.32).Altogether, our results suggest that lower brain uptake of DHA in APOE4 than in APOE2 mice may limit the accumulation of DHA in cerebral tissues. These data provide a mechanistic explanation for the lack of benefit of DHA in APOE4 carriers on cognitive function and the risk of AD. Keywords: Alzheimer's disease, apolipoprotein E, bloodbrain barrier, docosahexaenoic acid, long-chain omega-3 polyunsaturated fatty acids.

Fatty acids are among the most studied nutrients in human metabolism and health. Endogenous fatty acid status influences health and disease via multiple mechanisms at all stages of the life cycle. Despite widespread interest, attempts to summarize the results of multiple studies addressing similar fatty acid–related outcomes via meta-analyses and systematic reviews have been disappointing, largely because of heterogeneity in study design, sampling, and laboratory and data analyses. Our purpose is to recommend best practices for fatty acid clinical nutrition and medical studies. Key issues in study design include judicious choice of sampled endogenous pools for fatty acid analysis, considering relevant physiologic state, duration of intervention and/or observation, consideration of specific fatty acid dynamics to link intake and endogenous concentrations, and interpretation of results with respect to known fatty acid ranges. Key laboratory considerations include proper sample storage, use of sample preparation methods known to be fit-for-purpose via published validation studies, detailed reporting or methods to establish proper fatty acid identification, and quantitative analysis, including calibration of differential response, quality control procedures, and reporting of data on a minimal set of fatty acids to enable comprehensive interpretation. We present a checklist of recommendations for fatty acid best practices to facilitate design, review, and evaluation of studies with the intention of improving study reproducibility.

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by extracellular amyloid β (Aβ) and intraneuronal tau protein aggregations. One risk factor for developing AD is the APOE gene coding for the apolipoprotein E protein (apoE). Humans have three versions of APOE gene: ε2, ε3, and ε4 allele. Carrying the ε4 allele is an AD risk factor while carrying the ε2 allele is protective. ApoE is a component of lipoprotein particles in the plasma at the periphery, as well as in the cerebrospinal fluid (CSF) and in the interstitial fluid (ISF) of brain parenchyma in the central nervous system (CNS). ApoE is a major lipid transporter that plays a pivotal role in the development, maintenance, and repair of the CNS, and that regulates multiple important signaling pathways. This review will focus on the critical role of apoE in AD pathogenesis and some of the currently apoE-based therapeutics developed in the treatment of AD.

Plasma n-3 fatty acid response to an n-3 fatty acid supplement is modulated by apoE 14 but not by the common PPAR-a L162V polymorphism in men The risk of Alzheimer's disease is increased for carriers of apoE4 (E4) or the PPAR-a L162V polymorphism (L162V), but it is decreased in fish and seafood consumers. The link between high fish intake and reduced risk of cognitive decline in the elderly appears not to hold in carriers of E4, possibly because better cognition is linked to EPA þ DHA in the blood, but only in non-carriers of E4. As yet, no such studies exist in carriers of L162V. Our objective was to determine whether the plasma fatty acid response to a dietary supplement of EPA þ DHA was altered in carriers of L162V and/or E4. This was an add-on project; in the original study, men were selected based on whether or not they were carriers of L162V (n 14 per group). E4 status was determined afterwards. All subjects received an EPA þ DHA supplement for 6 weeks. L162V polymorphism did not interact with the supplement in a way to alter EPA and DHA incorporation into plasma lipids. However, when the groups were separated based on the presence of E4, baseline EPA and DHA in plasma TAG were 67 and 60 % higher, respectively, in E4 carriers. After the supplementation, there were significant gene £ diet interactions in which only non-carriers had increased EPA and DHA in plasma NEFA and TAG, respectively.