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Carrying at least one apolipoprotein E ε4 allele (E4+) is the main genetic risk factor for Alzheimer's disease (AD). Epidemiological studies support that consuming fatty fish rich in docosahexaenoic acid (DHA; 22:6ω3) is protective against development of AD. However, this protective effect seems not to hold in E4+. The involvement of APOE genotype on the relationship between DHA intake and cognitive decline could be mediated through cholesterol. Many studies show a link between cholesterol metabolism and AD progression. In this study, we investigated whether cholesterol metabolism is improved in E3+ and E4+ mice consuming a diet rich in DHA. Plasma cholesterol was 36% lower in E4+ mice compared to E3+ mice fed the control diet (P=.02), and in the liver, there was a significant genotype effect where cholesterol levels were 18% lower in E4+ mice than E3+ mice. The low-density lipoprotein receptor was overexpressed in the liver of E4+ mice. Plasma cholesterol levels were 33% lower after the DHA diet (P=.02) in E3+ mice only, and there was a significant diet effect where cholesterol level was 67% lower in the liver of mice fed DHA. Mice fed the DHA diet also had 62% less lipolysis stimulated lipoprotein receptor expression in the liver compared to mice fed the control diet (P<.0001), but there was no genotype effect. These findings suggest that plasma and liver cholesterol homeostasis and the receptors regulating uptake of cholesterol in the liver are modulated differently and independently by APOE allele and DHA intake.

Little information is available concerning whether incorporation of dietary omega-3 fatty acids into plasma lipids changes during healthy aging. Elderly (74 ± 4 years old) and young (24 ± 2 years old) adults were given a fish oil supplement for 3 weeks that provided 680 mg/day of docosahexaenoic acid and 320 mg/day of eicosapentaenoic acid, followed by a 2 week wash-out period. Compliance was monitored by spiking the capsules with carbon-13 glucose, the excretion of which was measured in breath CO2. In response to the supplement, plasma docosahexaenoic acid rose 42% more in the elderly but eicosapentaenoic responded similarly in both groups. Despite raising docosahexaenoic acid intake by five to tenfold, the supplement did not raise plasma free docosahexaenoic acid (% or mg/dL) in either group. We conclude that healthy aging is accompanied by subtle but significant changes in DHA incorporation into plasma lipids.

Objectives: We investigated whether a dietary supplement rich in eicosapentaenoic acid (EPA) increases fasting plasma ketones or postprandial ketone responses in healthy young and elderly subjects. Methods: Ten young (22 ± 1 y old) and 10 elderly (75 ± 1 y old) subjects were recruited and participated in two identical study days, one before and one 6 wk after providing an EPA-enriched supplement (1.4 g/d of EPA and 0.2 g/d of docosahexaenoic acid). On the study days, blood samples were collected at fasting and every hour for 6 h after giving a breakfast. Fasting and postprandial plasma β-hydroxybutyrate (β-OHB), free fatty acid (FFA), triacylglycerol, glucose, and insulin responses were measured. Fatty acid profiles were assessed in fasting plasma samples before and after the EPA supplement. Results: After the EPA supplement, postprandial plasma β-OHB responses decreased by 44% in the young and by 24% in the elderly subjects, in addition to 20% and 34% lower FFA responses in the young and elderly adults, respectively. β-OHB and FFAs were positively and significantly correlated in young but not in elderly subjects before and after the EPA supplement. In both groups, postprandial plasma triacylglycerols, glucose, and insulin were not significantly different after the intake of the EPA supplement. Before and after the EPA supplement, fasting plasma EPA was 50% higher in the elderly but increased by about five times in both groups after intake of the EPA supplement. Conclusion: Contrary to our expectations, EPA supplementation lowered postprandial β-OHB response and, in the elderly subjects, the concentration of postprandial β-OHB was not lowered after intake of the EPA supplement.

La communauté scientifique accorde beaucoup d’intérêt à plusieurs acides gras polyinsaturés (PUFA) et à leur atténuation potentielle du taux de mortalité et de morbidité causée par les maladies dégénératives du système cardiovasculaire et du cerveau. Il n’en demeure pas moins que la confusion demeure au sujet du taux de conversion chez l’humain des PUFA en amont – acide linoléique ou α-linolénique (ALA) – en des substances respectives à plus longue chaîne. On ne connaît toujours pas les bienfaits potentiels de l’ALA en amont de l’acide eicosapentaénoïque (EPA) ou de l’acide docosahexaénoïque (DHA). La confusion est en partie née du fait que les mammifères disposent des enzymes nécessaires pour synthétiser les PUFA à chaîne longue à partir des PUFA en amont alors que les études in vivo chez l’humain révèlent que ≈5 % de l’ALA est converti en EPA et moins de 0,5 % de l’ALA est converti en DHA. Du fait de la très faible capacité de cette voie de synthèse chez des humains en bonne santé non végétariens, même un grand apport alimentaire d’ALA a un effet négligeable sur la concentration plasmatique de DHA ; on observe le même phénomène chez les PUFA oméga-6 : l’apport alimentaire d’acide linoléique a peu d’effet sur la concentration plasmatique de l’acide arachidonique. Nonobstant cette conversion à faible rendement, l’ALA et l’EPA ont potentiellement un rôle à jouer au plan de la santé chez l’humain qui n’a rien à voir avec la conversion en DHA dans la voie de désaturation-élongation des acides gras., 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.

Polyunsaturated fatty acids omega-3 (n-3 PUFA), such as docosahexaenoic acid (DHA), have been shown to prevent, and partially reverse, neurotoxin-induced nigrostriatal denervation in animal models of Parkinson's disease (PD). However, the accumulation of α-synuclein (αSyn) in cerebral tissues is equally important to the pathophysiology. To determine whether DHA intake improves various aspects related to synucleinopathy, ninety male mice overexpressing human αSyn under the Thy-1 promoter (Thy1-αSyn) were fed one of three diets (specially formulated control, low n-3 PUFA or high DHA) and compared to non-transgenic C57/BL6 littermate mice exposed to a control diet. Thy1-αSyn mice displayed impaired motor skills, lower dopaminergic neuronal counts within the substantia nigra (− 13%) in parallel to decreased levels of the striatal dopamine transporter (DAT) (− 24%), as well as reduced NeuN (− 41%) and synaptic proteins PSD-95 (− 51%), synaptophysin (− 80%) and vesicular acetylcholine transporter (VChAT) (− 40%) in the cerebral cortex compared to C57/BL6 mice. However, no significant difference in dopamine concentrations was observed by HPLC analysis between Thy1-αSyn and non-transgenic C57/BL6 littermates under the control diet. The most striking finding was a favorable effect of DHA on the survival/longevity of Thy1-αSyn mice (+ 51% survival rate at 12 months of age). However, dietary DHA supplementation did not have a significant effect on other parameters examined in this study, despite increased striatal dopamine concentrations. While human αSyn monomers and oligomers were detected in the cortex of Thy1-αSyn mice, the effects of the diets were limited to a small increase of 42 kDa oligomers in insoluble protein fractions upon n-3 PUFA deprivation. Overall, our data indicate that a diet rich in n-3 PUFA has a beneficial effect on the longevity of a murine model of α-synucleinopathy without a major impact on the dopamine system and motor impairments, nor αSyn levels.

Objectives: Omega-3 polyunsaturated fatty acid (ω-3 PUFA) metabolism seems to be disrupted in carriers of the epsilon 4 allele of apolipoprotein E (E4+). The objective of this study was to investigate whether the ω-3 PUFA distribution in the high and low density lipoproteins is APOE-genotype dependant before and after supplementation with ω-3 PUFAs. Methods: Eighty participants, aged between 20 and 35 y old were recruited and supplemented with 900 mg of eicosapentaenoic acid plus 680 mg of docosahexaenoic acid for 4 wk. Over the 4-wk intervention, blood samples were collected and HDL and LDL particles were obtained using sucrose gradient ultracentifugation. Fatty acid profiles of the HDL and LDL fractions were performed by gas chromatography. Results: Baseline anthropometric characteristics of participants were not significantly different between the two APOE-groups (E4+, N = 10; E4−, N = 70). At baseline, in the LDL of E4+ subjects, the ω-6/ω-3 PUFA ratio was 17% higher than E4− subjects. At week 4, the ω-6/ω-3 PUFA ratio was significantly higher in the LDL of E4+ than E4− subjects. There was a significant genotype × time interaction for 16:0 in HDL and LDL and for 18:2 ω-6 in HDL. DHA in the HDL was positively correlated to HDL-C levels pre- and postsupplementation in E4− only. Conclusions: Contrary to what we anticipated, ω-3 PUFAs content? in HDL and LDL were not APOE isoform-dependant in young participants. However, young E4+ participants already had a tendency toward lower baseline-DHA levels in LDL particles as well as a more atherogenic ω-6/ω-3 PUFA ratio in LDL pre- and post-supplementation

The risk of Alzheimer's disease is increased for carriers of apoE4 (E4) or the PPAR-α 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+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+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+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.

Epidemiological studies suggest a protective role of omega-3 poly-unsaturated fatty acids (n-3 PUFA) against Alzheimer's disease (AD). However, most intervention studies of supplementation with n-3 PUFA have yielded disappointing results. One reason for such discordant results may result from inadequate targeting of individuals who might benefit from the supplementation, in particular because of their genetic susceptibility to AD. The ε4 allele of the apolipoprotein E gene (ApoE) is a genetic risk factor for late-onset AD. ApoE plays a key role in the transport of cholesterol and other lipids involved in brain composition and functioning. The action of n-3 PUFA on the aging brain might therefore differ according to ApoE polymorphism. The aim of this review is to examine the interaction between dietary fatty acids and ApoE genotype on the risk for AD. Carriers of the ε4 allele tend to be the most responsive to changes in dietary fat and cholesterol. Conversely, several epidemiological studies suggest a protective effect of long-chain n-3 PUFA on cognitive decline only in those who do not carry ε4 but with inconsistent results. An intervention study showed that only non-carriers had increased concentrations of long-chain n-3 PUFA in response to supplementation. The mechanisms underlying this gene-by-diet interaction on AD risk may involve impaired fatty acids and cholesterol transport, altered metabolism of n-3 PUFA, glucose or ketones, or modification of other risk factors of AD in ε4 carriers. Further research is needed to explain the differential effect of n-3 PUFA on AD according to ApoE genotype.

Background: Docosahexaenoic acid (DHA) kinetics appear to change with intake, which is an effect that we studied in an older population by using uniformly carbon-13–labeled DHA (13C-DHA). Objective: We evaluated the influence of a fish-oil supplement over 5 mo on the kinetics of 13C-DHA in older persons. Design: Thirty-four healthy, cognitively normal participants (12 men, 22 women) aged between 52 and 90 y were recruited. Two identical kinetic studies were performed, each with the use of a single oral dose of 40 mg 13C-DHA. The first kinetic study was performed before participants started taking a 5-mo supplementation that provided 1.4 g DHA/d plus 1.8 g eicosapentaenoic acid (EPA)/d (baseline); the second study was performed during the final month of supplementation (supplement). In both kinetic studies, blood and breath samples were collected ≤8 h and weekly over 4 wk to analyze 13C enrichment. Results: The time × supplement interaction for 13C-DHA in the plasma was not significant, but there were separate time and supplement effects (P < 0.0001). The area under the curve for plasma 13C-DHA was 60% lower while subjects were taking the supplement than at baseline (P < 0.0001). The uniformly carbon-13–labeled EPA concentration was 2.6 times as high 1 d posttracer while patients were taking the supplement as it was at baseline. The mean (±SEM) plasma 13C-DHA half-life was 4.5 ± 0.4 d at baseline compared with 3.0 ± 0.2 d while taking the supplement (P < 0.0001). Compared with baseline, the mean whole-body half-life was 61% lower while subjects were taking the supplement. The loss of 13C-DHA through β-oxidation to carbon dioxide labeled with carbon-13 increased from 0.085% of dose/h at baseline to 0.208% of dose/h while subjects were taking the supplement. Conclusions: In older persons, a supplement of 3.2 g EPA + DHA/d increased β-oxidation of 13C-DHA and shortened the plasma 13C-DHA half-life. Therefore, when circulating concentrations of EPA and DHA are increased

Purpose: There is an increased interest in the benefits of conjugated α-linolenic acid (CLNA) on obesity-related complications such as insulin resistance and diabetes. The aim of the study was to investigate whether a 1 % dietary supplementation of mono-CLNA isomers (c9-t11-c15-18:3 + c9-t13-c15-18:3) improved glucose and lipid metabolism in neonatal pigs. Methods: Since mono-CLNA isomers combine one conjugated two-double-bond system with an n-3 polyunsaturated fatty acid (PUFA) structure, the experimental protocol was designed to isolate the dietary structural characteristics of the molecules by comparing a CLNA diet with three other dietary fats: (1) conjugated linoleic acid (c9-t11-18:2 + t10-c12-18:2; CLA), (2) non-conjugated n-3 PUFA, and (3) n-6 PUFA. Thirty-two piglets weaned at 3 weeks of age were distributed among the four dietary groups. Diets were isoenergetic and food intake was controlled by a gastric tube. After 2 weeks of supplementation, gastro-enteral (OGTT) and parenteral (IVGTT) glucose tolerance tests were conducted. Results: Dietary supplementation with mono-CLNA did not modify body weight/fat or blood lipid profiles (p > 0.82 and p > 0.57, respectively) compared with other dietary groups. Plasma glucose, insulin, and C-peptide responses to OGTT and IVGTT in the CLNA group were not different from the three other dietary groups (p > 0.18 and p > 0.15, respectively). Compared to the non-conjugated n-3 PUFA diet, CLNA-fed animals had decreased liver composition in three n-3 fatty acids (18:3n-3; 20:3n-3; 22:5n-3; p < 0.001). Conclusions: These results suggest that providing 1 % mono-CLNA is not effective in improving insulin sensitivity in neonatal pigs.

Carrying the apoE ε4 allele (E4+) is the most important genetic risk for Alzheimer's disease. Unlike non-carriers (E4 − ), E4+ 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 E4+. The aim of the present study was to evaluate [13C]DHA metabolism over 28 d in E4+v. E4 − . A total of forty participants (twenty-six women and fourteen men) received a single oral dose of 40 mg [13C]DHA, and its metabolism was monitored in blood and breath over 28 d. Of the participants, six were E4+ and thirty-four were E4 − . In E4+, mean plasma [13C]DHA was 31 % lower than that in E4 − , and cumulative β-oxidation of [13C]DHA was higher than that in E4 − 1–28 d post-dose (P≤ 0·05). A genotype × time interaction was detected for cumulative β-oxidation of [13C]DHA (P≤ 0·01). The whole-body half-life of [13C]DHA was 77 % lower in E4+ compared with E4 − (P≤ 0·01). In E4+ and E4 − , the percentage dose of [13C]DHA recovered/h as 13CO2 correlated with [13C]DHA concentration in plasma, but the slope of linear regression was 117 % steeper in E4+ compared with E4 − (P≤ 0·05). These results indicate that DHA metabolism is disturbed in E4+, and may help explain why there is no association between DHA levels in plasma and cognition in E4+. However, whether E4+ disturbs the metabolism of 13C-labelled fatty acids other than DHA cannot be deduced from the present study.

Cognitive decline in the elderly, particularly Alzheimer’s disease (AD), is a major socio-economic and healthcare concern. We review here the literature on one specific aspect of diet affecting AD, that of the ω3 fatty acids, particularly the brain’s principle ω3 fatty acid – docosahexaenoic acid (DHA). DHA has deservedly received wide attention as a nutrient supporting both optimal brain development and for cardiovascular health. Our aim here is to critically assess the quality of the present literature as well as the potential of ω3 fatty acids to treat or delay the onset of AD. We start with a brief description of cognitive decline in the elderly, followed by an overview of well recognized biological functions of DHA. We then turn to epidemiological studies, which are largely supportive of protective effects of fish and DHA against risk of AD. However, biological studies, including blood and brain DHA analyses need careful interpretation and further investigation, without which the success of clinical trials with DHA may continue to struggle. We draw attention to some of the methodological issues that need resolution as well as an emerging mechanism that may explain how DHA could be linked to protecting brain function in the elderly.

Background: Conjugated linoleic acid (CLA) is a group of polyunsaturated fatty acids which have been extensively studied in the past two decades. However, conjugated octadecatrienoic acid such as cis-9,trans-11,cis-15 and cis-9,trans-13,cis-15, recently identified, have not been extensively investigated. This work presents bioavailability and tissue incorporation of a mixture of conjugated octadecatrienoic (CLnA) acids ingested as free fatty acids (FFA) and triacylglycerols (TAG). Results: Male Wistar rats were fed rumenic acid (RA: cis-9,trans-11 18:2) and a CLnA mixture (cis9,trans-11,cis-15 18:3 and cis-9,trans-13,cis-15 18:3) as FFA and TAG for 8 days. RA and CLnA were both totally absorbed when given as FFA as well as TAG. Both isomers of CLnA as FFA or TAG were incorporated into neutral lipids. Metabolites up to 22:6 conjugated isomers were present in liver and plasma phospholipids of rats fed the CLnA diets. Conclusion: Finally, CLnA are as well absorbed as RA in vivo and their incorporation into tissues and bioconversion are similar when ingested as FFA or as TAG.

Epidemiological studies fairly convincingly suggest that higher intakes of fatty fish and n-3 fatty acids are associated with reduced risk of Alzheimer's disease (AD). DHA in plasma is normally positively associated with DHA intake. However, despite being associated with lower fish and DHA intake, unexpectedly, plasma (or brain) DHA is frequently not lower in AD. This review will highlight some metabolic and physiological factors such as ageing and apoE polymorphism that influence DHA homeostasis. Compared with young adults, blood DHA is often slightly but significantly higher in older adults without any age-related cognitive decline. Higher plasma DHA in older adults could be a sign that their fish or DHA intake is higher. However, our supplementation and carbon-13 tracer studies also show that DHA metabolism, e.g. transit through the plasma, apparent retroconversion and β-oxidation, is altered in healthy older compared with healthy young adults. ApoE4 increases the risk of AD, possibly in part because it too changes DHA homeostasis. Therefore, independent of differences in fish intake, changing DHA homeostasis may tend to obscure the relationship between DHA intake and plasma DHA which, in turn, may contribute to making older adults more susceptible to cognitive decline despite older adults having similar or sometimes higher plasma DHA than in younger adults. In conclusion, recent development of new tools such as isotopically labelled DHA to study DHA metabolism in human subjects highlights some promising avenues to evaluate how and why DHA metabolism changes during ageing and AD.

Background: We have previously demonstrated that carrying the apolipoprotein (apo) E epsilon 4 (E4+) genotype disrupts omega-3 fatty acids (n − 3 PUFA) metabolism. Here we hypothesise that the postprandial clearance of n − 3 PUFA from the circulation is faster in E4+ compared to non-carriers (E4−). The objective of the study was to investigate the fasted and postprandial fatty acid (FA) profile of triacylglycerol-rich lipoprotein (TRL) fractions: Sf >400 (predominately chylomicron CM), Sf 60 − 400 (VLDL1), and Sf 20 − 60 (VLDL2) according to APOE genotype. Methods: Postprandial TRL fractions were obtained in 11 E4+ (ε3/ε4) and 12 E4− (ε3/ε3) male from the SATgenε study following high saturated fat diet + 3.45 g/d of docosahexaenoic acid (DHA) for 8-wk. Blood samples were taken at fasting and 5-h after consuming a test-meal representative of the dietary intervention. FA were characterized by gas chromatography. Results: At fasting, there was a 2-fold higher ratio of eicosapentaenoic acid (EPA) to arachidonic acid (P = 0.046) as well as a trend towards higher relative% of EPA (P = 0.063) in the Sf >400 fraction of E4+. Total n − 3 PUFA in the Sf 60 − 400 and Sf 20 − 60 fractions were not APOE genotype dependant. At 5 h, there was a trend towards a time × genotype interaction (P = 0.081) for EPA in the Sf >400 fraction. When sub-groups were form based on the level of EPA at baseline within the Sf >400 fraction, postprandial EPA (%) was significantly reduced only in the high-EPA group. EPA at baseline significantly predicted the postprandial response in EPA only in E4+ subjects (R2 = 0.816). Conclusion: Despite the DHA supplement contain very low levels of EPA, E4+ subjects with high EPA at fasting potentially have disrupted postprandial n − 3 PUFA metabolism after receiving a high-dose of DHA.

Apolipoprotein E (ApoE) is a protein playing a pivotal role in lipid homeostasis since it regulates cholesterol, triglyceride and phospholipid metabolism in the blood and the brain. APOE gene regulates the expression of this protein and has three different alleles: ε2, ε3 and ε4. Carrying an APOE4 allele is recognised as a genetic risk factor of late-onset Alzheimer’s disease (LOAD) and coronary heart disease (CHD). Consuming fatty fish, rich in long chain omega-3 fatty acids (LC omega-3), seems to be associated with risk reduction of developing LOAD and CHD but this link seems not to hold in APOE4 carriers, at least in LOAD. In CHD trials, APOE4 carriers supplemented with LC omega-3 were categorized as differential responders to the treatment with regards to CHD risk markers. This is potentially because fatty acid metabolism is disturbed in APOE4 carriers compared to the non-carriers. More specifically, homeostasis of LC omega-3 is disrupted in carriers of APOE4 allele and this is potentially because they β-oxidize more LC omega-3 than the non-carriers. Therefore, there is a potential shift in fatty acid selection for β-oxidation towards LC omega-3 which are usually highly preserved for incorporation into cell membranes.

Benefits on cognition from docosahexaenoic acid (DHA,22 : 6 n-3) intake are absent in humans carrying apolipopro-tein Ee4 allele (APOE4), the most important genetic risk factorfor Alzheimer’s disease (AD). To test the hypothesis thatcarryingAPOE4impairs DHA distribution, we evaluatedplasma and brain fatty acid profiles and uptake of [14C]-DHAusingin situcerebral perfusion through the blood–brain barrierin 4- and 13-month-old male and femaleAPOE-targetedreplacement mice (APOE2,APOE3, andAPOE4), fed with aDHA-depleted diet. Cortical and plasma DHA were 9% lowerand 34% higher inAPOE4compared toAPOE2mice,respectively. Brain uptake of [14C]-DHA was 24% lower inAPOE4versusAPOE2mice. A significant relationship wasestablished between DHA and apoE concentrations in thecortex of mice (r2=0.21) and AD patients (r2=0.32).Altogether, our results suggest that lower brain uptake ofDHA inAPOE4than inAPOE2mice may limit the accumu-lation of DHA in cerebral tissues. These data provide amechanistic explanation for the lack of benefit of DHA inAPOE4carriers on cognitive function and the risk of AD.Keywords:Alzheimer’s disease, apolipoprotein E, blood–brain barrier, docosahexaenoic acid, long-chain omega-3polyunsaturated fatty acids

Very preterm infants are vulnerable to deficiency in DHA. In a longitudinal study, 10 mothers who delivered #29 wk gestation and planned to breast-feed received DHA (1200 mg/d) until 36 wk after conception. The plasma DHA status was assessed in their 12 infants (including 2 pairs of twins) from birth to d 49. Fatty acid profiles were measured weekly in breast milk, and in plasma of mothers and infants at baseline and at d15 and 49. Plasma and breast milk fatty acid concentrations in the DHA-supplemented group at d 49 were compared with a reference group of very preterm infants (n = 24, including triplets) whose mothers (n = 22) did not receive DHA during lactation. The infants’ plasma DHA concentration tended to be greater in the DHA group than in the reference group (P = 0.10) and was greater when expressed as a percentage of total fatty acids (P = 0.009). At d 49, maternal milk DHA in the DHA group (1.92 6 1.10 mmol/L) was ;12 times higher than in the reference group (0.15 6 0.27 mmol/L) (P , 0.001). The amount of DHA provided to the infants increased from wk 1 through wk 7 in the DHA group (P , 0.001). Although enteral intake at wk 7 did not differ between the DHA group [119 6 51 mL/(kg. d)] and the reference group [113 6 66 mL/(kg·d)], DHA group infants received 55 6 38 mg/(kg. d) of DHA, and the reference group infants received 7 6 11 mg/(kg·d) (P , 0.001). Early supplementation with DHA to lactating mothers with low dietary DHA intake successfully increased the plasma DHA status in very preterm infants. J. Nutr. 141: 231–236, 2011.

Prospective cohort studies and animal models support the concept that low docosahexaenoic acid intake is implicated in the etiology or progression of Alzheimer’s disease. However, other studies crucial to this relationship are less encouraging. To date, the few trials using docosahexaenoic acid to treat declining cognition in the elderly have either been very small or, in the largest trial, the beneficial effect was mild and limited to a sub-group of patients. The supplements used in each of these clinical trials contained at least one polyunsaturated fatty acid other than docosahexaenoic acid, so the active ingredient remains unclear. One widely cited study reported markedly lower brain docosahexaenoic acid in Alzheimer’s disease but at least five other much less commonly cited reports have not corroborated this effect. There are numerous inconsistencies or confounders in the data and several challenges to overcome before definitively attributing a specific role to docosahexaenoic acid in the protection of cognitive function in the elderly

Conjugated linoleic acids (CLA) are positional and geometric isomers of linoleic acid. In animals, CLA consumption reduces body fat but results in humans are less conclusive. This review of the literature on CLA and loss of body fat or body weight in humans was conducted to explore the reasons for the discrepancy between animal and clinical trials. It indicates that the incongruity between human and animal data is largelyrelatedto methodological differences inthe experimental design, including age and gender and, to a lesser extent, to CLA dose and isomers. The relatively unknown metabolic fate of CLA in humans may also be a contributing factor that helps explain the lack of consistency for CLA efficacy across studies.

In intestinal epithelial cells (IEC), it was reported that the activation of the P2X7 receptor leads to the internalization of the glucose transporter GLUT2, which is accompanied by a reduction of IEC capacity to transport glucose. In this study, we used P2rx7−/− mice to decipher P2X7 functions in intestinal glucose transport and to evaluate the impacts on metabolism. Immunohistochemistry analyses revealed the presence of GLUT2 at the apical domain of P2rx7−/− jejunum enterocytes. Positron emission tomography and biodistribution studies demonstrated that glucose was more efciently delivered to the circulation of knockout animals. These fndings correlated with increase blood glucose, insulin, triglycerides and cholesterol levels. In fact, P2rx7−/− mice had increased serum triglyceride and cholesterol levels and displayed glucose intolerance and resistance to insulin. Finally, P2rx7−/− mice developed a hepatic steatosis characterized by a reduction of Acaca, Acacb, Fasn and Acox1 mRNA expression, as well as for ACC and FAS protein expression. Our study suggests that P2X7 could play a central role in metabolic diseases.

DHA, an omega-3 fatty acid, is an important constituent of brain membranes and has a key role in brain development and function. This review aims to highlight recent research on DHA’s role during age-related cognitive decline and Alzheimer’s disease. Animal and in vitro studies have provided some interesting mechanistic leads, especially on brain glucose metabolism, that may be involved in neuroprotection by DHA. However, results from human studies are more mitigated, perhaps due to changing DHA metabolism during aging. Recent innovative tools such as 13C-DHA for metabolic studies and 11C-DHA for PET provide interesting opportunities to study factors that affect DHA homeostasis during aging and to better understand whether and how to use DHA to delay or treat Alzheimer’s disease.

In Canada, 5.5 million (16% of Canadians) adults are >65 years old and projections suggest this number will be approximately 20% of Canadians by 2024. A major concern regarding old age is a decline in health, especially if this entails a loss of self-sufficiency and independence caused by a decline in cognition. The brain contains 60% of fat and is one of the most concentrated organs in long chain omega-3 fatty acids such as docosahexaenoic acid (DHA). During aging, there are physiological modifications in the metabolism of lipids that could also have consequences on brain structure and levels of DHA. This review will hence discuss the physiological modifications in the metabolism of lipids during aging with a focus on long chain omega-3 and omega-6 fatty acids and also outline the structural and functional modifications of the brain during aging including brain lipid modifications and its relation to higher levels of DHA and cognition. Therefore, in this review, we outline the importance of collecting more data on the biology of aging since it might highly improve our understanding about what are «normal» modifications occurring during aging and what can become pathological.

OBJECTIVE: To determine whether the metabolism of glucose or ketones differs in the healthy elderly compared to young or middle-aged adults during mild, short-term ketosis induced by a ketogenic breakfast. DESIGN AND PARTICIPANTS: Healthy subjects in three age groups (23 +/- 1, 50 +/- 1 and 76 +/- 2 y old) were given a ketogenic meal and plasma beta -hydroxybutyrate, glucose, insulin, triacylglycerols, total cholesterol, non-esterified fatty acids and breath acetone were measured over the subsequent 6 h. Each subject completed the protocol twice in order to determine the oxidation of a tracer dose of both carbon-13 (13C) glucose and 13C-beta-hydroxybutyrate. The tracers were given separately in random order. Apolipoprotein E genotype was also determined in all subjects. RESULTS: Plasma glucose decreased and beta-hydroxybutyrate, acetone and insulin increased similarly over 6 h in all three groups after the ketogenic meal. There was no significant change in cholesterol, triacylglycerols or non-esterified fatty acids over the 6 h. 13C-glucose and 13C-beta-hydroxybutyrate oxidation peaked at 2-3 h postdose for all age groups. Cumulative 13C-glucose oxidation over 24 h was significantly higher in the elderly but only versus the middle-aged group. There was no difference in cumulative 13C-beta-hydroxybutyrate oxidation between the three groups. Apolipoprotein E (epsilon 4) was associated with elevated fasting cholesterol but was unrelated to the other plasma metabolites. CONCLUSION: Elderly people in relatively good health have a similar capacity to produce ketones and to oxidize 13C-beta-hydroxybutyrate as middle-aged or young adults, but oxidize 13C-glucose a little more rapidly than healthy middle-aged adults

Objective: To quantify marine food product consumption and EPA + DHA intake among Quebecers, and to compare the results with the most recent recommendations. Design: Data were obtained from a representative cross-sectional telephone survey (June 2006). Intakes of marine food product species and EPA + DHA were estimated from a validated FFQ on the consumption of marine food products during the previous month. Prevalence of fish oil consumption in the last 6 months was also assessed. Setting: Province of Quebec (Canada). Subjects: A representative sample (n 1001) of adults in the province of Quebec. Of these, eight were excluded from the present analysis (n 993). Results: Mean and median EPA + DHA intakes for all participants were estimated to be 291 mg/d (sem 11) and 207 mg/d, respectively. 85·0 % (95 % CI 82·7, 87·3) of Quebecers had an EPA + DHA intake lower than 500 mg/d, which is the amount internationally recommended for the prevention of CVD. Mean and median DHA intakes among women of childbearing age (n 128, 18–34 years) were estimated to be 169 mg/d (sem 17) and 126 mg/d, respectively. Of these women, 27·7 % had a daily intake >200 mg DHA and 15·9 % had an intake >300 mg DHA. We noted that 13 % of Quebecers take ≥1 capsule of fish oil/d. Conclusions: Consumption of marine food products and EPA + DHA among Quebecers clearly appears to be lower than international recommendations. Since EPA + DHA confer health benefits and may reduce health costs, strategies to increase their consumption should be implemented to improve public health in Quebec.

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.

The elderly reportedly have a significantly higher % of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids in plasma and red cell lipids. However, these observations are from a few small studies and the health status of the elderly in these studies is for the most part unclear. Since the elderly are susceptible to cardiovascular and neurological illnesses that seem to be related in part to lower intake of n-3 fatty acids it seems paradoxical that their blood levels of EPA and DHA would be higher than in young adults. We report here plasma fatty acid profiles and their response to supplementation with two types of fish oils from several of our recent studies in the moderately healthy elderly. We define the moderately healthy elderly as those who were in good physical condition, had no cognitive decline and, if present, in whom hypothyroidism, hyperlipidemia and/or hypertension were well-controlled. As shown previously, we confirm the higher % EPA and % total n-3 fatty acids (but not DHA) in fasting plasma and extend these findings to include higher plasma concentrations (mg/L) of n-3 fatty acids as well. The EPA-predominant supplement raised DHA only in the young, whereas the DHA-predominant supplement raised EPA more in the young than in the elderly. The moderately healthy elderly clearly have higher plasma n-3 fatty acids but whether this reflects differences in intake versus aging-related changes in n-3 fatty acid metabolism remains to be elucidated.

Evidences suggest that omega-3 fatty acid (n-3 PUFA) metabolism is imbalanced in apolipoprotein E epsilon 4 isoform carriers (APOE4). This study aimed to investigate APOE genotype-dependant modulation of FA profiles, protein and enzyme important to fatty acid (FA) metabolism in the adipose tissue, the liver and the plasma using human APOE-targeted replacement mouse-model (N=37). FA transport (FATP) and binding (FABP) protein levels in tissues and concentrations of liver carnitine palmitoyltransferase 1 (CPT1) were performed. N-3 PUFA concentration was >45% lower in the adipose tissue and liver of APOE4 mice compared to APOE3 mice. In APOE4 mice, there were higher levels of FATP and FABP in the liver and higher FATP in the adipose tissue compared to APOE2 mice. There was a trend towards higher CPT1 concentrations in APOE4 mice compared to APOE3 mice. Therefore, since APOE-isoform differences were not always in line with the unbalanced n-3 PUFA profiles in organs, other proteins may be involved in maintaining n-3 PUFA homeostasis in mice with different APOE-isoforms.

OBJECTIVE: To evaluate the fatty acid profile of cord blood phospholipids (PL), cholesteryl esters (CE), triglycerides (TG) and non-esterified fatty acids (NEFA) in neonates born to mothers with gestational diabetes mellitus (GDM) compared to non-diabetic mothers. METHODS: The offspring of 30 pregnant women (15 non-diabetic controls, 15 with diet- or insulin-controlled GDM) were recruited before delivery. Cord blood was collected. After lipid extraction, PL, CE, TG and NEFA were separated by thin layer chromatography and analysed by gas chromatography. RESULTS: In GDM vs. control mothers, maternal glycated haemoglobin (A1C, mean±SD) was not different between groups: 5.3±0.5% vs. 5.3±0.3% (p=0.757), respectively. Cord plasma fatty acids were not different in TG, CE and NEFA between GDM and non-diabetic mothers. However, in PL, levels of palmitate, palmitoleate, oleate, vaccinate and di-homo-gamma-linolenate were significantly lower, with a trend for lower arachidonate (p=0.078), in neonates born to GDM mothers compared to controls. CONCLUSION: In contrast to other studies on cord blood docosahexaenoic acid (DHA) levels in GDM mothers, we did not found lower levels of DHA in cord PL, CE, TG or NEFA in neonates born to GDM compared to non-diabetic mothers.

Carlson and Kingston ([2007]: Am J Hum Biol 19:132–141) propose that preformed dietary docosahexaenoic acid (an omega-3 fatty acid in fish) did not have a significant role in hominin encephalization. Their position hinges on claiming that humans are able to make sufficient docosahexaenoic acid from the plant-based \parent" omega-3 fatty acid—alinolenic acid. They also suggest that hominin fish consumption occurred too late to have materially influenced encephalization. The authors quantify here a summary of the published data showing that humans cannot make sufficient docosahexaenoic acid to maintain normal infant brain development. The authors also provide evidence that the fossil record shows that some of the earliest hominins were regularly consuming fish. Hence, we reject Carlson and Kingston’s position and reiterate support for the concept that access to shore-based diets containing docosahexaenoic acid was necessary for hominin encephalization beyond the level seen in the great apes. Am. J. Hum. Biol. 19:578–581, 2007.

The usefulness of conjugated linoleic acid (CLA) as a nutraceutical remains ambiguous. Our objective was, therefore, to investigate the effect of CLA on body composition, blood lipids, and safety biomarkers in overweight, hyperlipidemic men. A double-blinded, 3-phase crossover trial was conducted in overweight (BMI $ 25 kg/m2 ), borderline hypercholesterolemic [LDL-cholesterol (C) $ 2.5 mmol/L] men aged 18–60 y. During three 8-wk phases, each separated by a 4-wk washout period, 27 participants consumed under supervision in random order 3.5 g/d of safflower oil (control), a 50:50 mixture of trans 10, cis 12 and cis 9, trans 11 (c9, t11) CLA:Clarinol G-80, and c9, t11 isomer:c9, t11 CLA. At baseline and endpoint of each phase, body weight, body fat mass, and lean body mass were measured by DXA. Blood lipid profiles and safety biomarkers, including insulin sensitivity, blood concentrations of adiponectin, and inflammatory (high sensitiveC-reactive protein, TNFa, and IL-6) and oxidative (oxidized-LDL) molecules, were measured. The effect of CLA consumption on fatty acid oxidation was also assessed. Compared with the control treatment, the CLA treatments did not affect changes in body weight, body composition, or blood lipids. In addition, CLA did not affect the b-oxidation rate of fatty acids or induce significant alterations in the safety markers tested. In conclusion, although no detrimental effects were caused by supplementation, these results do not confirm a role for CLA in either body weight or blood lipid regulation in humans. J. Nutr. 141: 1286–1291, 2011.

Au Canada, 17 millions d’adultes âgés entre 30–64 ans pourraient bénéficier d’une intervention en prévention pour diminuer leur risque de développer la maladie d’Alzheimer (MA). L’un des groupes les plus à risque de développer la MA, les porteurs de l’allèle epsilon 4 de l’apolipoprotéine E (E4), est au centre des recherches menées par mon groupe. Environ 20 % de la population des pays industrialisés sont porteurs d’E4 mais ce ne sont pas tous les porteurs qui développeront la MA, ce qui suggère que des facteurs environnementaux puissent moduler l’expression clinique et le risque de la MA chez les porteurs. Nous avons découvert que le métabolisme de l’acide docosahexaénoïque (DHA) est débalancé pendant le vieillissement et chez les porteurs de l’E4. Ces découvertes ont été répliquées dans un modèle de souris transgénique dont l’apolipoprotein de souris a été remplacé par de l’E4 humaine (hAPOE4). Nous avons récemment montré qu’une diète riche en DHA prévenait les déficits comportementaux chez la souris hAPOE4. Un autre groupe a montré que le ratio acide arachidonique (ARA) : DHA était débalancé dans le plasma des humains E4 et que ce marqueur constituait un marqueur pré-clinique de déclin cognitif léger/MA chez les E4. Avec notre approche de cinétique des acides gras uniformément marqués au carbone 13, nous avons montré que les cinétiques du 13C-DHA et du 13C-eicosapentaénoïque (EPA) étaient modifiées avec l’âge et chez les porteurs de l’E4. Cependant, la cinétique du 13C-ARA n’était pas modifiée avec l’âge. Nous avons également rapporté que, chez les personnes âgées, la synthèse du 13C-DHA débutait 2 h après la consommation du 13C-EPA tandis que cette production débutait seulement 7 jours après sa consommation chez les participants jeunes. Il est donc important de comprendre si les besoins en DHA des personnes âgées sont plus importants que ceux des jeunes, d’où sa synthèse précoce à partir de l’EPA ou si l’habilité des participants âgés à utiliser le DHA est plus, In Canada, ∼17 millions of adults between 30–64 years old could benefit from a prevention strategy to lower the risk of Alzheimer’s disease (AD). My group is working on a population that is particularly at risk of AD, the carriers of an epsilon 4 allele of apolipoprotein E (E4), a genetic risk. Around 20% of the population in industrial countries have this genetic risk but not all carriers will develop AD, suggesting that environmental factors modulate the clinical manifestation and risk of AD in the carriers. My group has discovered that the metabolism of docosahexaenoic acid (DHA) is disrupted during aging and in E4 carriers, a finding replicated in homozygous mice knocked-in for human E4 allele (hAPOE4). We recently showed that a diet containing DHA prevented behavioral deficits in hAPOE4 mice. Another group reported in E4 carriers that the ratio of arachidonic acid (ARA): DHA is disrupted in the plasma and constitute a preclinical marker of mild cognitive impairment/AD in E4 carriers. Using our kinetics approaches with uniformly labelled carbon 13 fatty acids, we showed that the kinetics of 13C-DHA is modified by age and E4 carriage. The kinetics of 13C-arachidonic acid was however not modified by age conversely to that of 13C-eicosapentaenoic acid (EPA). We also reported that the synthesis of 13C-DHA from 13C-EPA started 2 h after the tracer intake in older adults conversely to 7 d in young men. Whether old men needs in DHA is higher or whether their ability to use it is lower remains to be established. These differences in the DHA and EPA metabolism seems, however related to physiological modifications occurring during aging and in E4 carriers and obscure the relationship between plasma DHA and EPA levels, dietary fatty fish intake and cognitive status.