A Randomized Placebo-Controlled Pilot Trial of Omega-3 Fatty Acids and Alpha Lipoic Acid in Alzheimer’s Disease Is Antioxidant and n–3 Supplementation Able to Improve Functional Status in Poststroke Patients? Results from the Nutristroke Trial Cognitive function after supplementation with B vitamins and long-chain omega-3 fatty acids: ancillary findings from the SU.FOL.OM3 randomized trial. Effects of DHA Supplementation on Hippocampal Volume and Cognitive Function in Older Adults with Mild Cognitive Impairment: A 12-Month Randomized, Double-Blind, Placebo-Controlled Trial. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. DHA supplementation improved both memory and reaction time in healthy young adults: a randomized controlled trial. Mediterranean Diet and Age-Related Cognitive Decline: A Randomized Clinical Trial. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial Incorporation of eicosapentaenoic and docosahexaenoic acids into lipid pools when given as supplements providing doses equivalent to typical intakes of oily fish1234 The n-3 Polyunsaturated Fatty Acids Supplementation Improved the Cognitive Function in the Chinese Elderly with Mild Cognitive Impairment: A Double-Blind Randomized Controlled Trial Health, wellbeing and nutritional status of older people living in UK care homes: an exploratory evaluation of changes in food and drink provision Over-the-Counter Supplement Interventions to Prevent Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer-Type Dementia The effects of omega-3 fatty acids monotherapy in Alzheimer's disease and mild cognitive impairment: A preliminary randomized double-blind placebo-controlled study Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial. The SU.FOL.OM3 Study: a secondary prevention trial testing the impact of supplementation with folate and B-vitamins and/or Omega-3 PUFA on fatal and non fatal cardiovascular events, design, methods and participants characteristics Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. Pilot feasibility and safety study examining the effect of medium chain triglyceride supplementation in subjects with mild cognitive impairment: A randomized controlled trial Mediterranean diet improves cognition: the PREDIMED-NAVARRA randomised trial Fish oil supplementation increases event-related posterior cingulate activation in older adults with subjective memory impairment ω-3 fatty acid treatment in multiple sclerosis (OFAMS Study): a randomized, double-blind, placebo-controlled trial. Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. Docosahexaenoic acid supplementation improves the moderately severe dementia from thrombotic cerebrovascular diseases Effects of Omega-3 Fatty Acids on Inflammatory Markers in Cerebrospinal Fluid and Plasma in Alzheimer’s Disease: The OmegAD Study EFFECTS OF CHANGES IN FAT, FISH, AND FIBRE INTAKES ON DEATH AND MYOCARDIAL REINFARCTION: DIET AND REINFARCTION TRIAL (DART) Beneficial effects of dietary docosahexaenoic acid intervention on cognitive function and mental health of the oldest elderly in Japanese care facilities and nursing homes n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. Ethyl-EPA in Huntington disease Effect of fish oil on cognitive performance in older subjects Effects of n‐3 Fatty Acid Supplements in Diabetes Mellitus Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. Retraction and Republication: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. N Engl J Med 2013;368:1279-90. n-3 fatty acids and cardiovascular events after myocardial infarction.
Oxidative stress , inflammation , and increased cholesterol levels are all mechanisms that have been associated with Alzheimer ’s disease ( AD ) pathology . Several epidemiologic studies have reported a decreased risk of AD with fish consumption . This pilot study was design ed to evaluate the effects of supplementation with omega-3 fatty acids alone ( ω-3 ) or omega-3 plus alpha lipoic acid ( ω-3 + LA ) compared to placebo on oxidative stress biomarkers in AD . The primary outcome measure was peripheral F2-isoprostane levels ( oxidative stress measure ) . Secondary outcome measures included performance on : Mini-Mental State Examination ( MMSE ) , Activities of Daily Living/Instrumental Activities of Daily Living ( ADL/IADL ) , and Alzheimer Disease Assessment Scale-cognitive subscale ( ADAS-cog ) . Thirty-nine AD subjects were r and omized to one of three groups : 1 ) placebo , 2 ) ω-3 , or 3 ) ω-3 + LA for a treatment duration of 12 months . Eighty seven percent ( 34/39 ) of the subjects completed the 12-month intervention . There was no difference between groups at 12 months in peripheral F2-isoprostane levels ( p = 0.83 ) . The ω-3 + LA and ω-3 were not significantly different than the placebo group in ADAS-cog ( p = 0.98 , p = 0.86 ) and in ADL ( p = 0.15 , p = 0.82 ) . Compared to placebo , the ω-3+LA showed less decline in MMSE ( p < 0.01 ) and IADL ( p= 0.01 ) and the ω-3 group showed less decline in IADL ( p < 0.01 ) . The combination of ω-3+LA  slowed cognitive and functional decline in AD over 12 months . Because the results were generated from a small sample size , further evaluation of the combination of omega-3 fatty acids plus alpha-lipoic acid as a potential treatment in AD is warranted Background : To test whether supplementary antioxidants and n–3 fatty acids , alone or in combination , could improve functional status in stroke survivors . Methods : We performed a r and omized , double-blind , placebo-controlled clinical trial in 72 stroke patients ( 47 males ; age 65.3 ± 12.9 years ) admitted to a rehabilitation hospital for sequelae of first-ever ischemic stroke , and divided them into 4 subgroups . Group 1 patients received daily oral antioxidants , group 2 received n–3 polyunsaturated fatty acids , group 3 both supplements , and group 4 placebo , all for 12 months . No difference at baseline was observed among groups in neurological severity or in disability . All measures were repeated after 6 and 12 months of treatment . All major clinical events were recorded . Results : At baseline , 25 % of the patients had a low plasma vitamin status , and 48.5 % was at risk of undernutrition . At the 1-year follow-up , we observed a trend for lower mortality ( p = 0.060 ) in subgroups treated with n–3 fatty acids , but without significant differences in rehabilitation result status among groups . Conclusions : Malnutrition is widely observed in patients admitted to a rehabilitative hospital for stroke rehabilitation , and dietary supplementation , even if not able to improve rehabilitation results , is likely to reduce mortality at the 1-year follow-up BACKGROUND Rapid aging of the population worldwide necessitates a heightened concern about preventing cognitive decline . OBJECTIVE We investigated the effects of B vitamins and omega-3 ( n-3 ) fatty acid supplementation on cognition in a high-risk population . DESIGN This was an ancillary study of the SU.FOL.OM3 ( SUpplementation with FOLate , vitamins B-6 and B-12 and /or OMega-3 fatty acids ) secondary prevention trial conducted in France between 2003 and 2009 . The present sample included 1748 men and women aged 45 - 80 y with a history of myocardial infa rct ion , unstable angina , or ischemic stroke and who were recruited via a network of 417 physicians . With the use of block r and omization with stratification by sex , age , prior cardiovascular disease , and city of residence , participants were assigned in a 2 × 2 factorial design to 1 of 4 groups : 1 ) 5-methyltetrahydrofolate ( folate , 0.56 mg ) and vitamins B-6 ( 3 mg ) and B-12 ( 0.02 mg ) , 2 ) eicosapentaenoic and docosahexaenoic acids ( 600 mg ) in a 2:1 ratio , 3 ) B vitamins and omega-3 fatty acids , or 4 ) placebo .  Cognitive function after 4 y of supplementation was assessed with the French version of the modified Telephone Interview for Cognitive Status . RESULTS No significant main effects of group assignment on cognitive function were found ; however , we found some evidence of disease history- and age-specific effects . In the subgroup with prior stroke , for example , participants assigned to receive B vitamins plus omega-3 fatty acids were significantly less likely to have a decreased score on the temporal orientation task than were those assigned to receive placebo ( odds ratio : 0.43 ; 95 % CI : 0.21 , 0.86 ) . CONCLUSIONS If present , dietary effects on cognition are likely group-specific . These results could be useful in interventions aim ed at preventing cognitive decline in high-risk individuals . This trial is registered at controlled-trials.com as IS RCT N41926726 Docosahexaenoic acid ( DHA ) is important for brain function , and higher DHA intake is inversely correlated with relative risk of Alzheimer 's disease . The potential benefits of DHA supplementation in people with mild cognitive impairment ( MCI ) have not been fully examined . Our study aim ed to determine the effect of DHA supplementation on cognitive function and hippocampal atrophy in elderly subjects with MCI . This was a r and omized , double-blind , placebo-controlled trial in Tianjin , China . 240 individuals with MCI aged 65 years and over were recruited and equalized r and omly allocated to the DHA or the placebo group . Participants received 12-month DHA supplementation ( 2 g/day ) or corn oil as placebo . Both global and specific subdomains of cognitive function and hippocampal volume were measured at baseline , 6 months , and 12 months . Both changes were analyzed by repeated-measure analysis of variance ( ANOVA ) . This trial has been registered : ChiCTR-IOR-15006058 . A total of 219 participants ( DHA : 110 , Placebo : 109 ) completed the trial . The change in mean serum DHA levels was greater in the intervention group ( + 3.85 % ) compared to the control group ( + 1.06 % ) . Repeated- measures analyses of covariance showed that , over 12 months , there was a significant difference in the Full-Scale Intelligence Quotient ( ηp2 = 0.084 ; p = 0.039 ) , Information ( ηp2 = 0.439 ; p = 0.000 ) , and Digit Span ( ηp2 = 0.375 ; p = 0.000 ) between DHA-treated versus the placebo group . In addition , there were significant differences in volumes of left hippocampus ( ηp2 = 0.121 , p = 0.016 ) , right hippocampus ( ηp2 = 0.757 , p = 0.008 ) , total hippocampus ( ηp2 = 0.124 , p = 0.023 ) , and global cerebrum ( ηp2 = 0.145 , p = 0.032 ) between the two groups . These findings suggest that DHA supplementation ( 2 g/day ) for 12 months in MCI subjects can significantly improve cognitive function and slow the progression of hippocampal atrophy . Larger , longer-term confirmatory studies are warranted Depressive symptoms may increase the risk of progressing from mild cognitive impairment ( MCI ) to dementia . Consumption of n-3 PUFA may alleviate both cognitive decline and depression . The aim of the present study was to investigate the benefits of supplementing a diet with n-3 PUFA , DHA and EPA , for depressive symptoms , quality of life ( QOL ) and cognition in elderly people with MCI . We conducted a 6-month double-blind , r and omised controlled trial . A total of fifty people aged > 65 years with MCI were allocated to receive a supplement rich in EPA ( 1·67 g EPA + 0·16 g DHA/d ; n 17 ) , DHA ( 1·55 g DHA + 0·40 g EPA/d ; n 18 ) or the n-6 PUFA linoleic acid ( LA ; 2·2 g/d ; n 15 ) . Treatment allocation was by minimisation based on age , sex and depressive symptoms ( Geriatric Depression Scale , GDS ) . Physiological and cognitive assessment s , question naires and fatty acid composition of erythrocytes were obtained at baseline and 6 months ( completers : n 40 ; EPA n 13 , DHA n 16 , LA n 11 ) . Compared with the LA group , GDS scores improved in the EPA ( P=0·04 ) and DHA ( P=0·01 ) groups and verbal fluency ( Initial Letter Fluency ) in the DHA group ( P=0·04 ) . Improved GDS scores were correlated with increased DHA plus EPA ( r 0·39 , P=0·02 ) . Improved self-reported physical health was associated with increased DHA . There were no treatment effects on other cognitive or QOL parameters . Increased intakes of DHA and EPA benefited mental health in older people with MCI . Increasing n-3 PUFA intakes may reduce depressive symptoms and the risk of progressing to dementia . This needs to be investigated in larger , depressed sample s with MCI BACKGROUND Docosahexaenoic acid ( DHA ) is important for brain function , and its status is dependent on dietary intakes . Therefore , individuals who consume diets low in omega-3 ( n-3 ) polyunsaturated fatty acids may cognitively benefit from DHA supplementation . Sex and apolipoprotein E genotype ( APOE ) affect cognition and may modulate the response to DHA supplementation . OBJECTIVES We investigated whether a DHA supplement improves cognitive performance in healthy young adults and whether sex and APOE modulate the response . DESIGN Healthy adults ( n = 176 ; age range : 18 - 45 y ; nonsmoking and with a low intake of DHA ) completed a 6-mo r and omized , placebo-controlled , double-blind intervention in which they consumed 1.16 g DHA/d or a placebo .  Cognitive performance was assessed by using a computerized cognitive test battery . For all tests , z scores were calculated and clustered into cognitive domains as follows : episodic and working memory , attention , reaction time ( RT ) of episodic and working memory , and attention and processing speed . ANCOVA was conducted with sex and APOE as independent variables . RESULTS RTs of episodic and working memory improved with DHA compared with placebo [ mean difference ( 95 % CI ) : -0.18 SD ( -0.33 , -0.03 SD ) ( P = 0.02 ) and -0.36 SD ( -0.58 , -0.14 SD ) ( P = 0.002 ) , respectively ] . Sex × treatment interactions occurred for episodic memory ( P = 0.006 ) and the RT of working memory ( P = 0.03 ) . Compared with the placebo , DHA improved episodic memory in women [ 0.28 SD ( 0.08 , 0.48 SD ) ; P = 0.006 ] and RTs of working memory in men [ -0.60 SD ( -0.95 , -0.25 SD ) ; P = 0.001 ] . APOE did not affect cognitive function , but there were some indications of APOE × sex × treatment interactions . CONCLUSIONS DHA supplementation improved memory and the RT of memory  in healthy , young adults whose habitual diets were low in DHA  . The response was modulated by sex . This trial was registered at the New Zeal and Clinical Trials Registry ( http://www.anzctr.org.au/default.aspx ) as ACTRN12610000212055 IMPORTANCE Oxidative stress and vascular impairment are believed to partly mediate age-related cognitive decline , a strong risk factor for development of dementia . Epidemiologic studies suggest that a Mediterranean diet , an antioxidant-rich cardioprotective dietary pattern , delays cognitive decline , but clinical trial evidence is lacking . OBJECTIVE To investigate whether a Mediterranean diet supplemented with antioxidant-rich foods influences cognitive function compared with a control diet . DESIGN , SETTING , AND PARTICIPANTS Parallel-group r and omized clinical trial of 447 cognitively healthy volunteers from Barcelona , Spain ( 233 women [ 52.1 % ] ; mean age , 66.9 years ) , at high cardiovascular risk were enrolled into the Prevención con Dieta Mediterránea nutrition intervention trial from October 1 , 2003 , through December 31 , 2009 . All patients underwent neuropsychological assessment at inclusion and were offered retesting at the end of the study . INTERVENTIONS Participants were r and omly assigned to a Mediterranean diet supplemented with extravirgin olive oil ( 1 L/wk ) , a Mediterranean diet supplemented with mixed nuts ( 30 g/d ) , or a control diet ( advice to reduce dietary fat ) . MAIN OUTCOMES AND MEASURES Rates of cognitive change over time based on a neuropsychological test battery : Mini-Mental State Examination , Rey Auditory Verbal Learning Test ( RAVLT ) , Animals Semantic Fluency , Digit Span subtest from the Wechsler Adult Intelligence Scale , Verbal Paired Associates from the Wechsler Memory Scale , and the Color Trail Test . We used mean z scores of change in each test to construct 3 cognitive composites : memory , frontal ( attention and executive function ) , and global . RESULTS Follow-up cognitive tests were available in 334 participants after intervention ( median , 4.1 years ) . In multivariate analyses adjusted for confounders , participants allocated to a Mediterranean diet plus olive oil scored better on the RAVLT ( P = .049 ) and Color Trail Test part 2 ( P = .04 ) compared with controls ; no between-group differences were observed for the other cognitive tests . Similarly adjusted cognitive composites ( mean z scores with 95 % CIs ) for changes above baseline of the memory composite were 0.04 ( -0.09 to 0.18 ) for the Mediterranean diet plus olive oil , 0.09 ( -0.05 to 0.23 ; P = .04 vs controls ) for the Mediterranean diet plus nuts , and -0.17 ( -0.32 to -0.01 ) for the control diet . Respective changes from baseline of the frontal cognition composite were 0.23 ( 0.03 to 0.43 ; P = .003 vs controls ) , 0.03 ( -0.25 to 0.31 ) , and -0.33 ( -0.57 to -0.09 ) . Changes from baseline of the global cognition composite were 0.05 ( -0.11 to 0.21 ; P = .005 vs controls ) for the Mediterranean diet plus olive oil , -0.05 ( -0.27 to 0.18 ) for the Mediterranean diet plus nuts , and -0.38 ( -0.57 to -0.18 ) for the control diet .  All cognitive composites significantly ( P < .05 ) decreased from baseline in controls . CONCLUSIONS AND RELEVANCE In an older population , a Mediterranean diet supplemented with olive oil or nuts is associated with improved cognitive function . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N35739639 BACKGROUND Epidemiologic and animal studies have suggested that dietary fish or fish oil rich in omega-3 fatty acids , for example , docosahexaenoic acid and eicosapentaenoic acid , may prevent Alzheimer disease ( AD ) . OBJECTIVE To determine effects of dietary omega-3 fatty acid supplementation on cognitive functions in patients with mild to moderate AD . DESIGN R and omized , double-blind , placebo-controlled clinical trial . PARTICIPANTS Two hundred four patients with AD ( age range [ mean + /- SD ] , 74 + /- 9 years ) whose conditions were stable while receiving acetylcholine esterase inhibitor treatment and who had a Mini-Mental State Examination ( MMSE ) score of 15 points or more were r and omized to daily intake of 1.7 g of docosahexaenoic acid and 0.6 g of eicosapentaenoic acid ( omega-3 fatty acid-treated group ) or placebo  for 6 months , after which all received omega-3 fatty acid supplementation for 6 months more . MAIN OUTCOME MEASURES The primary outcome was cognition measured with the MMSE and the cognitive portion of the Alzheimer Disease Assessment Scale . The secondary outcome was global function as assessed with the Clinical Dementia Rating Scale ; safety and tolerability of omega-3 fatty acid supplementation ; and blood pressure determinations . RESULTS One hundred seventy-four patients fulfilled the trial . At baseline , mean values for the Clinical Dementia Rating Scale , MMSE , and cognitive portion of the Alzheimer Disease Assessment Scale in the 2 r and omized groups were similar . At 6 months , the decline in cognitive functions as assessed by the latter 2 scales did not differ between the groups . However , in a subgroup ( n = 32 ) with very mild cognitive dysfunction ( MMSE > 27 points ) , a significant ( P<.05 ) reduction in MMSE decline rate was observed in the omega-3 fatty acid-treated group compared with the placebo group . A similar arrest in decline rate was observed between 6 and 12 months in this placebo subgroup when receiving omega-3 fatty acid supplementation . The omega-3 fatty acid treatment was safe and well tolerated . CONCLUSIONS Administration of omega-3 fatty acid in patients with mild to moderate AD did not delay the rate of cognitive decline according to the MMSE or the cognitive portion of the Alzheimer Disease Assessment Scale . However , positive effects were observed in a small group of patients with very mild AD ( MMSE > 27 points ) BACKGROUND No large trials have been done to investigate the efficacy of an intervention combining a specific compound and several lifestyle interventions compared with placebo for the prevention of cognitive decline . We tested the effect of omega 3 polyunsaturated fatty acid supplementation and a multidomain intervention ( physical activity , cognitive training , and nutritional advice ) , alone or in combination , compared with placebo , on cognitive decline . METHODS The Multidomain Alzheimer Preventive Trial was a 3-year , multicentre , r and omised , placebo-controlled superiority trial with four parallel groups at 13 memory centres in France and Monaco . Participants were non-demented , aged 70 years or older , and community-dwelling , and had either relayed a spontaneous memory complaint to their physician , limitations in one instrumental activity of daily living , or slow gait speed . They were r and omly assigned ( 1:1:1:1 ) to either the multidomain intervention ( 43 group sessions integrating cognitive training , physical activity , and nutrition , and three preventive consultations ) plus omega 3 polyunsaturated fatty acids ( ie , two capsules a day providing a total daily dose of 800 mg docosahexaenoic acid and 225 mg eicosapentaenoic acid ) , the multidomain intervention plus placebo , omega 3 polyunsaturated fatty acids alone , or placebo alone . A computer-generated r and omisation procedure was used to stratify patients by centre . All participants and study staff were blinded to polyunsaturated fatty acid or placebo assignment , but were unblinded to the multidomain intervention component . Assessment of cognitive outcomes was done by independent neuropsychologists blinded to group assignment . The primary outcome was change from baseline to 36 months on a composite Z score combining four cognitive tests ( free and total recall of the Free and Cued Selective Reminding test , ten Mini-Mental State Examination orientation items , Digit Symbol Substitution Test , and Category Naming Test ) in the modified intention-to-treat population . The trial was registered with Clinical Trials.gov ( NCT00672685 ) . FINDINGS 1680 participants were enrolled and r and omly allocated between May 30 , 2008 , and Feb 24 , 2011 . In the modified intention-to-treat population ( n=1525 ) , there were no significant differences in 3-year cognitive decline between any of the three intervention groups and the placebo group . Between-group differences compared with placebo were 0·093 ( 95 % CI 0·001 to 0·184 ; adjusted p=0·142 ) for the combined intervention group , 0·079 ( -0·012 to 0·170 ; 0·179 ) for the multidomain intervention plus placebo group , and 0·011 ( -0·081 to 0·103 ; 0·812 ) for the omega 3 polyunsaturated fatty acids group . 146 ( 36 % ) participants in the multidomain plus polyunsaturated fatty acids group , 142 ( 34 % ) in the multidomain plus placebo group , 134 ( 33 % ) in the polyunsaturated fatty acids group , and 133 ( 32 % ) in the placebo group had at least one serious emerging adverse event . Four treatment-related deaths were recorded ( two in the multidomain plus placebo group and two in the placebo group ) . The interventions did not raise any safety concerns and there were no differences between groups in serious or other adverse events . INTERPRETATION The multidomain intervention and polyunsaturated fatty acids , either alone or in combination , had no significant effects on cognitive decline over 3 years in elderly people with memory complaints . An effective multidomain intervention strategy to prevent or delay cognitive impairment and the target population remain to be determined , particularly in real-world setting s. FUNDING French Ministry of Health , Pierre Fabre Research Institute , Gerontopole , Exhonit Therapeutics , Avid Radiopharmaceuticals Background : Estimation of the intake of oily fish at a population level is difficult . The measurement of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) in biological sample s may provide a useful biomarker of intake . Objective : We identified the most appropriate biomarkers for the assessment of habitual oily fish intake and changes in intake by elucidating the dose- and time-dependent response of EPA and DHA incorporation into various biological sample s that represent roles in fatty acid transport , function , and storage . Design : This was a double-blind , r and omized , controlled intervention trial in 204 men and women that lasted 12 mo .  EPA and DHA capsules were provided in a manner to reflect sporadic consumption of oily fish ( ie , 1 , 2 , or 4 times/wk ) .  EPA and DHA  were assessed at 9 time points over 12 mo in 9 sample types ( red blood cells , mononuclear cells , platelets , buccal cells , adipose tissue , plasma phosphatidylcholine , triglycerides , cholesteryl esters , and nonesterified fatty acids ) . Results : A dose response ( P < 0.05 ) was observed for EPA and DHA in all pools except for red blood cell EPA ( P = 0.057 ) . EPA and DHA measures in plasma phosphatidylcholine and platelets were best for the discrimination between different intakes ( P < 0.0001 ) . The rate of incorporation varied between sample types , with the time to maximal incorporation ranging from days ( plasma phosphatidylcholine ) to months ( mononuclear cells ) to > 12 mo ( adipose tissue ) . Conclusions : Plasma phosphatidylcholine EPA plus DHA was identified as the most suitable biomarker of acute changes in  EPA and DHA intake , and platelet and mononuclear cell EPA plus DHA were the most suitable biomarkers of habitual intake . This trial was registered at Current Controlled Trials ( www.controlled-trials.com ) as IS RCT N48398526 Objective : Intake of n-3 polyunsaturated fatty acids ( n-3 PUFAs ) may protect against mild cognitive impairment ( MCI ) . However , there is still a lack of the n-3 PUFAs intervention in the elderly with MCI in China . The aim of the present study was to investigate the effect of n-3 PUFA supplementation on cognitive function in the Chinese elderly with MCI . Methods : Eighty six MCI individuals aged 60 years or older were r and omly assigned to receive either n-3 PUFAs ( 480 mg DHA and 720 mg EPA per day , n = 44 ) or placebo ( olive oil , n = 42 ) capsules . The changes of cognitive functions were assessed using Basic Cognitive Aptitude Tests ( BCAT ) . Results : The mean age of participants was 71 years old , and 59 % of the participants were men .  n-3 PUFA supplementation was associated with improved total BCAT scores , perceptual speed , space imagery efficiency , and working memory ( p < 0.01 ) , but not with mental arithmetic efficiency or recognition memory ( p > 0.05 ) . Subgroup analysis by sex showed that n-3 PUFAs significantly improved perceptual speed ( p = 0.001 ) , space imagery efficiency ( p = 0.013 ) , working memory ( p = 0.018 ) , and total BCAT scores ( p = 0.000 ) in males . However , in females , the significant beneficial effects can only be observed in perceptual speed ( p = 0.027 ) , space imagery efficiency ( p = 0.006 ) , and total BCAT scores ( p = 0.015)—not working memory ( p = 0.113 ) . Conclusion : n-3 PUFAs can improve cognitive function in people with MCI . Further studies with different fish oil dosages , longer intervention periods , and larger sample sizes should be investigated before definite recommendations can be made Background Food and drink are important determinants of physical and social health in care home residents . This study explored whether a pragmatic methodology including routinely collected data was feasible in UK care homes , to describe the health , wellbeing and nutritional status of care home residents and assess effects of changed provision of food and drink at three care homes on residents '  falls ( primary outcome ) , anaemia , weight , dehydration , cognitive status , depression , lipids and satisfaction with food and drink provision . Methods We measured health , wellbeing and nutritional status of 120 of 213 residents of six care homes in Norfolk , UK . An intervention comprising improved dining atmosphere , greater food choice , extended restaurant hours , and readily available snacks and drinks machines was implemented in three care homes . Three control homes maintained their previous system . Outcomes were assessed in the year before and the year after the changes . Results Use of routinely collected data was partially successful , but loss to follow up and levels of missing data were high , limiting power to identify trends in the data .This was a frail older population ( mean age 87 , 71 % female ) with multiple varied health problems . During the first year 60 % of residents had one or more falls , 40 % a wound care visit , and 40 % a urinary tract infection . 45 % were on diuretics , 24 % antidepressants , and 43 % on psychotropic medication . There was a slight increase in falls from year 1 to year 2 in the intervention homes , and a much bigger increase in control homes , leading to a statistically non-significant 24 % relative reduction in residents ' rate of falls in intervention homes compared with control homes ( adjusted rate ratio 0.76 , 95 % CI 0.57 to 1.02 , p = 0.06 ) . Conclusions Care home residents are frail and experience multiple health risks . This intervention to improve food and drink provision was well received by residents , but effects on health indicators ( despite the relative reduction in falls rate ) were inconclusive , partly due to problems with routine data collection and loss to follow up . Further research with more homes is needed to underst and which , if any , components of the intervention may be successful . Trial registration Trial registration : IS RCT N86057119 Fear of losing cognitive ability to Alzheimer disease and related dementias drives a growing industry of over-the-counter ( OTC ) supplements intended to boost brain health and prevent or slow cognitive decline . The Alzheimer 's Research and Prevention Foundation recommends that people be sure to take [ their ] vitamins and memory-specific nutrients and suggests optimal dosages for an array of vitamins and nutrients ( 1 ) . An estimated 63 % of older adults use OTC supplements ( 2 ) . In 2015 , Americans spent $ 37 billion on OTC supplements and $ 91 million on ginkgo bilobajust one of a growing number of supplements marketed to boost memory ( 3 ) . Whether any dietary or herbal supplement or specific food can prevent or delay cognitive decline is unclear . This review summarizes the evidence on efficacy and harms of OTC supplements to prevent or delay cognitive decline , mild cognitive impairment ( MCI ) , or clinical Alzheimer-type dementia . Methods We developed and followed a st and ard protocol ( https://effectivehealthcare.ahrq.gov/topics/cognitive-decline/ research - protocol ) . Data Sources and Search es We search ed Ovid MEDLINE , PsycINFO , EMBASE , and the Cochrane Central Register of Controlled Trials for relevant literature published between 2009 and July 2017 ( see Part A of the Supplement for search strategies ) . We identified studies published before 2009 by search ing citations in systematic review s and pertinent studies ( 48 ) . Supplement . Supplementary Material Study Selection Two investigators independently review ed titles and abstract s and screened the full text of potentially eligible references . We included r and omized and nonr and omized controlled trials of any OTC supplements  that enrolled adults with normal cognition or MCI . Because the review focused on prevention , we excluded studies of adults with dementia . We included only studies that followed participants for at least 6 months , reported incident MCI or dementia ( our main outcome of interest ) or cognitive performance outcomes , and were published in English . There were no restrictions on sample size or comparator type . Disagreements about eligibility were resolved by consensus . Data Extraction and Quality Assessment One review er extracted information on study design , population , intervention , comparator , setting , and funding source from eligible studies . For each study , 2 review ers read the full text and independently rated risk of bias for the overall study and for each outcome and time point as low , medium , or high according to Agency for Healthcare Research and Quality ( AHRQ ) guidance ( 9 ) . Outcomes and adverse events were extracted from studies with low to medium risk of bias . A second review er checked the quality of all data . Data Synthesis and Analysis We summarized results for studies with low to medium risk of bias by intervention , baseline cognitive status ( presumed normal cognition or MCI ) , and outcome . Because studies used highly variable outcome measures , neuropsychological tests were categorized according to the following 4 specific cognitive domains to facilitate analysis : executive function , attention , and processing speed ; memory ; language ; and visuospatial abilities ( see Supplement Table A1 for the list of cognitive outcomes that were used and Supplement Table A2 for measurement properties , including change indices , of neuropsychological tests that were used ) . We grouped executive function , attention , and processing speed because a large number of cognitive tests frequently measure all 3 of these related domains . Our preliminary work found that studies analyzed and reported cognitive test results in widely varying ways , frequently making it impossible to determine effect size or assess whether between-group differences in scores or subscores were clinical ly meaningful . We instead analyzed and report cognitive test results by direction of effect and statistical significance . When there were at least 2 studies or 1 large study ( > 500 participants ) for a treatment comparison , 2 review ers grade d strength of evidence for each outcome on the basis of study limitations , directness , consistency , and precision ; otherwise , strength of evidence was grade d as insufficient ( 10 ) . Assessment s were confirmed by consensus . Role of the Funding Source This review was funded by the National Institute on Aging and the AHRQ . These agencies and members of the National Academies Committee on Preventing Dementia and Cognitive Impairment helped refine the scope and review ed a draft report of findings . The authors are solely responsible for the content , preparation , and writing of the manuscript and the decision to su bmi t it for publication . Results We identified 63 publications of 56 unique studies covering 13 categories of OTC treatments ( Appendix Figure ) . A third of the studies were at least partially funded by industry . Eighteen were assessed as having high risk of bias and were not further analyzed . Table 1 depicts the interventions and population s of the 38 studies judged as having low or medium risk of bias . Detailed evidence tables and risk-of-bias assessment s are presented for studies involving adults with normal cognition in Part B of the Supplement and for studies involving adults with MCI in Part C of the Supplement ; these tables are also available in the parent technical report ( 11 ) . Table 2 summarizes the strength of evidence for the findings . Appendix Figure . Evidence search and selection . Table 1 . Number of Studies With Low or Moderate Risk of Bias , by Intervention Type and Population Table 2 . Effect of OTC Supplement Interventions Versus Control on Cognitive Outcomes in Adults With Normal Cognition and MCI * Table . Continued . -3 Fatty Acids Normal Cognition Seven r and omized trials with low to medium risk of bias ( n= 21027 ) that enrolled adults with presumed normal cognition compared -3 fatty acids with placebo ( 1218 ) . Interventions lasted from 6 months to more than 6 years . Five trials reported cognitive exclusion criteria , including a Mini-Mental State Examination ( MMSE ) score less than 22 ( 14 , 15 ) , less than 24 ( 13 ) , or less than 26 ( 16 , 17 ) out of a possible 30 points . One study used only docosahexaenoic acid ( DHA ) ( 17 ) ; all others used some combination of eicosapentaenoic acid ( EPA ) plus DHA . The largest study ( n= 15077 ) allowed participation of adults who were already using -3 supplementation  ( 18 ) . Population s varied in baseline health and risk for cognitive decline . Participants included patients with diabetes or impaired glucose tolerance ( 18 ) , patients with a history of ischemic heart disease ( 12 ) or coronary artery disease ( 14 ) , and healthy adults ( 13 , 1517 ) . None of the studies reported on incident Alzheimer-type dementia or MCI . A large multinational study of adults with diabetes or impaired glucose tolerance ( n= 15077 ) used a combination of clinical diagnosis or an MMSE score less than 24 and found no difference in probable dementia incidence between the EPA/DHA group and the placebo group at a median follow-up of 6.2 years ( hazard ratio [ HR ] , 0.93 [ 95 % CI , 0.86 to 1.0 ] ) ( 18 ) . Overall , studies provided low-strength evidence suggesting that -3 fatty acids do not improve cognitive performance in adults with normal cognition compared with placebo . Of 67 reported cognitive testsincluding 9 brief cognitive tests ( 12 , 14 , 17 , 18 ) ; 1 test of multidomain neuropsychological performance ( 13 ) ; 32 tests of executive function , attention , and processing speed ( 13 , 1518 ) ; and 25 memory tests ( 13 , 1517)only 5 showed scores that were statistically significantly better in -3treated groups than in control groups . These 5 tests were administered in 2 studies that had relatively short follow-up ( 6 months ) and included fewer than 5 % of the total participants in the 7 studies ( 16 , 17 ) . Four studies did not report adverse events , and no studies reported statistically significant differences in adverse events between the -3 and placebo groups . The parent technical report provides details on adverse events ( 11 ) . Subgroups were examined in 4 studies . No statistically significant differences in effect were found by age ( 12 , 14 , 15 , 18 ) , sex ( 14 , 15 , 18 ) , time since myocardial infa rct ion ( 14 ) , or diabetes status ( 18 ) . One study ( n= 884 ) with 4-year follow-up examined the comparative effectiveness of -3 fatty acids and B vitamins on cognition ( 12 ) . No between-group differences were found for any cognitive outcome between -3 fatty acids ( alone or in combination with B vitamins ) and B vitamins alone . Adverse events were not reported . MCI Evidence was insufficient for benefits of -3 fatty acids on cognitive outcomes compared with placebo after 1 year in the single small study of adults with MCI that we identified ( n= 36 ) ( 19 ) . No serious adverse events were reported . Soy Normal Cognition  Five r and omized trials with low to medium risk of bias that enrolled 35 to 350 participants ( n= 829 ) and lasted 6 months to 2.5 years compared soy supplementation with placebo ( 2025 ) . Population s included older adults without dementia ( 20 ) and generally healthy postmenopausal women ( 21 , 2325 ) . Baseline testing excluded persons with cognitive impairment in 2 of the studies ( 20 , 21 ) . Mean reported baseline MMSE scores  ranged from 28 to 29 ( 2023 ) . None of the trials reported MCI or Alzheimer-type dementia outcomes . Evidence was deemed insufficient to determine soy 's effect on brief cognitive test performance ( 21 , 25 ) and multidomain neuropsychological test performance ( 21 , 24 ) and low-strength for soy having no effect on executive function , attention , and processing speed ( 20 , 21 , 2325 ) or memory ( 2025 ) for up to 2.5 years . Two studies reported no serious adverse events and no statistically significant differences in adverse events between the soy and placebo groups ( 21 , 25 ) . MCI Evidence was insufficient to determine any beneficial effect on cognitive outcomes from soybean-derived phosphatidylserine at 2 doses ( 100 and 300 mg daily ) compared with placebo after 9 months in a single small study of adults A 24-week , r and omized , double-blind placebo-controlled study was carried out to test the feasibility of using omega-3 polyunsaturated fatty acids ( PUFAs ) monotherapy in people with cognitive impairment and to explore its effects on cognitive function and general clinical condition in these participants . Twenty three participants with mild or moderate Alzheimer 's disease and twenty three with mild cognitive impairment were r and omized to receive omega-3 PUFAs 1.8 g/day or placebo ( olive oil ) . The data of 35 ( 76 % ) participants with at least one post-treatment visit was analyzed . There were no severe adverse effects in either group and it suggests that omega-3 PUFAs were well tolerable in this population . The treatment group showed better improvement on the Clinician 's Interview-Based Impression of Change Scale ( CIBIC-plus ) than those in the placebo group over the 24 week follow-up ( p=0.008 ) . There was no significant difference in the cognitive portion of the Alzheimer 's Disease Assessment Scale ( ADAS-cog ) change during follow-up in these two groups . However , the omega-3 fatty acids group showed significant improvement in ADAS-cog compared to the placebo group in participants with mild cognitive impairment ( p=0.03 ) , which was not observed in those with Alzheimer 's disease . Higher proportions of eicosapentaenoic acid on RBC membranes were also associated with better cognitive outcome ( p=0.003 ) . Further studies should be considered with a larger- sample size , diet registration , higher dosages , comparisons between different combinations of PUFAs , and greater homogeneity of participants , especially those with mild Alzheimer 's disease and mild cognitive impairment IMPORTANCE Observational data have suggested that high dietary intake of saturated fat and low intake of vegetables may be associated with increased risk of Alzheimer disease . OBJECTIVE To test the effects of oral supplementation with nutrients on cognitive function . DESIGN , SETTING , AND PARTICIPANTS In a double-masked r and omized clinical trial ( the Age-Related Eye Disease Study 2 [ AREDS2 ] ) , retinal specialists in 82 US academic and community medical centers enrolled and observed participants who were at risk for developing late age-related macular degeneration ( AMD ) from October 2006 to December 2012 . In addition to annual eye examinations , several vali date d cognitive function tests were administered via telephone by trained personnel at baseline and every 2 years during the 5-year study . INTERVENTIONS Long-chain polyunsaturated fatty acids ( LCPUFAs ) ( 1 g ) and /or lutein ( 10 mg)/zeaxanthin ( 2 mg ) vs placebo were tested in a factorial design . All participants were also given varying combinations of vitamins C , E , beta carotene , and zinc . MAIN OUTCOMES AND MEASURES The main outcome was the yearly change in composite scores determined from a battery of cognitive function tests from baseline . The analyses , which were adjusted for baseline age , sex , race , history of hypertension , education , cognitive score , and depression score , evaluated the differences in the composite score between the treated vs untreated groups . The composite score provided an overall score for the battery , ranging from -22 to 17 , with higher scores representing better function . RESULTS A total of 89 % ( 3741/4203 ) of AREDS2 participants consented to the ancillary cognitive function study and 93.6 % ( 3501/3741 ) underwent cognitive function testing . The mean ( SD ) age of the participants was 72.7 ( 7.7 ) years and 57.5 % were women . There were no statistically significant differences in change of scores for participants r and omized to receive supplements vs those who were not . The yearly change in the composite cognitive function score was -0.19 ( 99 % CI , -0.25 to -0.13 ) for participants r and omized to receive LCPUFAs vs -0.18 ( 99 % CI , -0.24 to -0.12 ) for those r and omized to no LCPUFAs ( difference in yearly change , -0.03 [ 99 % CI , -0.20 to 0.13 ] ; P = .63 ) . Similarly , the yearly change in the composite cognitive function score was -0.18 ( 99 % CI , -0.24 to -0.11 ) for participants r and omized to receive lutein/zeaxanthin vs -0.19 ( 99 % CI , -0.25 to -0.13 ) for those r and omized to not receive lutein/zeaxanthin ( difference in yearly change , 0.03 [ 99 % CI , -0.14 to 0.19 ] ; P = .66 ) . Analyses were also conducted to assess for potential interactions between LCPUFAs and  lutein/zeaxanthin and none were found to be significant . CONCLUSIONS AND RELEVANCE Among older persons with AMD , oral supplementation with LCPUFAs or lutein/zeaxanthin had no statistically significant effect on cognitive function . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00345176 Background During the last decades , many basic and clinical research have pointed to the role of B vitamins ( folate , vitamins B6 and B12 ) and n-3 fatty acids as nutritional factors that might have a protective effect on the development of cardiovascular diseases ( CVD ) . Methods / design The SU.FOL.OM3 ( SUpplementation with FOlate , vitamin B6 and B12 and /or OMega-3 fatty acids ) trial is a r and omized double-blind , placebo-controlled , secondary -prevention trial design ed to test the efficacy of 5-methyl tetra-hydro-folates ( 5-MTHF ) supplementation , in combination with vitamin B6 and B12 and /or n-3 fatty acids , at nutritional doses , on fatal and non fatal ischemic CVD in a 2 × 2 factorial design . A total of 2501 patients aged between 45 and 80 years who had a past history , in the previous year , of myocardial infa rct ion ( n = 1151 ) or instable angina pectoris ( n = 711 ) or an ischemic stroke ( n = 639 ) were included . Subjects have to be supplemented and followed up for five years . Daily supplementation comprised nutritional doses of 5-MTHF ( 560 μg ) , vitamin B6 ( 3 mg ) and B12 ( 20 μg ) and /or n-3 fatty acids ( 600 mg with an EPA : DHA ratio of 2:1 ) . A factorial design 2 × 2 has been applied to investigate the separate effects of the B-vitamins , and the n-3 fatty acids , as well as their interaction as compared to the placebo . The primary endpoint is a combination of myocardial infa rct ion , ischemic stroke and cardiovascular death . Secondary endpoints are events of the composite endpoint taken separately , total mortality , and other cardiovascular events such as acute coronary syndromes , coronary revascularization , cardiac failure , arrhythmia ... Conclusion Baseline socio-demographic and medical characteristics of participants are totally comparable in the four r and omized groups . Trial registration Current Controlled Trials IS RCT Rationale Epidemiological studies have suggested a beneficial effect of fish oil supplementation in halting the initial progression of Alzheimer ’s disease . However , it remains unclear whether fish oil affects cognitive function in older people with mild cognitive impairment ( MCI ) . Objectives This study investigated the effects of fish oil supplementation on cognitive function in elderly person with MCI . Methods This was a 12-month , r and omised , double-blind , placebo-controlled study using fish oil supplementation with concentrated docosahexaenoic acid ( DHA ) .  Thirty six low-socioeconomic-status elderly subjects with MCI were r and omly assigned to receive either concentrated DHA fish oil ( n = 18 ) or placebo ( n = 18 ) capsules . The changes of memory , psychomotor speed , executive function and attention , and visual-constructive skills were assessed using cognitive tests . Secondary outcomes were safety and tolerability of the DHA concentrate . Results The fish oil group showed significant improvement in short-term and working memory ( F = 9.890 ; ηp2 = 0.254 ; p < 0.0001 ) , immediate verbal memory ( F = 3.715 ; ηp2 = 0.114 ; p < 0.05 ) and delayed recall capability ( F = 3.986 ; ηp2 = 0.121 ; p < 0.05 ) . The 12-month change in memory ( p < 0.01 ) was significantly better in the fish oil group . Fish oil consumption was well tolerated , and the side effects were minimal and self-limiting . Conclusions This study suggested the potential role of fish oil to improve memory function in MCI subjects . Studies with larger sample sizes , longer intervention periods , different fish oil dosages and genetic determinations should be investigated before definite recommendations can be made Objective To investigate whether dietary supplementation with B vitamins or omega 3 fatty acids , or both , could prevent major cardiovascular events in patients with a history of ischaemic heart disease or stroke . Design Double blind , r and omised , placebo controlled trial ; factorial design . Setting Recruitment throughout France via a network of 417 cardiologists , neurologists , and other physicians . Participants 2501 patients with a history of myocardial infa rct ion , unstable angina , or ischaemic stroke . Intervention Daily dietary supplement containing 5-methyltetrahydrofolate ( 560 μg ) , vitamin B-6 ( 3 mg ) , and vitamin B-12 ( 20 μg ) or placebo ; and containing omega 3 fatty acids ( 600 mg of eicosapentanoic acid and docosahexaenoic acid at a ratio of 2:1 ) or placebo . Median duration of supplementation was 4.7 years . Main outcome measures Major cardiovascular events , defined as a composite of non-fatal myocardial infa rct ion , stroke , or death from cardiovascular disease . Results Allocation to B vitamins lowered plasma homocysteine concentrations by 19 % compared with placebo , but had no significant effects on major vascular events ( 75 v 82 patients , hazard ratio , 0.90 ( 95 % confidence interval 0.66 to 1.23 , P=0.50 ) ) . Allocation to omega 3 fatty acids  increased plasma concentrations of omega 3 fatty acids by 37 % compared with placebo , but also had no significant effect on major vascular events ( 81 v 76 patients , hazard ratio 1.08 ( 0.79 to 1.47 , P=0.64 ) ) . Conclusion This study does not support the routine use of dietary supplements containing B vitamins or omega 3 fatty acids for prevention of cardiovascular disease in people with a history of ischaemic heart disease or ischaemic stroke , at least when supplementation is introduced after the acute phase of the initial event . Trial registration Current Controlled Trials IS RCT N41926726 CONTEXT Docosahexaenoic acid ( DHA ) is the most abundant long-chain polyunsaturated fatty acid in the brain . Epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of Alzheimer disease . Animal studies demonstrate that oral intake of DHA reduces Alzheimer-like brain pathology . OBJECTIVE To determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease . DESIGN , SETTING , AND PATIENTS A r and omized , double-blind , placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease ( Mini-Mental State Examination scores , 14 - 26 ) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer 's Disease Cooperative Study . INTERVENTION Participants were r and omly assigned to algal DHA at a dose of 2 g/d or to identical placebo ( 60 % were assigned to DHA and 40 % were assigned to placebo ) . Duration of treatment was 18 months . MAIN OUTCOME MEASURES Change in the cognitive subscale of the Alzheimer 's Disease Assessment Scale ( ADAS-cog ) and change in the Clinical Dementia Rating ( CDR ) sum of boxes . Rate of brain atrophy was also determined by volumetric magnetic resonance imaging in a sub sample of participants ( n = 102 ) . RESULTS A total of 402 individuals were r and omized and a total of 295 participants completed the trial while taking study medication ( DHA : 171 ; placebo : 124 ) . Supplementation with DHA had no beneficial effect on rate of change on ADAS-cog score , which increased by a mean of 7.98 points ( 95 % confidence interval [ CI ] , 6.51 - 9.45 points ) for the DHA group during 18 months vs 8.27 points ( 95 % CI , 6.72 - 9.82 points ) for the placebo group ( linear mixed-effects model : P = .41 ) . The CDR sum of boxes score increased by 2.87 points ( 95 % CI , 2.44 - 3.30 points ) for the DHA group during 18 months compared with 2.93 points ( 95 % CI , 2.44 - 3.42 points ) for the placebo group ( linear mixed-effects model : P = .68 ) . In the sub population of participants ( DHA : 53 ; placebo : 49 ) , the rate of brain atrophy was not affected by treatment with DHA . Individuals in the DHA group had a mean decline in total brain volume of 24.7 cm(3 ) ( 95 % CI , 21.4 - 28.0 cm(3 ) ) during 18 months and a 1.32 % ( 95 % CI , 1.14%-1.50 % ) volume decline per year compared with 24.0 cm(3 ) ( 95 % CI , 20 - 28 cm(3 ) ) for the placebo group during 18 months and a 1.29 % ( 95 % CI , 1.07%-1.51 % ) volume decline per year ( P = .79 ) . CONCLUSION Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline  in patients with mild to moderate Alzheimer disease . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00440050 Background Impaired brain glucose metabolism appears to be a potential pathogenic feature of mild cognitive impairment ( MCI ) . This study examined the potential for increasing circulating ketone bodies through medium chain triglyceride ( MCT ) supplementation , as a means to beneficially modulate brain homeostasis in subjects with MCI . Methods Six participants with MCI were enrolled in a r and omized placebo-controlled trial . Participants received 56 g/day of either medium chain triglycerides ( MCTs ) or placebo for 24 weeks . Serum β-hydroxybutyrate concentrations , apolipoprotein-E4 status , and cognitive assessment s were carried out . Due to the small number of participants only the raw scores were examined . Results Intake of MCT oil  increased serum ketone bodies and improved memory , while intake of placebo did not show improvement in any of the cognitive measures tested . Conclusions Consumption of 56 g/day of MCTs for 24 weeks increases serum ketone concentrations and appears to be a c and i date for larger r and omized control trials in the future that quantify the modulation of cognitive function through supplementation with ketone precursors , in patients with MCI Objective Previous observational studies reported beneficial effects of the Mediterranean diet ( MedDiet ) on cognitive function , but results were inconsistent . We assessed the effect on cognition of a nutritional intervention using MedDiets in comparison with a low-fat control diet . Methods We assessed 522 participants at high vascular risk ( 44.6 % men , age 74.6 ± 5.7 years at cognitive evaluation ) enrolled in a multicentre , r and omised , primary prevention trial ( PREDIMED ) , after a nutritional intervention comparing two MedDiets ( supplemented with either extra-virgin olive oil ( EVOO ) or mixed nuts ) versus a low-fat control diet . Global cognitive performance was examined by  Mini-Mental State Examination ( MMSE ) and  Clock Drawing Test ( CDT ) after 6.5 years of nutritional intervention . Research ers who assessed the outcome were blinded to group assignment . We used general linear models to control for potential confounding . Results After adjustment for sex , age , education , Apolipoprotein E genotype , family history of cognitive impairment/dementia , smoking , physical activity , body mass index , hypertension , dyslipidaemia , diabetes , alcohol and total energy intake , participants allocated to the MedDiet+EVOO showed higher mean MMSE and CDT scores with significant differences versus control ( adjusted differences : + 0.62 95 % CI + 0.18 to + 1.05 , p=0.005 for MMSE , and + 0.51 95 % CI + 0.20 to + 0.82 , p=0.001 for CDT ) . The adjusted means of MMSE and CDT scores were also higher for participants allocated to the MedDiet+Nuts versus control ( adjusted differences : + 0.57 ( 95 % CI + 0.11 to + 1.03 ) , p=0.015 for MMSE and + 0.33 ( 95 % CI + 0.003 to + 0.67 ) , p=0.048 for CDT ) . These results did not differ after controlling for incident depression . Conclusions An intervention with MedDiets enhanced with either EVOO or nuts appears to improve cognition compared with a low-fat diet . IS RCT Objective To determine the effects of long-chain omega-3 ( LCn-3 ) fatty acids found in fish oil , including eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) , on cortical blood oxygen level-dependent ( BOLD ) activity during a working memory task in older adults with subjective memory impairment . Design R and omized , double-blind , placebo-controlled study . Setting Academic medical center . Participants Healthy older adults ( 62–80 years ) with subjective memory impairment , but not meeting criteria for mild cognitive impairment or dementia . InterventionFish oil ( EPA+DHA : 2.4 g/d , n=11 ) or placebo ( corn oil , n=10 ) for 24 weeks . Measurements Cortical BOLD response patterns during performance of a sequential letter n-back working memory task were determined at baseline and week 24 by functional magnetic resonance imaging ( fMRI ) . Results At 24 weeks erythrocyte membrane EPA+DHA composition increased significantly from baseline in participants receiving fish oil ( + 31 % , p≤0.0001 ) but not placebo ( −17 % , p=0.06 ) . Multivariate modeling of fMRI data identified a significant interaction among treatment , visit , and memory loading in the right cingulate ( BA 23/24 ) , and in the right sensorimotor area ( BA 3/4 ) . In the fish oil group , BOLD increases at 24 weeks were observed in the right posterior cingulate and left superior frontal regions during memory loading . A region-of-interest analysis indicated that the baseline to endpoint change in posterior cingulate cortex BOLD activity signal was significantly greater in the fish oil group compared with the placebo group during the 1-back ( p=0.0003 ) and 2-back ( p=0.0005 ) conditions . Among all participants , the change in erythrocyte EPA+DHA during the intervention was associated with performance in the 2-back working memory task ( p = 0.01 ) , and with cingulate BOLD signal during the 1-back ( p = 0.005 ) with a trend during the 2-back ( p = 0.09 ) . Further , cingulate BOLD activity was related to performance in the 2-back condition . Conclusions Dietary fish oil supplementation increases red blood cell omega-3 content , working memory performance , and BOLD signal in the posterior cingulate cortex during greater working memory load in older adults with subjective memory impairment suggesting enhanced neuronal response to working memory challenge OBJECTIVE To investigate whether ω-3 fatty acids reduce magnetic resonance imaging ( MRI ) and clinical disease activity in patients with multiple sclerosis , both as monotherapy and in combination with interferon beta-1a treatment . DESIGN Multicenter , r and omized , double-blind , placebo-controlled clinical trial conducted from 2004 to 2008 . SETTING Thirteen public neurology departments in Norway . PARTICIPANTS Patients aged 18 to 55 years with active relapsing-remitting multiple sclerosis , with a disability score equivalent to 5.0 or less on the Kurtzke Exp and ed Disability Status Scale . Ninety-two patients were r and omized to  ω-3 fatty acids ( n = 46 ) or placebo capsules ( n = 46 ) . INTERVENTIONS Administration of 1350 mg of eicosapentaenoic acid and 850 mg of docosahexaenoic acid daily or placebo . After 6 months , all patients in addition received subcutaneously 44 μg of interferon beta-1a 3 times per week for another 18 months . MAIN OUTCOME MEASURE The primary outcome measure was MRI disease activity as measured by the number of new T1-weighted gadolinium-enhancing lesions during the first 6 months . Secondary outcome measures included MRI disease activity after 9 months and 24 months , relapse rate , disability progression , fatigue , quality of life , and safety . RESULTS The cumulative number of gadolinium-enhancing MRI lesions during the first 6 months were similar in the ω-3 fatty acids and placebo groups ( median difference , 1 ; 95 % CI , 0 to 3 ; P = .09 ) . No difference in relapse rate was detected after 6 ( median difference , 0 ; 95 % CI , 0 to 0 ; P = .54 ) or 24 ( median difference , 0 ; 95 % CI , 0 to 0 ; P = .72 ) months . The proportion of patients without disability progression was 70 % in both groups ( P > .99 ) . No differences were detected in fatigue or quality -of-life scores , and no safety concerns appeared . Serum analyses of fatty acids showed an increase in ω-3 fatty acids ( mean difference , 7.60 ; 95 % CI , 5.57 to 7.91 ; P < .001 ) in the patients treated with ω-3 fatty acids compared with the placebo group . CONCLUSION No beneficial effects on disease activity were detected from ω-3 fatty acids when compared with placebo as monotherapy or in combination with interferon beta-1a . Magnetic resonance imaging disease activity was reduced as expected by interferon beta-1a . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00360906 BACKGROUND Increased consumption of n-3 ( omega-3 ) long-chain polyunsaturated fatty acids ( LC PUFAs ) , especially eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) , may maintain cognitive function in later life . OBJECTIVE We tested the hypothesis that n-3 LC PUFA supplementation would benefit cognitive function in cognitively healthy older people . DESIGN At total of 867 cognitively healthy adults , aged 70 - 79 y , from 20 general practice s in Engl and and Wales were r and omly assigned into a double-blind controlled trial of daily capsules providing 200 mg EPA plus 500 mg DHA or olive oil for 24 mo . Treatment-allocation codes were obtained from a central computerized r and omization service . Trained research nurses administered a battery of cognitive tests , including the primary outcome , the California Verbal Learning Test ( CVLT ) , at baseline and 24 mo . Intention-to-treat analysis of covariance , with adjustment for baseline cognitive scores , age , sex , and age at leaving full-time education , included 748 ( 86 % ) individuals who completed the study . RESULTS The mean age of participants was 75 y ; 55 % of the participants were men .  Withdrawals and deaths were similar in active ( n = 49 and n = 9 , respectively ) and placebo ( n = 53 and n = 8 , respectively ) arms . Mean ( + /-SD ) serum EPA and DHA concentrations were significantly higher in the active arm than in the placebo arm at 24 mo ( 49.9 + /- 2.7 mg EPA/L in the active arm compared with 39.1 + /- 3.1 mg EPA/L in the placebo arm ; 95.6 + /- 3.1 mg DHA/L in the active arm compared with 70.7 + /- 2.9 mg DHA/L in the placebo arm ) . There was no change in cognitive function scores over 24 mo , and intention-to-treat analysis showed no significant differences between trial arms at 24 mo in the CVLT or any secondary cognitive outcome . CONCLUSIONS Cognitive function did not decline in either study arm over 24 mo . The lack of decline in the control arm and the relatively short intervention period may have limited our ability to detect any potential beneficial effect of fish oil on cognitive function in this study . The Older People And n-3 Long-chain polyunsaturated fatty acids ( OPAL ) Study was registered at www.controlled-trials.com as IS RCT N 72331636 T. Terano a , * , S. Fujishiro b , T. Ban c , K. Yamamoto d , T. Tanaka e , Y. Noguchi e , Y. Tamura ~ , K. Yazawa g and T. Hirayama h aDepartment of Internal Medicine , Chiba Municipal Hospital Chiba 260 , bKyoundou Hospital , Tokyo , ~Kuniyoshi Hospital , Chiba , dKimitsu Central Hospital , Chiba , e2nd Department Internal Medicine , Chiba University , Chiba , ~Kyoundou Hiratsuka Hospital , Kanagawa , gSagami Chemical Research Center , Kanagawa , and hHirayama Hospital , Chiba , Background : ω-3 fatty acids ( ω-3 FAs ) found in dietary fish or fish oils are anti-inflammatory agents that may influence Alzheimer ’s disease ( AD ) . Objective : To study the effects of dietary ω-3 FA supplementation on inflammatory markers in cerebrospinal fluid ( CSF ) and plasma from patients with mild to moderate AD . Methods : Thirty-five patients ( 70.3 ± 8.2 years ) were r and omized to a daily intake of 2.3 g ω-3 FAs or placebo for 6 months . The inflammatory markers interleukin (IL)-6 , tumour necrosis factor-α and soluble interleukin-1 receptor type II ( sIL-1RII ) were analysed in CSF and plasma at baseline and at 6 months . The AD markers tau-protein , hyperphosphorylated tau-protein and β-amyloid ( Aβ1–42 ) were assessed in CSF . High-sensitivity C-reactive protein was assessed in plasma . A possible relation to the APOE genotype was investigated . Results : There was no significant treatment effect of ω-3 FAs  on inflammatory and AD biomarkers in CSF or on inflammatory markers in plasma , nor was there any relation with APOE . A significant correlation was observed at baseline between sIL-1RII and Aβ1–42 levels in CSF . Conclusions : Treatment of AD patients  with ω-3 FAs for 6 months did not influence inflammatory or biomarkers in CSF or plasma . The correlation between sIL-1RII and Aβ1–42 may reflect the reciprocal interactions between IL-1 and Aβ peptides A r and omised controlled trial with a factorial design was done to examine the effects of dietary intervention in the secondary prevention of myocardial infa rct ion ( MI ) . 2033 men who had recovered from MI were allocated to receive or not to receive advice on each of three dietary factors : a reduction in fat intake and an increase in the ratio of polyunsaturated to saturated fat , an increase in fatty fish intake , and an increase in cereal fibre intake . The advice on fat was not associated with any difference in mortality , perhaps because it produced only a small reduction ( 3 - 4 % ) in serum cholesterol . The subjects advised to eat fatty fish had a 29 % reduction in 2 year all-cause mortality compared with those not so advised . This effect , which was significant , was not altered by adjusting for ten potential confounding factors . Subjects given fibre advice had a slightly higher mortality than other subjects ( not significant ) . The 2 year incidence of reinfa rct ion plus death from ischaemic heart disease was not significantly affected by any of the dietary regimens . A modest intake of fatty fish ( two or three portions per week ) may reduce mortality in men who have recovered from MI AIM We examined the effects of the administration of docosahexaenoic acid (DHA)-enriched meals on cognitive function in the oldest elderly with cognitive impairment , such as dementia , living in nursing homes , and on the improvement in caregiver burden at aging agencies . METHODS Participants in elderly care facilities and nursing homes ( n = 75 ; 88.5 ± 0.6 years ) were r and omized in active and placebo groups . The active group had family-style meals containing an additional 1720 mg of docosahexaenoic acid per day for 12 months . At baseline , and after 6 and 12 months of intervention , cognitive function was assessed using Hasegawa 's Dementia Scale-Revised and the Mini-Mental State Examination ; mental health condition was assessed with the Apathy scale and the Zung Self-Rating Depression Scale ; caregiver burden was evaluated using Zarit Burden Interview scores ; and participants ' serum biochemical factors were measured . RESULTS The participants were suggested to have dementia . After 12 months , the mean change in Mini-Mental State Examination subitem " Registration " score from baseline to month 12 showed a tendency to be greater in the active group than that in the placebo group . Mean changes in the Apathy scale from baseline to month 12 were less , and the changes in the Zung Self-Rating Depression Scale and the total Zarit Burden Interview scores showed a tendency to be lower in the active group than in the placebo group , respectively . CONCLUSION These results suggest that docosahexaenoic acid-enriched meals protect against age-related cognitive decline , and also improve apathy and caregiver burden for the oldest-elderly Japanese with cognitive impairment , such as dementia . Geriatr Gerontol Int 2017 ; 17 : 330 - 337 BACKGROUND The use of n-3 fatty acids may prevent cardiovascular events in patients with recent myocardial infa rct ion or heart failure . Their effects in patients with ( or at risk for ) type 2 diabetes mellitus are unknown . METHODS In this double-blind study with a 2-by-2 factorial design , we r and omly assigned 12,536 patients who were at high risk for cardiovascular events and had impaired fasting glucose , impaired glucose tolerance , or diabetes to receive a 1-g capsule containing at least 900 mg ( 90 % or more ) of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin glargine or st and ard care . The primary outcome was death from cardiovascular causes . The results of the comparison between n-3 fatty acids and placebo are reported here . RESULTS During a median follow up of 6.2 years , the incidence of the primary outcome was not significantly decreased among patients receiving n-3 fatty acids , as compared with those receiving placebo ( 574 patients [ 9.1 % ] vs. 581 patients [ 9.3 % ] ; hazard ratio , 0.98 ; 95 % confidence interval [ CI ] , 0.87 to 1.10 ; P=0.72 ) . The use of n-3 fatty acids also had no significant effect on the rates of major vascular events ( 1034 patients [ 16.5 % ] vs. 1017 patients [ 16.3 % ] ; hazard ratio , 1.01 ; 95 % CI , 0.93 to 1.10 ; P=0.81 ) , death from any cause ( 951 [ 15.1 % ] vs. 964 [ 15.4 % ] ; hazard ratio , 0.98 ; 95 % CI , 0.89 to 1.07 ; P=0.63 ) , or death from arrhythmia ( 288 [ 4.6 % ] vs. 259 [ 4.1 % ] ; hazard ratio , 1.10 ; 95 % CI , 0.93 to 1.30 ; P=0.26 ) . Triglyceride levels were reduced by 14.5 mg per deciliter ( 0.16 mmol per liter ) more among patients receiving n-3 fatty acids than among those receiving placebo ( P<0.001 ) , without a significant effect on other lipids . Adverse effects were similar in the two groups . CONCLUSIONS Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events . ( Funded by Sanofi ; ORIGIN Clinical Trials.gov number , NCT00069784 . ) Background : Preliminary evidence suggests beneficial effects of pure ethyl-eicosapentaenoate ( ethyl-EPA ) in Huntington disease ( HD ) . Methods : A total of 135 patients with HD were r and omized to enter a multicenter , double-blind , placebo-controlled trial on the efficacy of 2 g/d ethyl-EPA vs placebo . The Unified Huntington 's Disease Rating Scale ( UHDRS ) was used for assessment . The primary end point was outcome at 12 months on the Total Motor Score 4 subscale ( TMS-4 ) . Analysis of covariance ( ANCOVA ) and a χ2 test on response , defined as absence of increase in the TMS-4 , were performed . Results : A total of 121 patients completed 12 months , and 83 did so without protocol violations ( PP cohort ) . Intent-to-treat ( ITT ) analysis revealed no significant difference between ethyl-EPA and placebo for TMS-4 . In the PP cohort , ethyl-EPA proved better than placebo on the χ2 test on TMS-4 ( p < 0.05 ) , but missed significance on ANCOVA ( p = 0.06 ) . Secondary end points ( ITT cohort ) showed no benefit of ethyl-EPA but a significantly worse outcome in the behavioral severity and frequency compared with placebo . Exploring moderators of the efficacy of ethyl-EPA on TMS-4 showed a significant interaction between treatment and a factor defining patients with high vs low CAG repeats . Reported adverse events were distributed equally between treatment arms . Conclusions : Ethyl-eicosapentaenoate ( ethyl-EPA ) ( purity > 95 % ) had no benefit in the intent-to-treat cohort of patients with Huntington disease , but exploratory analysis revealed that a significantly higher number of patients in the per protocol cohort , treated with ethyl-EPA , showed stable or improved motor function . Further studies of the potential efficacy of ethyl-EPA are warranted Background : High intake of n-3 polyunsaturated fatty acids may protect against age-related cognitive decline . However , results from epidemiologic studies are inconclusive , and results from r and omized trials in elderly subjects without dementia are lacking . Objective : To investigate the effect of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) supplementation on cognitive performance . Methods : Double-blind , placebo-controlled trial involving 302 cognitively healthy ( Mini-Mental State Examination score > 21 ) individuals aged 65 years or older . Participants were r and omly assigned to 1,800 mg/d EPA – DHA , 400 mg/d EPA – DHA , or placebo capsules for 26 weeks . Cognitive performance was assessed using an extensive neuropsychological test battery that included the cognitive domains of attention , sensorimotor speed , memory , and executive function . Results : The mean age of the participants was 70 years , and 55 % were male .  Plasma concentrations of EPA – DHA  increased by 238 % in the high-dose and 51 % in the low-dose fish oil group compared with placebo , reflecting excellent compliance . Baseline scores on the cognitive tests were comparable in the three groups . Overall , there were no significant differential changes in any of the cognitive domains for either low-dose or high-dose fish oil supplementation compared with placebo . Conclusions : In this r and omized , double-blind , placebo-controlled trial , we observed no overall effect of 26 weeks of eicosapentaenoic acid and docosahexaenoic acid supplementation on cognitive performance BACKGROUND Increased intake of n‐3 fatty acids has been associated with a reduced risk of cardiovascular disease in observational studies , but this finding has not been confirmed in r and omized trials . It remains unclear whether n‐3 ( also called omega‐3 ) fatty acid supplementation has cardiovascular benefit in patients with diabetes mellitus . METHODS We r and omly assigned 15,480 patients with diabetes but without evidence of atherosclerotic cardiovascular disease to receive 1‐g capsules containing either n‐3 fatty acids ( fatty acid group ) or matching placebo ( olive oil ) daily . The primary outcome was a first serious vascular event ( i.e. , nonfatal myocardial infa rct ion or stroke , transient ischemic attack , or vascular death , excluding confirmed intracranial hemorrhage ) . The secondary outcome was a first serious vascular event or any arterial revascularization . RESULTS During a mean follow‐up of 7.4 years ( adherence rate , 76 % ) , a serious vascular event occurred in 689 patients ( 8.9 % ) in the fatty acid group and in 712 ( 9.2 % ) in the placebo group ( rate ratio , 0.97 ; 95 % confidence interval [ CI ] , 0.87 to 1.08 ; P=0.55 ) . The composite outcome of a serious vascular event or revascularization occurred in 882 patients ( 11.4 % ) and 887 patients ( 11.5 % ) , respectively ( rate ratio , 1.00 ; 95 % CI , 0.91 to 1.09 ) . Death from any cause occurred in 752 patients ( 9.7 % ) in the fatty acid group and in 788 ( 10.2 % ) in the placebo group ( rate ratio , 0.95 ; 95 % CI , 0.86 to 1.05 ) . There were no significant between‐group differences in the rates of nonfatal serious adverse events . CONCLUSIONS Among patients with diabetes without evidence of cardiovascular disease , there was no significant difference in the risk of serious vascular events between those who were assigned to receive n‐3 fatty acid supplementation and those who were assigned to receive placebo . ( Funded by the British Heart Foundation and others ; Current Controlled Trials number , IS RCT N60635500 ; Clinical Trials.gov number , NCT00135226 . IMPORTANCE Oral supplementation with the Age-Related Eye Disease Study ( AREDS ) formulation ( antioxidant vitamins C and E , beta carotene , and zinc ) has been shown to reduce the risk of progression to advanced age-related macular degeneration ( AMD ) . Observational data suggest that increased dietary intake of lutein + zeaxanthin ( carotenoids ) , omega-3 long-chain polyunsaturated fatty acids ( docosahexaenoic acid [ DHA ] + eicosapentaenoic acid [ EPA ] ) , or both might further reduce this risk . OBJECTIVES To determine whether adding lutein + zeaxanthin , DHA + EPA , or both to the AREDS formulation decreases the risk of developing advanced AMD and to evaluate the effect of eliminating beta carotene , lowering zinc doses , or both in the AREDS formulation . DESIGN , SETTING , AND PARTICIPANTS The Age-Related Eye Disease Study 2 ( AREDS2 ) , a multicenter , r and omized , double-masked , placebo-controlled  phase 3 study with a 2 × 2 factorial design , conducted in 2006 - 2012 and enrolling 4203 participants aged 50 to 85 years at risk for progression to advanced AMD with bilateral large drusen or large drusen in 1 eye and advanced AMD in the fellow eye . INTERVENTIONS Participants were r and omized to receive lutein ( 10 mg ) + zeaxanthin ( 2 mg ) , DHA ( 350 mg ) + EPA ( 650 mg ) , lutein + zeaxanthin and DHA + EPA , or placebo . All participants were also asked to take the original AREDS formulation or accept a secondary r and omization to 4 variations of the AREDS formulation , including elimination of beta carotene , lowering of zinc dose , or both . MAIN OUTCOMES AND MEASURES Development of advanced AMD . The unit of analyses used was by eye . RESULTS Median follow-up was 5 years , with 1940 study eyes ( 1608 participants ) progressing to advanced AMD . Kaplan-Meier probabilities of progression to advanced AMD by 5 years were 31 % ( 493 eyes [ 406 participants ] ) for placebo , 29 % ( 468 eyes [ 399 participants ] ) for lutein + zeaxanthin , 31 % ( 507 eyes [ 416 participants ] ) for DHA + EPA , and 30 % ( 472 eyes [ 387 participants ] ) for lutein + zeaxanthin and DHA + EPA  . Comparison with placebo in the primary analyses demonstrated no statistically significant reduction in progression to advanced AMD ( hazard ratio [ HR ] , 0.90 [ 98.7 % CI , 0.76 - 1.07 ] ; P = .12 for lutein + zeaxanthin ; 0.97 [ 98.7 % CI , 0.82 - 1.16 ] ; P = .70 for DHA + EPA ; 0.89 [ 98.7 % CI , 0.75 - 1.06 ] ; P = .10 for lutein + zeaxanthin and DHA + EPA ) . There was no apparent effect of beta carotene elimination or lower-dose zinc on progression to advanced AMD . More lung cancers were noted in the beta carotene vs no beta carotene group ( 23 [ 2.0 % ] vs 11 [ 0.9 % ] , nominal P = .04 ) , mostly in former smokers . CONCLUSIONS AND RELEVANCE Addition of lutein + zeaxanthin , DHA + EPA , or both to the AREDS formulation in primary analyses did not further reduce risk of progression to advanced AMD . However , because of potential increased incidence of lung cancer in former smokers , lutein + zeaxanthin could be an appropriate carotenoid substitute in the AREDS formulation . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00345176 To the Editor : Because of irregularities in the r and omization procedures , we wish to retract the following article : Primary Prevention of Cardiovascular Disease with a Mediterranean Diet . N Engl J Med 2013;368:1279 - 90 . DOI : 10.1056/NEJMoa1200303.1 We have reanalyzed the data and have published a new report : Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts . N Engl J Med . DOI : 10.1056/NEJMoa1800389.2 . . BACKGROUND Results from prospect i ve cohort studies and r and omized , controlled trials have provided evidence of a protective effect of n-3 fatty acids against cardiovascular diseases . We examined the effect of the marine n-3 fatty acids eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) and of the plant-derived alpha-linolenic acid ( ALA ) on the rate of cardiovascular events among patients who have had a myocardial infa rct ion . METHODS In a multicenter , double-blind , placebo-controlled trial , we r and omly assigned 4837 patients , 60 through 80 years of age ( 78 % men ) , who had had a myocardial infa rct ion and were receiving state-of-the-art antihypertensive , antithrombotic , and lipid-modifying therapy to receive for 40 months one of four trial margarines : a margarine supplemented with a combination of EPA and DHA ( with a targeted additional daily intake of 400 mg of EPA-DHA ) , a margarine supplemented with ALA ( with a targeted additional daily intake of 2 g of ALA ) , a margarine supplemented with EPA-DHA and ALA , or a placebo margarine . The primary end point was the rate of major cardiovascular events , which comprised fatal and nonfatal cardiovascular events and cardiac interventions . Data were analyzed according to the intention-to-treat principle , with the use of Cox proportional-hazards models . RESULTS The patients consumed , on average , 18.8 g of margarine per day , which result ed in additional intakes of 226 mg of EPA combined with 150 mg of DHA , 1.9 g of ALA , or both , in the active-treatment groups . During the follow-up period , a major cardiovascular event occurred in 671 patients ( 13.9 % ) . Neither EPA-DHA nor ALA reduced this primary end point ( hazard ratio with EPA-DHA , 1.01 ; 95 % confidence interval [ CI ] , 0.87 to 1.17 ; P=0.93 ; hazard ratio with ALA , 0.91 ; 95 % CI , 0.78 to 1.05 ; P=0.20 ) . In the prespecified subgroup of women , ALA , as compared with placebo and EPA-DHA alone , was associated with a reduction in the rate of major cardiovascular events that approached significance ( hazard ratio , 0.73 ; 95 % CI , 0.51 to 1.03 ; P=0.07 ) . The rate of adverse events did not differ significantly among the study groups . CONCLUSIONS Low-dose supplementation with EPA-DHA or ALA did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infa rct ion and who were receiving state-of-the-art antihypertensive , antithrombotic , and lipid-modifying therapy . ( Funded by the Netherl and s Heart Foundation and others ; Clinical Trials.gov number , NCT00127452 . )
OBJECTIVES Neurocognitive function may be influenced by polyunsaturated fat intake .
Many older adults consume omega-3 supplements hoping to prevent  cognitive decline  .
We assessed effects of increasing omega-3 , omega-6 , or total polyunsaturated fats on new neurocognitive illness and cognition .
DESIGN AND INCLUSION CRITERIA We carried out a systematic review and meta- analysis of r and omized controlled trials ( RCTs ) in adults , with duration ≥24 weeks , assessing effects of higher vs lower omega-3 , omega-6 , or total polyunsaturated fats and outcomes : new neurocognitive illness , newly impaired cognition , and /or continuous measures of cognition .