Ageing and apoE change DHA homeostasis: relevance to age-related cognitive decline

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

Lifetime exposure to ambient ultraviolet radiation and the risk for cataract extraction and age-related macular degeneration : the Alienor Study

While exposure to ultraviolet radiation (UVR) is a recognized risk factor for cataract, its association is more controversial with age-related macular degeneration (AMD). We report the associations of lifetime exposure to ambient UVR with cataract extraction and AMD. The Alienor Study is a population-based study of 963 residents of Bordeaux (France), aged 73 years or more. Lifetime exposure to ambient UVR was estimated from residential history and Eurosun satellite-based estimations of ground UVR. It was divided in three groups (lower quartile, intermediate quartiles, upper quartile), using the intermediate quartiles as the reference. Early and late AMD was classified from retinal color photographs. Cataract extraction was defined as absence of the natural lens at slit-lamp. After multivariate adjustment, subjects in the upper quartile of lifetime ambient UVR exposure were at increased risk for cataract extraction (odds ratio [OR] = 1.53; 95% confidence interval [CI], 1.04-2.26; P = 0.03) and for early AMD (OR = 1.59; 95% CI, 1.04-2.44; P = 0.03), by comparison with subjects in the intermediate quartiles. Subjects in the lower quartile of UVR exposure also were at increased risk for early AMD (OR = 1.69; 95% CI, 1.06-2.69; P = 0.03), by comparison with those with medium exposure. Associations of late AMD with UVR exposure was not statistically significant. This study further confirms the increased risk for cataract extraction in subjects exposed to high ambient UVR. Moreover, it suggests that risk for early AMD is increased in subjects exposed to high UVR, but also to low UVR, by comparison with medium exposures

Seropositivity to Herpes Simplex Virus Antibodies and Risk of Alzheimer's Disease: A Population-Based Cohort Study

International audienceBACKGROUND: Herpes Simplex Virus (HSV) infection has been proposed as a possible risk factor of Alzheimer's Disease (AD) notably because it is neurotropic, ubiquitous in the general population and able to establish lifelong latency in the host. The fact that HSV was present in elderly subjects with AD suggests that the virus could be a co-factor of the disease. We investigated the risk of developing AD in anti-HSV immunoglobulin G (IgG) positive subjects (indicator of a lifelong infection to HSV) and IgM-positive subjects (indicator of primary infection or reactivation of the virus) in a longitudinal population-based cohort of elderly subjects living in the community. METHODS: Cox proportional hazard models were used to study the risk of developing AD according to the presence or not of anti-HSV IgG and IgM antibodies, assessed in the sera of 512 elderly initially free of dementia followed for 14 years. RESULTS: During the follow-up, 77 incident AD cases were diagnosed. Controlled for age, gender, educational level and Apolipoprotein E4 (APOE4) status, IgM-positive subjects showed a significant higher risk of developing AD (HR = 2.55; 95% CI [1.38-4.72]), although no significant increased risk was observed in IgG-positive subjects (HR = 1.67; 95%CI [0.75-3.73]). No modification effect with APOE4 status was found. CONCLUSION: Reactivation of HSV seropositivity is highly correlated with incident AD. HSV chronic infection may therefore be contributive to the progressive brain damage characteristic of AD

Nutrition for the ageing brain: towards evidence for an optimal diet

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

ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies.

IMPORTANCE: The role of ω-3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers. OBJECTIVE: To evaluate biomarkers of seafood-derived eicosapentaenoic acid (EPA; 20:5ω-3), docosapentaenoic acid (DPA; 22:5ω-3), and docosahexaenoic acid (DHA; 22:6ω-3) and plant-derived α-linolenic acid (ALA; 18:3ω-3) for incident CHD. DATA SOURCES: A global consortium of 19 studies identified by November 2014. STUDY SELECTION: Available prospective (cohort, nested case-control) or retrospective studies with circulating or tissue ω-3 biomarkers and ascertained CHD. DATA EXTRACTION AND SYNTHESIS: Each study conducted standardized, individual-level analysis using harmonized models, exposures, outcomes, and covariates. Findings were centrally pooled using random-effects meta-analysis. Heterogeneity was examined by age, sex, race, diabetes, statins, aspirin, ω-6 levels, and FADS desaturase genes. MAIN OUTCOMES AND MEASURES: Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI). RESULTS: The 19 studies comprised 16 countries, 45 637 unique individuals, and 7973 total CHD, 2781 fatal CHD, and 7157 nonfatal MI events, with ω-3 measures in total plasma, phospholipids, cholesterol esters, and adipose tissue. Median age at baseline was 59 years (range, 18-97 years), and 28 660 (62.8%) were male. In continuous (per 1-SD increase) multivariable-adjusted analyses, the ω-3 biomarkers ALA, DPA, and DHA were associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95% CI, 0.84-0.98) for ALA, 0.90 (95% CI, 0.85-0.96) for DPA, and 0.90 (95% CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95% CI, 0.90-0.99), ALA (RR, 1.00; 95% CI, 0.95-1.05), EPA (RR, 0.94; 95% CI, 0.87-1.02), and DHA (RR, 0.95; 95% CI, 0.91-1.00) were not. Significant associations with nonfatal MI were not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses. CONCLUSIONS AND RELEVANCE: On the basis of available studies of free-living populations globally, biomarker concentrations of seafood and plant-derived ω-3 fatty acids are associated with a modestly lower incidence of fatal CHD.ARIC was carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. CHS was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grant U01HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health The Costa-Rican adult study was supported by grant R01HL081549 from the National Institutes of Health. EURAMIC was supported by the Commission of the European Communities, as a Concerted Action within Directorate General-XII, with additional support from Directorate General-V Europe against Cancer. The national studies were financed by the Dutch Ministry of Health. Ulster Cancer Foundation and Milk Intervention Board. Grant AKT76 from Cancer Research Switzerland. Swiss National Science Foundation Grant 32-9257-87. Spanish FIS and Ministry of Science and Education, and German Federal Health Office EPIC-Norfolk was funded by grants from Medical Research Council and Cancer Research UK. Dr. Imamura also received support from the Medical Research Council Epidemiology Unit Core Support (MC_UU_12015/5). HPFS was supported by the NIH grants UM1 CA167552, R01 HL35464, AA11181, HL35464, CA55075, HL60712 and P30 DK46200 The InChianti study was supported as a ‘targeted project’ (ICS 110.1\RS97.71) by the Italian Ministry of Health and in part by the Intramural Research Program of the NIH (Contracts N01-AG-916413 and N01-AG-821336 and Contracts 263 MD 9164 13 and 263 MD 821336) KIND (Kuopio Ischaemic Heart Disease Risk Factor Study) was supported by grants from the Academy of Finland, Helsinki, Finland (grants 41471, 1041086) MCCS (Melbourne Collaborative Cohort Study) recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-MEHC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, and UL1-TR-000040. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetric Genome-Wide Human SNP Array 6.0. NSHDS I & II (The Northern Sweden Health & Disease Study I & II) was supported by the Swedish Cancer Society and the Swedish Research Council NHS (Nurses’ Health Study) was supported by research grants UM1 CA186107, R01 CA49449, R01 HL034594, P01CA87969, R01HL034594, and R01HL088521 of the National Institutes of Health The PHS (Physician’s Health Study) was supported by grant R21 HL088081, CA-34944 and CA-40360, and CA-097193 from the National Cancer Institute and grants HL-26490 and HL-34595from the National Heart, Lung, and Blood Institute, Bethesda, MD. The 3C (Three-City) study was conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale (INSERM), the University Bordeaux 2 Victor Segalen and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The Three-City study was also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Conseils Régionaux d’Aquitaine et Bourgogne, Fondation de France, Ministry of Research-INSERM Programme “Cohortes et collections de données biologiques”, Agence Nationale de la Recherche (grant number COGINUT ANR-06-PNRA-005), the Fondation Plan Alzheimer (grant number FCS 2009-2012), and the Caisse Nationale pour la Solidarité et l’Autonomie (CNSA) . Dr Samieri was on a grant from the “Fondation Plan Alzheimer” SHHEC (Scottish Heart Health Extended Cohort) study was funded by the Scottish Health Department Chief Scientist Organization; British Heart Foundation; FP Fleming Trust. The authors would like to acknowledge Dr. Roger Tavendale for his work with the Scottish Heart Health Study. SCHS (Singapore Chinese Health Study) was supported by the Singapore National Medical Research Council (grant number: NMRC 1270/2010) and the U.S. NIH (grant numbers: R01CA 144034 and UM1 CA182876) ULSAM 50 and 70 were funded by the Swedish Research Council for Health, Working Life and Welfare (FORTE) Uppsala City Council (ALF) and Swedish Research CouncilThis is the final version of the article. It first appeared from American Medical Association via http://dx.doi.org/10.1001/jamainternmed.2016.292

Nutrition for the ageing brain: towards evidence for an optimal diet

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

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics