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Background The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT. Methods The analysis used baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes. Results APOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6–10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized β= −0.555, p=0.035) and left hippocampal volumes (standardized β= −0.577, p=0.028) only in APOE4 carriers. Conclusion HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.

Contains fulltext : 282473.pdf (Publisher’s version ) (Open Access) Observational studies suggest that nutritional factors have a potential cognitive benefit. However, systematic reviews of randomised trials of dietary and nutritional supplements have reported largely null effects on cognitive outcomes and have highlighted study inconsistencies and other limitations. In this Personal View, the Nutrition for Dementia Prevention Working Group presents what we consider to be limitations in the existing nutrition clinical trials for dementia prevention. On the basis of this evidence, we propose recommendations for incorporating dietary patterns and the use of genetic, and nutrition assessment tools, biomarkers, and novel clinical trial designs to guide future trial developments. Nutrition-based research has unique challenges that could require testing both more personalised interventions in targeted risk subgroups, identified by nutritional and other biomarkers, and large-scale and pragmatic study designs for more generalisable public health interventions across diverse populations.

The term Mediterranean diet first appeared in the late 1940s (1). It is described by UNESCO as ‘a set of skills, knowledge, practices and traditions ranging from the landscape to the table, including the crops, harvesting, fishing, conservation, processing, preparation and, particularly, consumption of food’. A Mediterranean dietary pattern (MDP) varies in composition between the 21 countries which make up the Mediterranean region but is typically characterised by high intakes of minimally processed plant-based foods such as fruits, vegetables, nuts, seeds, legumes and wholegrains. Extra virgin olive oil is the main culinary fat, with a moderate intake of dairy products, and a variety of herbs and spices used as condiments, rather than salt. Fish/seafood is typically consumed two-three times per week. Red and processed meat, and discretionary foods including sugar or honey sweetened food and drink are consumed in low amounts. Wine, and in particular red wine, is consumed in moderation and with meals. Although in many ways analogous to other global healthy plant based dietary patterns, it is the high intakes of olive oil, nuts and red wine, which makes the MDP unique. The MDP has been used as a benchmark for comparison with other dietary patterns (2) and has influenced the dietary guidelines for non-Mediterranean countries like the USA, Canada and Australia. Refereed/Peer-reviewed

With growing and ageing populations, the incidence of dementia is expected to triple globally by 2050. In the absence of effective drugs to treat or reverse the syndrome, dietary approaches which prevent or delay disease onset have considerable population health potential. Prospective epidemiological studies and mechanistic insight from experimental models strongly support a positive effect of a high fish and long chain

Ageing is a multifactorial process associated with reduced function and increased risk of morbidity and mortality. Recently, nine cellular and molecular hallmarks of ageing have been identified, which characterise the ageing process and, collectively, may be key determinants of the ageing trajectory. These include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Healthier dietary patterns reduce the risk of age-related diseases and increase longevity and may influence positively one or more of these hallmarks. The Mediterranean dietary pattern (MedDiet) is a plant-based eating pattern that was typical of countries such as Greece, Spain, and Italy pre-globalisation of the food system and which is associated with better health during ageing. Here we review the potential effects of a MedDiet on each of the nine hallmarks of ageing, and provide evidence that the MedDiet as a whole, or individual elements of this dietary pattern, may influence each hallmark positively – effects which may contribute to the beneficial effects of this dietary pattern on age-related disease risk and longevity. We also highlight potential avenues for future research.

In Mediterranean countries, adherence to a traditional Mediterranean dietary pattern (MedDiet) is associated with better cognitive function and reduced dementia risk. It is unclear if similar benefits exist in non-Mediterranean regions.The aims of this study were to examine associations between MedDiet adherence and cognitive function in an older UK population and to investigate whether associations differed between individuals with high compared with low cardiovascular disease (CVD) risk.We conducted an analysis in 8009 older individuals with dietary data at Health Check 1 (1993-1997) and cognitive function data at Health Check 3 (2006-2011) of the European Prospective Investigation into Cancer and Nutrition-Norfolk (EPIC-Norfolk). Associations were explored between MedDiet adherence and global and domain-specific cognitive test scores and risk of poor cognitive performance in the entire cohort, and when stratified according to CVD risk status.Higher MedDiet adherence defined by the Pyramid MedDiet score was associated with better global cognition (β ± SE = -0.012 ± 0.002; P 0.001), verbal episodic memory (β ± SE = -0.009 ± 0.002; P 0.001), and simple processing speed (β ± SE = -0.002 ± 0.001; P = 0.013). Lower risk of poor verbal episodic memory (OR: 0.784; 95% CI: 0.641, 0.959; P = 0.018), complex processing speed (OR: 0.739; 95% CI: 0.601, 0.907; P = 0.004), and prospective memory (OR: 0.841; 95% CI: 0.724, 0.977; P = 0.023) was also observed for the highest compared with the lowest Pyramid MedDiet tertiles. The effect of a 1-point increase in Pyramid score on global cognitive function was equivalent to 1.7 fewer years of cognitive aging. MedDiet adherence defined by the Mediterranean Diet Adherence Screener (MEDAS) score (mapped through the use of both binary and continuous scoring) showed similar, albeit less consistent, associations. In stratified analyses, associations were evident in individuals at higher CVD risk only (P 0.05).Higher adherence to the MedDiet is associated with better cognitive function and lower risk of poor cognition in older UK adults. This evidence underpins the development of interventions to enhance MedDiet adherence, particularly in individuals at higher CVD risk, aiming to reduce the risk of age-related cognitive decline in non-Mediterranean populations.

BACKGROUND: Hip fracture represents a substantial acute inflammatory trauma, which may constitute a significant insult to the degenerating brain. Research suggests that an injury of this kind can affect memory and thinking in the future but it is unclear whether, and how, inflammatory trauma injures the brain. The impact of Acute SystematiC inflammation upon cerebRospinal fluId and blood BiomarkErs of brain inflammation and injury in Dementia: a study in acute hip fracture patients (ASCRIBED) explores this relationship, to understand the effect of inflammation on the progression of dementia.METHODS: This protocol describes a multi-centre sample collection observational study. The study utilises the unique opportunity provided by hip fracture operations undertaken via spinal anaesthesia to collect cerebrospinal fluid (CSF) and blood, to investigate the impact of acute brain inflammation caused by hip fracture on the exacerbation of dementia. We will recruit 200 hip fracture patients with a diagnosis or evidence of dementia; and 200 hip fracture patients without dementia. We will also recruit 'Suitable informants', individuals in regular contact with the patient, to provide further proxy evidence of a patient's potential cognitive decline. We will compare these 400 samples with existing CSF and blood samples from a cohort of dementia patients who had not experienced a systemic inflammatory response due to injury. This will provide a comparison between patients with and without dementia who are suffering a systemic inflammatory response; with stable patients living with dementia.DISCUSSION: We will test the hypothesis that hip fracture patients living with dementia show elevated markers of brain inflammation, as well as neuronal injury and Alzheimer-related plaque pathology, in comparison to (1) stable patients living with dementia and (2) hip fracture patients without dementia, as measured by biomarkers in CSF and blood. The findings will address the hypothesis that systemic inflammatory events can exacerbate underlying dementia and inform the search for new treatments targeting inflammation in dementia.TRIAL REGISTRATION: ISRCTN43803769 . Registered 11 May 2017.

OBJECTIVES: To provide baseline cohort descriptives and assess change in health behaviours since the UK COVID-19 lockdown. DESIGN: A prospective cohort (N = 1,044) of people recruited online, purposively targeting vulnerable populations. METHODS: After a baseline survey (April 2020), participants completed 3 months of daily ecological momentary assessments (EMA). Dietary, physical activity, alcohol, smoking, vaping and substance use behaviours collected retrospectively for the pre-COVID-19 period were compared with daily EMA surveys over the first 30 days during early lockdown. Predictors of behaviour change were assessed using multivariable regression models. RESULTS: 30% of the cohort had a COVID-19 at risk health condition, 37% were classed as deprived and 6% self-reported a mental health condition. Relative to pre-pandemic levels, participants ate almost one portion of fruit and vegetables less per day (vegetables mean difference -0.33, 95% CI -0.40, -0.25; fruit -0.57, 95% CI -0.64, -0.50), but showed no change in high sugar portions per day (-0.03, 95% CI -0.12, 0.06). Participants spent half a day less per week doing ≥30 min of moderate to vigorous physical activity (-0.57, 95% CI -0.73, -0.40) but slightly increased days of strength training (0.21, 95% CI 0.09, 0.34), increased alcohol intake (AUDIT-C score change 0.25, 95% CI 0.13, 0.37), though did not change smoking, vaping or substance use behaviour. Worsening health behaviour change was associated with being younger, female and higher body mass index. CONCLUSIONS: The cohort reported worsening health behaviours during early lockdown. Longer term changes will be investigated using further waves of data collection.

Objective: To conduct a systematic review and meta-analysis investigating effects of MedDiet on blood pressure in randomised controlled trials (RCTs) and associations of MedDiet with risk of hypertension in observational studies. Methods: PubMed, The Cochrane Library and EBSCOhost were searched from inception until January 2020 for studies that met the following criteria: 1) participants aged ≥18 years, 2) RCTs investigating effects of a MedDiet versus control on BP, 3) Observational studies exploring associations between MedDiet adherence and risk of hypertension. Random-effects meta-analyses were conducted. Meta-regression and subgroup analyses were performed for RCTs to identify potential effect moderators. Results: Nineteen RCTs reporting data on 4137 participants and 16 observational studies reporting data on 59,001 participants were included in the meta-analysis. MedDiet interventions reduced systolic and diastolic BP by a mean -1.4 mmHg (95% CI: -2.40 to -0.39 mmHg, p=0.007, I2=53.5%, Q=44.7, τ2=1.65, df=19) and -1.5 mmHg (95% CI: -2.74 to -0.32 mmHg, p=0.013, I2=71.5%, Q=51.6, τ2=4.72, df=19) versus control, respectively. Meta-regression revealed that longer study duration and higher baseline systolic BP was associated with a greater decrease in BP, in response to a MedDiet (p

IntroductionDementia prevalence continues to increase, and effective interventions are needed to prevent, delay or slow its progression. Higher adherence to the Mediterranean diet (MedDiet) and increased physical activity (PA) have been proposed as strategies to facilitate healthy brain ageing and reduce dementia risk. However, to date, there have been no dementia prevention trials in the UK focussed on combined dietary and PA interventions. This study aims to: (1) assess feasibility and acceptability of a theory-underpinned digital and group-based intervention for dementia risk reduction in an ‘at risk’ UK cohort; (2) evaluate behaviour change responses to the intervention; and, (3) provide information on cognitive, neurological, vascular and physiological outcomes to inform the design of a follow-on, full-scale efficacy trial.MethodsOne hundred and eight participants aged 55 to 74 years with a QRISK2 score of ≥10% will be recruited to take part in this 24-week multi-site study. Participants will be randomised into three parallel arms: (1) Control; (2) MedDiet; and, (3) MedDiet+PA. The study will evaluate a personalised website, group session and food delivery intervention to increase MedDiet adherence and PA in older adults at risk of dementia. Diet and PA will be monitored prior to, during and following the intervention. Feasibility, acceptability and hypothesised mediators will be assessed in addition to measures of cognitive function, brain structure/perfusion (MRI), vascular function and metabolic markers (blood, urine and faecal) prior to, and following, the intervention.DiscussionThis trial will provide insights into the feasibility, acceptability and mechanism of effect of a multi-domain intervention focussed on the MedDiet alone and PA for dementia risk reduction in an ‘at risk’ UK cohort.Ethics and disseminationThe study has received NHS REC and HRA approval (18/NI/0191). Findings will be disseminated via conference presentations, public lectures, and peer-reviewed publications.Trial registration detailsClinicalTrials.gov NCT03673722.

It is unclear what non-pharmacological interventions to prevent cognitive decline should comprise. We systematically reviewed lifestyle and psychosocial interventions that aimed to reduce cognitive decline in healthy people aged 50+, and people of any age with Subjective Cognitive Decline or Mild Cognitive Impairment. We narratively synthesised evidence, prioritising results from studies rated as at lower Risk of Bias (ROB) and assigning Centre for Evidence Based Medicine grades. We included 64 papers, describing: psychosocial (n = 12), multi-domain (n = 10), exercise (n = 36), and dietary (n = 6) interventions. We found Grade A evidence that over 4+ months: aerobic exercise twice weekly had a moderate effect on global cognition in people with/ without MCI; and interventions that integrate cognitive and motor challenges (e.g. dance, dumb bell training) had small to moderate effects on memory or global cognition in people with MCI. We found Grade B evidence that 4+ months of creative art or story-telling groups in people with MCI; 6 months of resistance training in people with MCI and a two-year, dietary, exercise, cognitive training and social intervention in people with or without MCI had small, positive effects on global cognition. Effects for some intervention remained up to a year beyond facilitated sessions.

● Global prevalence of dementia is predicted to almost triple by 2050 ● There are currently no effective drugs to prevent or treat dementia ● Improved eating behaviour holds significant potential to reduce the risk and population prevalence ● Owing to its multifactorial aetiology, multiple dietary components which target several physiological pathways and risk factors simultaneously are needed. Therefore dietary patterns and foods (rather than single dietary components), hold the most promise to meaningfully improve cognition in the medium term ● Randomised controlled trials with robust validated cognitive outcomes or, ideally, change in dementia or mild cognitive impairment incidence are needed in order to support the prospective cohort evidence, establish efficacy and effect size, and inform public health policy

The Virtual Supermarket Task (VST) and Sea Hero Quest detect high-genetic-risk Alzheimer`s disease (AD). We aimed to determine their test-retest reliability in a preclinical AD population. Over two time points, separated by an 18-month period, 59 cognitively healthy individuals underwent a neuropsychological and spatial navigation assessment. At baseline, participants were classified as low-genetic-risk of AD or high-genetic-risk of AD. We calculated two-way mixed effects intraclass correlation coefficients (ICC) for task parameters and used repeated measures ANOVAS to determine whether genetic risk or sex contributed to test-retest variability. The egocentric parameter of the VST measure showed the highest test-retest reliability (ICC = .72), followed by the SHQ distance travelled parameter (ICC = .50). Post hoc longitudinal analysis showed that boundary-based navigation predicts worsening episodic memory concerns in high-risk (F = 5.01, P = 0.03), but in not low-risk, AD candidates. The VST and the Sea Hero Quest produced parameters with acceptable test-retest reliability. Further research in larger sample sizes is desirable.

An apolipoprotein E ε4 (APOE-ε4) genotype is the strongest common genetic determinant of Alzheimer's disease (AD). The pleiotropic nature of apolipoprotein E has made elucidation of the aetiological basis difficult to establish, which is further complicated by the fact that the penetrance of the APOE-ε4 allele is modulated by sex, age, and nutrition. A greater metabolic consequence of the APOE-ε4 allele is likely to contribute to the fact that two-thirds of AD patients are female. A higher tissue status of the marine n-3 fatty acid docosahexaenoic acid (DHA) is associated with a lower AD risk. However, APOE-ε4 carriers appear less sensitive to the neurocognitive benefits, which may be due to defective blood-brain barrier transport of DHA exacerbated by aging and possibly sex. This suggests higher DHA requirements in this large population subgroup. This narrative review will consider the influence of sex and DHA in modulating APOE-ε4-mediated AD risk.

n-3 Fatty acids are associated with better cardiovascular and cognitive health. However, the concentration of EPA, DPA and DHA in different plasma lipid pools differs and factors influencing this heterogeneity are poorly understood. Our aim was to evaluate the association of oily fish intake, sex, age, BMI andAPOEgenotype with concentrations of EPA, DPA and DHA in plasma phosphatidylcholine (PC), NEFA, cholesteryl esters (CE) and TAG. Healthy adults (148 male, 158 female, age 20–71 years) were recruited according toAPOEgenotype, sex and age. The fatty acid composition was determined by GC. Oily fish intake was positively associated with EPA in PC, CE and TAG, DPA in TAG, and DHA in all fractions (P≤0·008). There was a positive association between age and EPA in PC, CE and TAG, DPA in NEFA and CE, and DHA in PC and CE (P≤0·034). DPA was higher in TAG in males than females (PPAPOEgenotype×sex interactions were observed: theAPOE4 allele associated with higher EPA in males (P=0·002), and there was also evidence for higher DPA and DHA (P≤0·032). In conclusion, EPA, DPA and DHA in plasma lipids are associated with oily fish intake, sex, age, BMI andAPOEgenotype. Such insights may be used to better understand the link between plasma fatty acid profiles and dietary exposure and may influence intake recommendations across population subgroups.

The workshop 'Nutrition for the Ageing Brain: Towards Evidence of an Optimal Diet' was organized with funds from the ILSI Europe Nutrition and Mental Performance Task Force. Industry members of this task force are listed on the ILSI Europe website at www.ilsi.eu. For further information about ILSI Europe, please email or call +32 2 771 00 14. This review was prepared taken into account the presentations at the workshop mentioned in the abstract and was conducted by an expert group of ILSI Europe. This publication was coordinated by Mr Jeroen Schuermans, Scientific Project Manager at ILSI Europe during the proceedings process. The authors would like to acknowledge Ms Catherine Collins, Ms Lilou van Lieshout and Dr Lucie Geurts for the finalisation and submission of this manuscript; As people age they become increasingly susceptible to chronic and extremely debilitating brain diseases. The precise cause of the neuronal degeneration underlying these disorders, and indeed normal brain ageing remains however elusive. Considering the limits of existing preventive methods, there is a desire to develop effective and safe strategies. Growing preclinical and clinical research in healthy individuals or at the early stage of cognitive decline has demonstrated the beneficial impact of nutrition on cognitive functions. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). The latest scientific advances specific to how dietary nutrients and non-nutrient may affect cognitive ageing are presented. Furthermore, several key points related to mechanisms contributing to brain ageing, pathological conditions affecting brain function, and brain biomarkers are also discussed. Overall, findings are inconsistent and fragmented and more research is warranted to determine the underlying mechanisms and to establish dose-response relationships for optimal brain maintenance in different population subgroups. Such approaches are likely to provide the necessary evidence to develop research portfolios that will inform about new dietary recommendations on how to prevent cognitive decline

Prospective observational studies support the use of long-chain omega-3 polyunsaturated fatty acids (PUFAs) in the primary prevention of atherosclerotic cardiovascular disease; however, randomised controlled trials, have often reported neutral findings. There is a long history of debate about the potential harmful effects of a high intake of omega-6 PUFAs, although this idea is not supported by prospective observational studies or randomised controlled trials. Health effects of PUFAs might be influenced by Δ-5 and Δ-6 desaturases, the key enzymes in the metabolism of PUFAs. The activity of these enzymes and modulation by variants in encoding genes (FADS1-2-3 gene cluster) are linked to several cardiometabolic traits. This Review will further consider non-genetic determinants of desaturase activity, which have the potential to modify the availability of PUFAs to tissues. Finally, we discuss the consequences of altered desaturase activity in the context of PUFA intake, that is, gene-diet interactions and their clinical and public health implications.

Navigation processes that are selectively mediated by functional activity in the entorhinal cortex may be a marker of preclinical Alzheimer's disease (AD). Here, we tested if a short path integration paradigm can detect the strongest genetic-risk phenotype of AD in large sample of apolipoprotein E (APOE)-genotyped individuals. We also examined the associations between APOE-mediated navigation process, subjective cognitive decline, and rest-stating network connectivity. Navigation discrepancies classified 77% the APOE-genotyped cohort into their respective low-risk ε3ε3 and high-risk ε3ε4 categories. When connectivity strength between entorhinal and the posterior cingulate cortices (also a functional correlate of strongest APOE-dependant behavioral characteristics) was considered, this classification accuracy increased to 85%. Our findings present a whole picture of at-genetic-risk AD, including select impairment in path integration, self-report cognitive decline, and altered network activity that is reminiscent of the pathological spread of preclinical AD disease. These findings may have important implications for the early detection of AD.

BACKGROUND: The endothelium plays a key role in the maintenance of vascular health and represents a potential physiological target for dietary and other lifestyle interventions designed to reduce the risk of cardiovascular diseases (CVD) including stroke or coronary heart disease. OBJECTIVE: To conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating the effects of the Mediterranean dietary pattern (MedDiet) on endothelial function. METHODS: Medline, Embase, and Scopus databases were searched from inception until January 2019 for studies that met the following criteria: 1) RCTs including adult participants, 2) interventions promoting the MedDiet, 3) inclusion of a control group, and 4) measurements of endothelial function. A random-effects meta-analysis was conducted. Metaregression and subgroup analyses were performed to identify whether effects were modified by health status (i.e., healthy participants versus participants with existing comorbidities), type of intervention (i.e., MedDiet alone or with a cointervention), study duration, study design (i.e., parallel or crossover), BMI, and age of participants. RESULTS: Fourteen articles reporting data for 1930 participants were included in the meta-analysis. Study duration ranged from 4 wk to 2.3 y. We observed a beneficial effect of the MedDiet on endothelial function [standardized mean difference (SMD): 0.35; 95% CI: 0.17, 0.53; P 0.05). CONCLUSIONS: MedDiet interventions improve endothelial function in adults, suggesting that the protective effects of the MedDiet are evident at early stages of the atherosclerotic process with important implications for the early prevention of CVD. This study has the PROSPERO registration number: CRD42018106188.

Background: Observational studies indicate that approximately a third of dementia cases are attributable to modifiable cardiometabolic, physical and mental health, and social and lifestyle risk factors. There is evidence that intensive behaviour change interventions targeting these factors can reduce cognitive decline. (Figure presented.) Our planned intervention [Colour figure can be viewed at wileyonlinelibrary.com]. Methods and analysis: We will design and test a low intensity, secondary dementia-prevention programme (Active Prevention in People at risk of dementia: Lifestyle, bEhaviour change and Technology to REducE cognitive and functional decline, “APPLE-Tree”) to slow cognitive decline in people with subjective cognitive decline with or without objective cognitive impairment. We will embed our work within social science research to understand how dementia prevention is currently delivered and structured. We will carry out systematic reviews and around 50 qualitative interviews with stakeholders, using findings to coproduce the APPLE-Tree intervention. We plan a 10-session group intervention, involving personalised goal-setting, with individual sessions for those unable or unwilling to attend groups, delivered by psychology assistants who will be trained and supervised by clinical psychologists. The coproduction group (including public and patient involvement [PPI], academic and clinical/third-sector professional representatives) will use the Behaviour Change Wheel theoretical framework to develop it. We will recruit and randomly allocate 704 participants, 1:1 to the intervention: informational control group. This sample size is sufficient to detect a between-group difference at 2 years of 0.15 on the primary outcome (cognition: modified neuropsychological test battery; 90% power, 5% significance, effect size 0.25, SD 0.6). Dissemination: We will work with Public Health England and third-sector partners to produce an effective national implementation approach, so that if our intervention works, it is used in practice.

BACKGROUND: Anthocyanin-rich blueberry intake is associated with reduced type 2 diabetes and cardiovascular disease (CVD) risk in prospective studies, although long-term randomized controlled trials (RCTs) have not been conducted in at-risk populations.OBJECTIVE: In the longest-duration RCT to date, we examined the effect of 6-mo blueberry intake on insulin resistance and cardiometabolic function in metabolic syndrome.METHODS: A double-blind, parallel RCT (n = 115; age 63 ± 7 y; 68% male; body mass index 31.2 ± 3.0 kg/m2) was conducted, which fed 2 dietarily achievable blueberry intakes [equivalent to 1/2 and 1 cup/d (75/150 g)] compared with matched placebo. Insulin resistance was assessed via the homeostasis model assessment of insulin resistance (primary endpoint) and confirmed by [6-6-2H2]-glucose-labeled, 2-step hyperinsulinemic clamp (n = 20). Clinically relevant cardiometabolic endpoints [including flow-mediated dilatation, augmentation index, lipoprotein status (by nuclear magnetic resonance spectroscopy), and nitric oxide (NO)-related metabolite assay] and anthocyanin metabolism were assessed.RESULTS: A daily intake of 1 cup of blueberries improved endothelial function (flow-mediated dilatation: +1.45%; 95% CI: 0.83%, 2.1%; P = 0.003), systemic arterial stiffness (augmentation index: -2.24%; 95% CI: -3.97%, -0.61%; P = 0.04) and attenuated cyclic guanosine monophosphate concentrations. In statin nonusers (n = 71), elevated high-density lipoprotein cholesterol (+0.08 mmol/L; P = 0.03), high-density lipoprotein particle density (+0.48n, ×10-6; P = 0.002) and apolipoprotein A-I (+0.05 g/L; P = 0.01) concentrations were observed following the 1-cup/d intervention. Treatment compliance was 94.1% (wrapper returns) and total concentrations of anthocyanin-derived phenolic acid metabolites significantly increased, dose-dependently, in serum and 24-h urine (P < 0.01 and P < 0.001, respectively). Insulin resistance, pulse wave velocity, blood pressure, NO, and overall plasma thiol status were unaffected. Likewise, a half cup per day had no effect on any biomarkers.CONCLUSIONS: Despite insulin resistance remaining unchanged we show, to our knowledge, the first sustained improvements in vascular function, lipid status, and underlying NO bioactivity following 1 cup blueberries/d. With effect sizes predictive of 12-15% reductions in CVD risk, blueberries should be included in dietary strategies to reduce individual and population CVD risk. This study was registered at clinicaltrials.gov as NCT02035592.

International audience; Spatial navigation is emerging as a critical factor in identifying preclinical Alzheimer's disease (AD). However, the impact of interindi-vidual navigation ability and demographic risk factors (e.g., APOE, age, and sex) on spatial navigation make it difficult to identify persons "at high risk" of AD in the preclinical stages. In the current study, we use spatial navigation big data (n = 27,108) from the Sea Hero Quest (SHQ) game to overcome these challenges by investigating whether big data can be used to benchmark a highly phenotyped healthy aging laboratory cohort into high-vs. low-risk persons based on their genetic (APOE) and demographic (sex, age, and educational attainment) risk factors. Our results replicate previous findings in APOE e4 carriers, indicative of grid cell coding errors in the entorhinal cortex, the initial brain region affected by AD pathophysiology. We also show that although baseline navigation ability differs between men and women, sex does not interact with the APOE genotype to influence the manifestation of AD-related spatial disturbance. Most importantly, we demonstrate that such high-risk preclinical cases can be reliably distinguished from low-risk participants using big-data spatial navigation benchmarks. By contrast, participants were undistinguishable on neuropsychological episodic memory tests. Taken together, we present evidence to suggest that, in the future, SHQ normative benchmark data can be used to more accurately classify spatial impairments in at-high-risk of AD healthy participants at a more individual level, therefore providing the steppingstone for individualized diagnostics and outcome measures of cognitive symptoms in preclinical AD. Alzheimer's disease | spatial navigation | personalized health care | APOE genotype | preclinical diagnosis S patial navigation is a promising cognitive fingerprint for underlying Alzheimer's disease (AD) pathophysiology (1-8) and has been adopted by many high-profile clinical trials (such as the European Prevention of Alzheimer's Dementia Consortium) to improve the sensitivity of neurocognitive testing and assess the efficacy of potentially disease-modifying treatments. In fact, brain areas affected by AD pathophysiology in the preclinical stage (including the entorhinal cortex, posterior cingulate cortex, and precuneus) form the key nodes in the spatial navigation network (6, 9-13). Recent evidence suggests that abnormal spatial navigation patterns may be present before episodic memory deficits, which are the current gold standard for AD diagnosis (6, 14, 15). A major challenge at this stage, however, is to understand how interindividual and demographic factors affect spatial navigation to identify earliest pathological spatial navigation changes in AD (16-19). Understanding diversifying factors that influence variability in spatial ability in the healthy population and individuals at risk to develop AD will advance the diagnostic power of the spatial tests and support more personalized diagnostic and treatment approaches (17, 20-23). Among factors underlying navigation, age is a well-documented predictor of declining spatial abilities, as older adults show a strong bias toward egocentric rather than allocentric strategies (24, 25) leading to suboptimal navigation performance (26). Age-related decline in allocentric process are due to changes in coding patterns of place, grid, border, and head direction cells that underpin our ability to form cognitive maps of the environment and intergrate environmental and self-motion cues to optimize navigational performance (27-29). However, decline in other cognitive domains such as general planning and cognitive control abilities (30) also contribute to spatial deficits in old age, suggesting that, like most diagnostic tests, age-range normative cutoff scores are required (30, 31). Similarly, sex differences in navigation behavior and underlying neuroanatomy have generated arguments for sex-specific clinico-pathological AD phenotypes (17, 21, 32-35). Rodent models of the Morris water maze have shown that male rats consistently outper-form females (36), and human studies display similar sex differences favoring males (37-40) across 57 countries in both map-dependent allocentric and map-independent egocentric navigational strategies (41). Therefore, although spatial navigation tools must retain sensitivity and specificity to preclinical AD pathophysiology, it will be critical to develop diagnostic tools that can adjust for underlying sex differences. Finally, one of the biggest challenges in preclinical AD studies is to identify those who are at high risk to develop symptomatic AD in the future. Genetic variation in the apolipoprotein E 4 allele carriers is currently the strongest known genetic risk factor for sporadic AD (7, 42-44). Compared with the e3e3 carriers, those with the e3e4 show a threefold to fourfold increased risk for AD (44, 45). Phenotypic characteristics of apoE e4 allele show that the cognitive profile of e4 carriers changes over the life span, with some cognitive advantage seen in young adulthood (39) and cognitive disturbances in mnemonic and spatial process in mid-adulthood (46-48). Recent findings also show that temporal grid cell-like representation in the

Purpose The health-promoting potential of food-derived plant bioactive compounds is evident but not always consistent across studies. Large inter-individual variability may originate from differences in digestion, absorption, distribution, metabolism and excretion (ADME). ADME can be modulated by age, sex, dietary habits, microbiome composition, genetic variation, drug exposure and many other factors. Within the recent COST Action POSITIVe, large-scale literature surveys were undertaken to identify the reasons and extent of inter-individual variability in ADME of selected plant bioactive compounds of importance to cardiometabolic health. The aim of the present review is to summarize the findings and suggest a framework for future studies designed to investigate the etiology of inter-individual variability in plant bioactive ADME and bioefficacy. Results Few studies have reported individual data on the ADME of bioactive compounds and on determinants such as age, diet, lifestyle, health status and medication, thereby limiting a mechanistic understanding of the main drivers of variation in ADME processes observed across individuals. Metabolomics represent crucial techniques to decipher inter-individual variability and to stratify individuals according to metabotypes reflecting the intrinsic capacity to absorb and metabolize bioactive compounds. Conclusion A methodological framework was developed to decipher how the contribution from genetic variants or microbiome variants to ADME of bioactive compounds can be predicted. Future study design should include (1) a larger number of study participants, (2) individual and full profiling of all possible determinants of internal exposure, (3) the presentation of individual ADME data and (4) incorporation of omics platforms, such as genomics, microbiomics and metabolomics in ADME and efficacy studies., Key messages Human intervention studies are typically too small and do not report data from individuals to allow investigations of relevant determinants of inter-individual variability in ADME and bioefficacy.For some plant food bioactive compounds (isoflavones and ellagitannins), particular metabolites are produced only in a subset of the population, i.e., among individuals with a specific metabotype.Microbiota is an important determinant of the ADME of many bioactive compounds but microbial gene annotation is often lacking and interference with background diet and temporal variability is high: microbial metabolism capacity is, therefore, difficult to predict.Genetic variability is considered an important determinant of the ADME of some bioactive compounds, but there is a large gap in knowledge for many families of plant bioactive compounds regarding biotransformation enzymes and transport proteins.Information on other determinants such as age, sex, and diet is too incomplete to make firm conclusions about their impact on the inter-individual variability for most compounds investigatedMetabotyping individuals appears as essential to increase our understanding and improve prediction of ADME and health effects of plant bioactive compounds. Yet successful stratification examples are scarce and if available (e.g., urolithins), validation studies in larger cohorts are still required.

BACKGROUND: Although many randomized controlled trials (RCTs) have examined the effects of the n-3 (ω-3) fatty acids eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) on blood pressure (BP) and vascular function, the majority have used doses of EPA+DHA of >3 g/d, which are unlikely to be achieved by dietary manipulation. OBJECTIVE: The objective was to examine, by using a retrospective analysis from a multicenter RCT, the impact of recommended EPA+DHA intakes achievable through diet on systolic and diastolic BPs and microvascular function in adults in the United Kingdom. METHODS: In a double-blind, placebo-controlled RCT, healthy men and women (n = 312) consumed a control oil or fish oil (FO) providing 0.7 or 1.8 g EPA+DHA/d, in random order, each for 8 wk. Fasting BP and microvascular function (using laser Doppler iontophoresis) were assessed and plasma collected for the quantification of markers of vascular function. Participants were retrospectively genotyped for the endothelial nitric oxide synthase (eNOS) rs1799983 variant. RESULTS: No effects of n-3 fatty acid treatment or any treatment × eNOS genotype interactions were evident in the group as a whole for any of the clinical or biochemical outcomes. Assessment of response according to hypertension status at baseline indicated a significant (P = 0.046) FO-induced reduction (mean: 5 mm Hg) in systolic BP, specifically in those with isolated systolic hypertension (n = 31). No dose response was observed. CONCLUSIONS: These findings indicate that in adults with isolated systolic hypertension, daily doses of EPA+DHA as low as 0.7 g show clinically meaningful BP reductions, which, at a population level, could be associated with lower cardiovascular disease risk. Confirmation of findings in an RCT in which participants are prospectively recruited on the basis of BP status is required to draw definite conclusions.

Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities.

At a population level APOE4 carriers (~25% Caucasians) are at higher risk of cardiovascular diseases. The penetrance of genotype is however variable and influenced by dietary fat composition, with the APOE4 allele associated with greater LDL-cholesterol elevation in response to saturated fatty acids (SFA). The etiology of this greater responsiveness is unknown. Here a novel surface plasmon resonance technique (SPR) is developed and used, along with hepatocyte (with the liver being the main organ modulating lipoprotein metabolism and plasma lipid levels) uptake studies to establish the impact of dietary fatty acid composition on, lipoprotein-LDL receptor (LDLR) binding, and hepatocyte uptake, according to APOE genotype status. In men prospectively recruited according to APOE genotype (APOE3/3 common genotype, or APOE3/E4), triglyceride-rich lipoproteins (TRLs) were isolated at fasting and 4–6 h following test meals rich in SFA, unsaturated fat and SFA with fish oil. In APOE4s a greater LDLR binding affinity of postprandial TRL after SFA, and lower LDL binding and hepatocyte internalization, provide mechanisms for the greater LDL-cholesterol raising effect. The SPR technique developed may be used for the future study of the impact of genotype, and physiological and behavioral variables on lipoprotein metabolism. Trial registration number NCT01522482.

We investigated the independent and interactive impact of the common APOE genotype and marine n-3 polyunsaturated fatty acids (PUFAs) on the development of obesity and associated cardiometabolic dysfunction in a murine model. Human APOE3 and APOE4 targeted replacement mice were fed either a control high-fat diet (HFD) or an HFD supplemented with 3% n-3 PUFAs from fish oil (HFD + FO) for 8 wk. We established the impact of intervention on food intake, body weight, and visceral adipose tissue (VAT) mass; plasma, lipids (cholesterol and triglycerides), liver enzymes, and adipokines; glucose and insulin during an intraperitoneal glucose tolerance test; and Glut4 and ApoE expression in VAT. HFD feeding induced more weight gain and higher plasma lipids in APOE3 compared to APOE4 mice (P < 0.05), along with a 2-fold higher insulin and impaired glucose tolerance. Supplementing APOE3, but not APOE4, animals with dietary n-3 PUFAs decreased body-weight gain, plasma lipids, and insulin (P < 0.05) and improved glucose tolerance, which was associated with increased VAT Glut4 mRNA levels (P < 0.05). Our findings demonstrate that an APOE3 genotype predisposes mice to develop obesity and its metabolic complications, which was attenuated by n-3 PUFA supplementation.—Slim, K. E., Vauzour, D., Tejera, N., Voshol, P. J., Cassidy, A., Minihane, A. M. The effect of dietary fish oil on weight gain and insulin sensitivity is dependent on APOE genotype in humanized targeted replacement mice.

The aim of this review was to determine the impact of the fatty acid desaturase (FADS) genotype on plasma and tissue concentrations of the long-chain (LC) n-3 PUFA, including EPA and DHA, which are associated with the risk of several diet-related chronic diseases, including CVD. In addition to dietary intakes, which are low for many individuals, tissue EPA and DHA are also influenced by the rate of bioconversion from α-linolenic acid (αLNA). Δ-5 and Δ-6 desaturase enzymes, encoded for by FADS1 and FADS2 genes, are key desaturation enzymes involved in the bioconversion of essential fatty acids (αLNA and linoleic acid (LA)) to longer chained PUFA. In general, carriers of FADS minor alleles tend to have higher habitual plasma and tissue levels of LA and αLNA, and lower levels of arachidonic acid, EPA and also to a lesser extent DHA. In conclusion, available research findings suggest that FADS minor alleles are also associated with reduced inflammation and CVD risk, and that dietary total fat and fatty acid intake have the potential to modify relationships between FADS gene variants and circulating fatty acid levels. However to date, neither the size-effects of FADS variants on fatty acid status, nor the functional SNP in FADS1 and 2 have been identified. Such information could contribute to the refinement and targeting of EPA and DHA recommendations, whereby additional LC n-3 PUFA intakes could be recommended for those carrying FADS minor alleles.

Highlights • The effect of diet and genotype on inflammatory response was explored in humans. • Cytokine production was not affected by apolipoprotein E (APOE) genotype. • TNF-α concentration significantly increased after a high saturated fat diet. • IL-10 concentration was significantly higher after a low fat diet. • The amount and type of dietary fat modulated cytokine production., Apolipoprotein E (APOE) genotype is believed to play an important role in cardiovascular risk. APOE4 carriers have been associated with higher blood lipid levels and a more pro-inflammatory state compared with APOE3/E3 individuals. Although dietary fat composition has been considered to modulate the inflammatory state in humans, very little is known about how APOE genotype can impact on this response. In a follow-up to the main SATgenε study, we aimed to explore the effects of APOE genotype, as well as, dietary fat manipulation on ex vivo cytokine production. Blood samples were collected from a subset of SATgenε participants (n = 52/88), prospectively recruited according to APOE genotype (n = 26 E3/E3 and n = 26 E3/E4) after low-fat (LF), high saturated fat (HSF) and HSF with 3.45 g docosahexaenoic acid (DHA) dietary periods (each diet eight weeks in duration assigned in the same order) for the measurement of ex vivo cytokine production using whole blood culture (WBC). Concentrations of IL-1beta, IL-6, IL-8, IL-10 and TNF-alpha were measured in WBC supernatant samples after stimulation for 24 h with either 0.05 or 1 μg/ml of bacterial lipopolysaccharide (LPS). Cytokine levels were not influenced by genotype, whereas, dietary fat manipulation had a significant impact on TNF-α and IL-10 production; TNF-α concentration was higher after consumption of the HSF diet compared with baseline and the LF diet (P

Fruit and vegetables are key elements of a cardioprotective diet, but benefits on plasma lipids, especially HDL-cholesterol (HDL-C), are inconsistent both within and between studies. In the present study, we investigated whether four selected HDL-C-related polymorphisms (cholesteryl ester transfer protein (CETP) Taq1B, APOA1 − 75G/A, hepatic lipase (LIPC) − 514C → T, and endothelial lipase (LIPG) I24582) modulate the plasma lipid response to a kiwifruit intervention. This is a retrospective analysis of data collected during a 12-week randomised controlled cross-over trial. A total of eighty-five hypercholesterolaemic men completed a 4-week healthy diet run-in period before being randomised to one of two 4-week intervention sequences of two green kiwifruit/d plus healthy diet (kiwifruit intervention) or healthy diet alone (control intervention). The measurement of anthropometric parameters and collection of fasting blood samples were carried out at baseline 1 and after the run-in (baseline 2) and intervention periods. At baseline 2, B1/B1 homozygotes of the CETPTaq1B gene had significantly higher total cholesterol:HDL-C, TAG:HDL-C, and apoB:apoA1 ratios and small-dense LDL concentrations than B2 carriers. A significant CETP Taq1B genotype × intervention interaction was observed for the TAG:HDL-C ratio (P= 0·03). B1/B1 homozygotes had a significantly lower TAG:HDL-C ( − 0·23 (sd 0·58) mmol/l; P= 0·03) ratio after the kiwifruit intervention than after the control intervention, whereas the ratio of B2 carriers was not affected. The lipid response was not affected by other gene polymorphisms. In conclusion, the significant decrease in the TAG:HDL-C ratio in B1/B1 homozygotes suggests that regular inclusion of green kiwifruit as part of a healthy diet may improve the lipid profiles of hypercholesterolaemic men with this genotype.

Scope: To determine the contribution of intestinally and liver-derived lipoproteins to the postprandial plasma triacylglycerol (TAG) response in APOE3/E3 and E3/E4 individuals following chronic dietary fat manipulation. Methods and results: In sequential order, participants (n = 12 E3/E3, n = 11 E3/E4) followed low fat (LF); high-fat, high-saturated fat (HSF); and HSF with 3.45 g/day docosahexaenoic acid (HSF-DHA) diets, each for 8 weeks. After each dietary period, an acute test meal with a macronutrient profile representative of the dietary intervention was consumed. Apolipoprotein (apo)B isoforms were determined in isolated TAG-rich lipoprotein fractions (Sf>400, Sf 60–400 and Sf 20–60) by specific ELISA. A genotype*meal/diet interaction for the Sf>400 fraction apoB-48 response (P400 particles. Fasting Sf 60–400 and 20–60 apoB-48 concentrations were also significantly higher in E4 carriers. No impact of genotype on the apoB-100 responses was evident. Conclusion: Our study revealed marked effects of dietary fat composition on the Sf>400 apoB-48 response and particle TAG content in E4 carriers relative to the ‘wild-type’ E3/E3 genotype, which suggest APOE genotype is a potential modulator of chylomicron particle synthesis.

Our objective was to investigate the impact of EPA versus DHA on arterial stiffness and reactivity and underlying mechanisms (with a focus on plasma oxylipins) in the postprandial state. In a three-arm crossover acute test meal trial, men (n = 26, 35–55 years) at increased CVD risk received a high-fat (42.4 g) test meal providing 4.16 g of EPA or DHA or control oil in random order. At 0 h and 4 h, blood samples were collected to quantify plasma fatty acids, long chain n-3 PUFA-derived oxylipins, nitrite and hydrogen sulfide, and serum lipids and glucose. Vascular function was assessed using blood pressure, reactive hyperemia index, pulse wave velocity, and augmentation index (AIx). The DHA-rich oil significantly reduced AIx by 13% (P = 0.047) with the decrease following EPA-rich oil intervention not reaching statistical significance. Both interventions increased EPA- and DHA-derived oxylipins in the acute postprandial state, with an (1.3-fold) increase in 19,20-dihydroxydocosapentaenoic acid evident after DHA intervention (P < 0.001). In conclusion, a single dose of DHA significantly improved postprandial arterial stiffness as assessed by AIx, which if sustained would be associated with a significant decrease in CVD risk. The observed increases in oxylipins provide a mechanistic insight into the AIx effect.

Ten years ago, it was assumed that disease risk prediction and personalised nutrition based on genetic information would now be in widespread use. However, this has not (yet) transpired. The interaction of genetic make-up, diet and health is far more complex and subtle than originally thought. With a few notable exceptions, the impact of identified common genetic variants on phenotype is relatively small and variable in their penetrance. Furthermore, the known variants account for only a fraction of what we believe to be the total genetic contribution to disease risk and heterogeneity in response to environmental change. Here, the question ‘how far have we progressed and are we likely to get there’ (Rimbach and Minihane, 2009) is revisited with regard to the translation of genetic knowledge into public health benefit. It is concluded that progress to date has been modest. It is hoped that recent technological developments allowing the detection of rarer variants and future use of more hypothesis-driven targeted data analysis will reveal most of the currently ‘hidden’ significant genetic variability.

Scope Our aim was to determine the effects of chronic dietary fat manipulation on postprandial lipaemia according to apolipoprotein (APO)E genotype. Methods and results Men (mean age 53 (SD 9) years), prospectively recruited for the APOE genotype (n = 12 E3/E3, n = 11 E3/E4), were assigned to a low fat (LF), high fat, high-saturated fat (HSF), and HSF diet with 3.45 g/day docosahexaenoic acid (HSF-DHA), each for an 8-week period in the same order. At the end of each dietary period, a postprandial assessment was performed using a test meal with a macronutrient profile representative of that dietary intervention. A variable postprandial plasma triacylglycerol (TAG) response according to APOE genotype was evident, with a greater sensitivity to the TAG-lowering effects of DHA in APOE4 carriers (p ≤ 0.005). There was a lack of an independent genotype effect on any of the lipid measures. In the groups combined, dietary fat manipulation had a significant impact on lipids in plasma and Svedberg flotation rate (Sf) 60–400 TAG-rich lipoprotein fraction, with lower responses following the HSF-DHA than HSF intervention (p < 0.05). Conclusion Although a modest impact of APOE genotype was observed on the plasma TAG profile, dietary fat manipulation emerged as a greater modulator of the postprandial lipid response in normolipidaemic men.

The Publisher's final version can be found by following the DOI link. Purpose Limited robust randomised controlled trials investigating fruit and vegetable (F&V) intake in people at risk of cardiovascular disease (CVD) exist. We aimed to design and validate a dietary strategy of increasing flavonoid-rich versus flavonoid-poor F&V consumption on nutrient biomarker profile. Methods A parallel, randomised, controlled, dose–response dietary intervention study. Participants with a CVD relative risk of 1.5 assessed by risk scores were randomly assigned to one of the 3 groups: habitual (control, CT), high-flavonoid (HF) or low-flavonoid (LF) diets. While the CT group (n = 57) consumed their habitual diet throughout, the HF (n = 58) and LF (n = 59) groups sequentially increased their daily F&V intake by an additional 2, 4 and 6 portions for 6-week periods during the 18-week study. Results Compliance to target numbers and types of F&V was broadly met and verified by dietary records, and plasma and urinary biomarkers. Mean (±SEM) number of F&V portions/day consumed by the HF and LF groups at baseline (3.8 ± 0.3 and 3.4 ± 0.3), 6 weeks (6.3 ± 0.4 and 5.8 ± 0.3), 12 weeks (7.0 ± 0.3 and 6.8 ± 0.3) and 18 weeks (7.6 ± 0.4 and 8.1 ± 0.4), respectively, was similar at baseline yet higher than the CT group (3.9 ± 0.3, 4.3 ± 0.3, 4.6 ± 0.4, 4.5 ± 0.3) (P = 0.015). There was a dose-dependent increase in dietary and urinary flavonoids in the HF group, with no change in other groups (P = 0.0001). Significantly higher dietary intakes of folate (P = 0.035), non-starch polysaccharides (P = 0.001), vitamin C (P = 0.0001) and carotenoids (P = 0.0001) were observed in both intervention groups compared with CT, which were broadly supported by nutrient biomarker analysis. Conclusions The success of improving nutrient profile by active encouragement of F&V intake in an intervention study implies the need for a more hands-on public health approach.

The cardioprotective actions of the fish oil (FO)-derived long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been demonstrated, and dose-response relationships have been defined. However, there is a substantial and well-recognized within-population heterogeneity in response to FO, the etiology of which is poorly understood. Genetic variation may influence responsiveness. Here we review the available literature relating to gene variants shown to influence tissue LC n-3 PUFA status and response to FO intervention. From this review we conclude that the available evidence is relatively limited. A number of individual genotype × LC-n3 PUFA × phenotype associations have been described, but few have been investigated in subsequent cohorts or confirmed in independent studies. In the context of a more stratified approach to the provision of dietary advice, there is a need for further research to refine current dietary EPA and DHA recommendations.

An apoE4 genotype is an important risk factor for cardiovascular and other chronic diseases. The higher cardiovascular disease risk of apoE4 carriers as compared to the apoE3 genotype has been mainly attributed to the differences in blood lipids between the two genotype subgroups. Recently, a potential protective role of the transcription factor Nrf2 in cardiovascular disease prevention has been suggested. In this study, we show that Nrf2-dependent gene expression is affected by the apoE genotype. ApoE4 vs. apoE3 mice exhibited lower hepatic Nrf2 nuclear protein levels. Furthermore, mRNA and protein levels of Nrf2 target genes including glutathione-S-transferase, heme oxygenase-1 and NAD(P)H dehydrogenase, quinone 1 were significantly lower in apoE4 as compared to apoE3 mice. Lower hepatic mRNA levels of phase II enzymes, as observed in apoE4 vs. apoE3 mice, were accompanied by higher mRNA levels of phase I enzymes including Cyp26a1 and Cyp3a16. Furthermore, miRNA-144, miRNA-125b, and miRNA-29a involved in Nrf2 signaling, inflammation, and regulation of phase I enzyme gene expression were affected by the apoE genotype. We provide first evidence that Nrf2 is differentially regulated in response to the apoE genotype.

The beneficial effects of green tea catechins, such as the proposed improvement in endothelial function, may be influenced by phase II metabolism during and after absorption. The methylation enzyme, catechol-O-methyltransferase (COMT), has a missense mutation rs4680 (G to A), proposed to result in a 40 % reduction in enzyme activity. In the present pilot study, twenty subjects (ten of each homozygous COMT genotype) were recruited. Green tea extract capsules (836 mg green tea catechins) were given in a fasted state, and a high-carbohydrate breakfast was given after 60 min. Blood samples and vascular function measurements were taken at regular intervals. The change in digital volume pulse stiffness index (SI) from baseline was shown to be different between genotype groups at 120 and 240 min, with a lower SI in the GG individuals (P ≤ 0·044). The change in blood pressure from baseline also differed between genotype groups, with a greater increase in systolic (P = 0·023) and diastolic (P = 0·034) blood pressure at 120 min in the GG group. The AA group was shown to have a greater increase in insulin concentrations at 120 min (P = 0·019) and 180 min (P = 0·008) compared with baseline, despite similar glucose profiles. No genotypic differences were found in vascular reactivity measured using laser Doppler iontophoresis, total nitrite, lipids, plasma total antioxidant capacity or inflammatory markers after ingestion of the green tea extract. In conclusion, SI and insulin response to the glucose load differed between the COMT genotype groups, and this may be suggestive of a green tea extract and genotype interaction.

The possible relationship between consumption of trans fatty acids (TFAs) and risk of insulin resistance or development of diabetes mellitus type II has been considered by a number of human and animal studies over the past decade. This review evaluates the evidence, and concludes that there is limited evidence for a weak association at high TFA intakes, but very little convincing evidence that habitual exposure as part of a standard western diet has a significant contribution to risk of diabetes or insulin resistance. The possibility of increased risk for individuals with particular genotypes (such as the FABP2 Thr54 allele) is of interest, but further work would be required to provide sufficient evidence of any association.

Cardiovascular disease (CVD) risk and rate of progression is determined by genetic, environmental and behavioural factors. Majority of genotype-diet-CVD phenotype research till date has focussed on the interactive impact of single nucleotide polymorphisms (SNP) and dietary fat composition, on blood lipids levels, with strong evidence of the existence of hypo- and hyper-responders. However, a recognised concern in the field of nutrigenetics is a lack of consistency between findings of different studies. This apparent lack of consistency is likely to be attributable to the impact of factors such as ethnicity and gender on the 'size' of nutrigenetic interactions, a clear understanding of which needs to be gained. Although not yet ready for widespread use, in the future a greater use of genetic profiling is likely to enhance current strategies of CVD prediction, and improve the design of more personalised approaches to minimise risk in the individual.

Objectives To investigate the impact of apolipoprotein E (apoE) genotype on the response of the plasma lipoprotein profile to eicosapentaenoic acid (EPA) versus docosahexaenoic acid (DHA) intervention in humans. Methods and results 38 healthy normolipidaemic males, prospectively recruited on the basis of apoE genotype ( n =20 E3/E3 and n =18 E3/E4), completed a double-blind placebo-controlled cross-over trial, consisting of 3×4 week intervention arms of either control oil, EPA-rich oil (ERO, 3.3g EPA/day) or DHA-rich oil (DRO, 3.7g DHA/day) in random order, separated by 10 week wash-out periods. A significant genotype-independent 28% and 19% reduction in plasma triglycerides in response to ERO and DRO was observed. For total cholesterol (TC), no significant treatment effects were evident; however a significant genotype by treatment interaction emerged ( P =0.045), with a differential response to ERO and DRO in E4 carriers. Although the genotype×treatment interaction for LDL-cholesterol ( P =0.089) did not reach significance, within DRO treatment analysis indicated a 10% increase in LDL ( P =0.029) in E4 carriers with a non-significant 4% reduction in E3/E3 individuals. A genotype-independent increase in LDL mass was observed following DRO intervention ( P =0.018). Competitive uptake studies in HepG2 cells using plasma very low density lipoproteins (VLDL) from the human trial, indicated that following DRO treatment, VLDL 2 fractions obtained from E3/E4 individuals resulted in a significant 32% ( P =0.002) reduction in LDL uptake relative to the control. Conclusions High dose DHA supplementation is associated with increases in total cholesterol in E4 carriers, which appears to be due to an increase in LDL-C and may in part negate the cardioprotective action of DHA in this population subgroup.

To examine the impact of age and the natural menopause on the postprandial triacylglycerol (TAG) response in healthy women.Thirty-seven premenopausal and sixty-one postmenopausal women underwent a sequential meal postprandial investigation, in which blood samples were taken at regular intervals after a test breakfast and lunch given at 0 and 330 min respectively. Lipids and glucose were measured in the fasting sample, with TAG analysed in the postprandial samples. Postmenopausal women were shown to have higher fasting total cholesterol, low density lipoprotein cholesterol (LDL-C) and glucose (P0.02). Marked differences in the postprandial TAG response were evident between the groups, with a greater incremental area under the curve (IAUC) and maximum TAG concentration in the postmenopausal women (P0.04). Multivariate regression analysis revealed both age and fasting TAG to be independently associated with the summary measures of the postprandial TAG response in the premenopausal women only. Interestingly, sub-division of the women into both younger and older pre- and postmenopausal subgroups, showed the most marked difference in TAG-IAUC to be between the younger and the older premenopausal women, whereas differences in fasting LDL-C were most evident between the older premenopausal and the younger postmenopausal women.Our results suggest a divergence in the relationship of age and menopausal status with fasting LDL-C and postprandial TAG which may reflect differences in the metabolic effects of age and the menopause on these lipid risk markers or a greater impact of early oestrogen decline on pathways of TAG rather than LDL metabolism.

The health benefits of green tea (Camellia sinensis) catechins are becoming increasingly recognised. Amongst the proposed benefits are the maintenance of endothelial function and vascular homeostasis and an associated reduction in atherogenesis and CVD risk. The mounting evidence for the influential effect of green tea catechins on vascular function from epidemiological, human intervention and animal studies is subject to review together with exploration of the potential mechanistic pathways involved. Epigallocatechin-3-gallate, one of the most abundant and widely studied catechin found in green tea, will be prominent in the present review. Since there is a substantial inconsistency in the published data with regards to the impact of green tea catechins on vascular function, evaluation and interpretation of the inter- and intra-study variability is included. In conclusion, a positive effect of green tea catechins on vascular function is becoming apparent. Further studies in animal and cell models using physiological concentrations of catechins and their metabolites are warranted in order to gain some insight into the physiology and molecular basis of the observed beneficial effects.

28 páginas, 1 tabla, 4 figuras., Epidemiological studies suggest that a moderate consumption of anthocyanins may be associated with protection against coronary heart disease. The main dietary sources of anthocyanins include red-coloured fruits and red wine. Although dietary anthocyanins comprise a diverse mixture of molecules, little is known how structural diversity relates to their bioavailability and biological function. The aim of the present study was to evaluate the absorption and metabolism of the 3-monoglucosides of delphinidin, cyanidin, petunidin, peonidin and malvidin in humans and to examine both the effect of consuming a red wine extract on plasma antioxidant status and on MCP-1 production in healthy human subjects. After a 12 h overnight fast, 7 healthy volunteers received 12 g of an anthocyanin extract and provided 13 blood samples in the 24 h following the test meal. Furthermore urine was collected during this 24h period. Anthocyanins were detected in their intact form in both plasma and urine samples. Other anthocyanin metabolites could also be detected in plasma and urine and were identified as glucuronides of peonidin and malvidin. Anthocyanins and their metabolites appeared in plasma about 30 minutes after ingestion of the test meal and reached their maximum value around 1.6 hours later for glucosides and 2.5 hours for glucuronides. Total urinary excretion of red wine anthocyanins was 0.05 ± 0.01% of the administered dose within 24 hours. About 94 % of the excreted anthocyanins were found in urine within 6 hours. In spite of the low concentration of anthocyanins found in plasma, an increase in the antioxidant capacity and a decrease in MCP-1 circulating levels in plasma were observed., Spanish/German Programme Acciones Integradas Hispano-Alemanas (HA2004- 0091) for financial support and Spanish MEC for a Ph.D. studentship to MGA.

Although chronic fish oil intervention had been shown to have a positive impact on vascular reactivity, very little is known about their acute effects during the postprandial phase. Our aim was to examine the impact of a fish oil-enriched test meal on postprandial vascular reactivity in healthy younger ( v. older ( ≥ 50 years) men. Vascular reactivity was measured at baseline (0 h), 2 and 4 h after the meal by laser Doppler iontophoresis and blood samples taken at 0 and 4 h for the measurement of plasma lipids, total nitrite, glucose and insulin. Acetylcholine- (ACh, endothelial-dependent vasodilator) and sodium nitroprusside (SNP, endothelial-independent vasodilator)-induced reactivities were greater at 4 h than at baseline or 2 h in the younger men (P P = 0·006) and SNP (P = 0·05) at 4 h in the younger compared with the older males. Postprandial NEFA concentrations were also greater at 4 h in the younger compared with the older men (P = 0·005), with no differences observed for any of the other analytes. Multiple regression analysis revealed age to be the most significant predictor of both ACh and SNP induced reactivity 4 h after the meal. In conclusion, the ingestion of a meal enriched in fish oil fatty acids was shown to improve postprandial vascular reactivity at 4 h in our younger men, with little benefit evident in our older men.

The present review comes from the authors of the recent Scientific Advisory Committee on Nutrition (SACN) review Update on Trans Fatty Acids and Health, and focuses on assessing the strength of the evidence for a link between trans-fatty acid (trans-FA) intake and cancer. It evaluates a range of human ecological, case–control and prospective studies with trans-FA exposure assessed using either dietary assessment methods or trans-FA levels in tissues. Relevant animal studies are also presented in order to elucidate potential mechanisms. It concludes that there is weak and inconsistent evidence for a relationship between trans-FA and breast or colorectal cancer. Evidence for an association between trans-FA and prostate cancer is limited, but a recent large case–control study has shown a strong interaction between risk and trans-FA intake for the RNASEL QQ/RQ genotype that is present in about 35 % of the population. This potential association requires further investigation. The single study on non-Hodgkin's lymphoma reported a strong positive association, but only used a single assessment of dietary trans-FA made at the start of the study in 1980, and the significant changes in trans-FA intakes between then and the end of follow-up in 1994 limit the reliability of this observation. There is insufficient evidence to allow any differentiation between the effects of trans-FA from animal or vegetable origin on cancer risk.

The molecular basis of the positive association between apoE4 genotype and CVD remains unclear. There is directin vitroevidence indicating that apoE4 is a poorer antioxidant relative to the apoE3 isoform, with some indirectin vivoevidence also available. Therefore it was hypothesised that apoE4 carriers may benefit from α-tocopherol (α-Toc) supplementation. Targeted replacement mice expressing the human apoE3 and apoE4 were fed with a diet poor (0 mg/kg diet) or rich (200 mg/kg diet) in α-Toc for 12 weeks. Neither apoE genotype nor dietary α-Toc exerted any effects on the antioxidant defence system, including glutathione, catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase activities. In addition, no differences were observed in mitogen-induced lymphocyte proliferation. α-Toc concentrations were modestly higher in plasma and lower in tissues of apoE4 compared with apoE3 mice, with the greatest differences evident in the lung, suggesting that an apoE4 genotype may reduce α-Toc delivery to tissues. A tendency towards increased plasma F2-isoprostanes in apoE4 mice was observed, while liver thiobarbituric acid-reactive substances did not differ between apoE3 and apoE4 mice. In addition, C-reactive protein (CRP) concentrations were reduced in apoE4 mice indicating that this positive effect on CRP may in part negate the increased CVD risk associated with an apoE4 genotype.

Although apolipoprotein A-V (apoA-V) polymorphisms have been consistently associated with fasting triglyceride (TG) levels, their impact on postprandial lipemia remains relatively unknown. In this study, we investigate the impact of two common apoA-V polymorphisms (−1131 T>C and S19W) and apoA-V haplotypes on fasting and postprandial lipid metabolism in adults in the United Kingdom (n = 259). Compared with the wild-type TT, apoA-V −1131 TC heterozygotes had 15% (P = 0.057) and 21% (P = 0.002) higher fasting TG and postprandial TG area under the curve (AUC), respectively. Significant (P = 0.038) and nearly significant (P = 0.057) gender × genotype interactions were observed for fasting TG and TG AUC, with a greater impact of genotype in males. Lower HDL-cholesterol was associated with the rare TC genotype (P = 0.047). Significant linkage disequilibrium was found between the apoA-V −1131 T>C and the apoC-III 3238 C>G variants, with univariate analysis indicating an impact of this apoC-III single nucleotide polymorphism (SNP) on TG AUC (P = 0.015). However, in linear regression analysis, a significant independent association with TG AUC (P = 0.007) was only evident for the apoA-V −1131 T>C SNP, indicating a greater relative importance of the apoA-V genotype.

In order to establish firm evidence for the health effects of dietary polyphenol consumption, it is essential to have quantitative information regarding their dietary intake. The usefulness of the current methods, which rely mainly on the assessment of polyphenol intake using food records and food composition tables, is limited as they fail to assess total intake accurately. This review highlights the problems associated with such methods with regard to polyphenol-intake predictions. We suggest that the development of biological biomarkers, measured in both blood and urine, are essential for making accurate estimates of polyphenol intake. However, the relationship between dietary intakes and nutritional biomarkers are often highly complex. This review identifies the criteria that must be considered in the development of such biomarkers. In addition, we provide an assessment of the limited number of potential biomarkers of polyphenol intake currently available.

Scope: Of the three human apolipoprotein E (APOE) alleles, the ε3 allele is most common, which may be a result of adaptive evolution. In this study, we investigated whether the APOE genotype affects body weight and energy metabolism through regulation of fatty acid utilization. Methods and results: Targeted replacement mice expressing the human APOE3 were significantly heavier on low- and high-fat diets compared to APOE4 mice. Particularly on high-fat feeding, food intake and dietary energy yields as well as fat mass were increased in APOE3 mice. Fatty acid mobilization determined as activation of adipose tissue lipase and fasting plasma nonesterified fatty acid levels were significantly lower in APOE3 than APOE4 mice. APOE4 mice, in contrast, exhibited higher expression of proteins involved in fatty acid oxidation in skeletal muscle. Conclusion: Our data suggest that APOE3 is associated with the potential to more efficiently harvest dietary energy and to deposit fat in adipose tissue, while APOE4 carriers tend to increase fatty acid mobilization and utilization as fuel substrates especially under high-fat intake. The different handling of dietary energy may have contributed to the evolution and worldwide distribution of the ε3 allele.