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BACKGROUND: Epidemiological studies suggest that coffee consumption may be inversely associated with risk of endometrial cancer (EC), the most common gynecological malignancy in developed countries. Furthermore, coffee consumption may lower circulating levels of estrogen and insulin, hormones implicated in endometrial carcinogenesis. Antioxidants and other chemopreventive compounds in coffee may have anticarcinogenic effects. Based on available meta-analyses, the World Cancer Research Fund concluded that consumption of coffee probably protects against EC.OBJECTIVE: Our main aim was to examine the association between coffee consumption and EC risk by combining individual-level data in a pooled analysis. We also sought to evaluate potential effect modification by other risk factors of EC.PATIENTS AND METHODS: We combined individual-level data from 19 epidemiologic studies (6 cohort, 13 case-control) of 12,159 endometrial cancer cases and 27,479 controls from the Epidemiology of Endometrial Cancer Consortium (E2C2). Logistic regression was used to calculate odds ratios (OR) and their corresponding 95% confidence intervals (CI). All models were adjusted for potential confounders including age, race, body mass index, smoking status, diabetes status, study design and study site.RESULTS: Coffee drinkers had a lower risk of EC compared to non-coffee drinkers (multi-adjusted OR = 0.87, 95% CI = 0.79,0.95). There was a dose-response relationship between higher coffee consumption and lower risk of EC: compared to non-coffee drinkers, the adjusted pooled ORs for those who drank 1, 2-3 and more than 4 cups/day were 0.90 (95% CI = 0.82,1.00), 0.86 (95% CI = 0.78,0.95), and 0.76 (95% CI = 0.66,0.87), respectively (p for trend < 0.001). The inverse association between coffee consumption and EC risk was stronger in participants with body mass index (BMI) over 25 kg/m2.CONCLUSION: The results of the largest analysis to date pooling individual-level data further support the potentially beneficial health effects of coffee consumption in relation to EC, especially among females with higher BMI.

Evidence linking body fatness to breast cancer (BC) prognosis is limited. While it seems that excess adiposity is associated with poorer BC survival, there is uncertainty over whether weight changes reduce mortality. This study aimed to assess the association between body fatness and weight changes pre- and postdiagnosis and overall mortality and BC-specific mortality among BC survivors. Our study included 13,624 BC survivors from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with a mean follow-up of 8.6 years after diagnosis. Anthropometric data were obtained at recruitment for all cases and at a second assessment during follow-up for a subsample. We measured general obesity using the body mass index (BMI), whereas waist circumference and A Body Shape Index were used as measures of abdominal obesity. The annual weight change was calculated for cases with two weight assessments. The association with overall mortality and BC-specific mortality were based on a multivariable Cox and Fine and Gray models, respectively. We performed Mendelian randomization (MR) analysis to investigate the potential causal association. Five-unit higher BMI prediagnosis was associated with a 10% (95% confidence interval: 5–15%) increase in overall mortality and 7% (0–15%) increase in dying from BC. Women with abdominal obesity demonstrated a 23% (11–37%) increase in overall mortality, independent of the association of BMI. Results related to weight change postdiagnosis suggested a U-shaped relationship with BC-specific mortality, with higher risk associated with losing weight or gaining > 2% of the weight annually. MR analyses were consistent with the identified associations. Our results support the detrimental association of excess body fatness on the survival of women with BC. Substantial weight changes postdiagnosis may be associated with poorer survival.

This file contains tables showing the association between BMI and each of ER and PR when adjusted for both risk factors and prognostic factors; associations between BMI and each of ER and PR when a consistent BMI reference group of normal weight is used; and risk stratification tables for the prediction of endometrial cancer-specific mortality using dichotomous tumor ER or PR status.

Background: Endometrial tumors arise from a hormonally responsive tissue. Defining subtypes by hormone receptor expression might better inform etiology and prediction of patient outcomes. We evaluated the potential role of tumor estrogen receptor (ER) and progesterone receptor (PR) expression to define endometrial cancer subtypes.Methods: We measured semi-continuous ER and PR protein expression in tissue specimens from 360 endometrial primary tumors from the Nurses' Health Study. To explore the impact of different definitions of marker positivity, we dichotomized ER and PR expression at different cut points in increments of 5% positive cells. Logistic regression was used to estimate associations between endometrial cancer risk factors, such as body mass index, with dichotomous ER or PR status. Reclassification statistics were used to assess whether adding dichotomous ER or PR status to standard prognostic factors of stage, grade, and histologic type would improve endometrial cancer-specific mortality prediction.Results: Compared with not being obese, obesity increased the odds of having an ER-positive tumor at cut points of 0% to 20% [maximum OR, 2.92; 95% confidence interval (CI), 1.34–6.33] as well as the odds of having a PR-positive tumor at cut points of 70% to 90% (maximum OR, 2.53; 95% CI, 1.36–4.68). Adding dichotomous tumor ER or PR status to the panel of standard predictors did not improve both model discrimination and calibration.Conclusions: Obesity may be associated with greater endometrial tumor expression of ER and PR. Adding either marker does not appear to improve mortality prediction beyond the standard predictors.Impact: Body mass index might explain some of the biological variation among endometrial tumors. Cancer Epidemiol Biomarkers Prev; 26(5); 727–35. ©2017 AACR.

This file provides detailed information on immunohistochemistry assay protocols as well as on the analytic handling of missing covariate data.

BackgroundObservational studies have shown that women with an early menopause are at higher risk of stroke compared to women with a later menopause. However, associations with stroke subtypes are inconsistent and the causality is unclear. Therefore, we conducted a large-scale analysis to investigate the observational association between age at menopause and different types of stroke accompanied by a Mendelian Randomization analysis to evaluate causality.MethodsWe analyzed data of the UK Biobank and EPIC-CVD study. Postmenopausal women without a history of stroke at baseline were eligible for inclusion. The study endpoints were total stroke and stroke subtypes (i.e., ischemic stroke, hemorrhagic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage). We investigated the observational association between age at menopause and risk of stroke using Cox-regression analysis in each study separately before combining effect sizes using random-effects meta-analysis. Cox-regression analyses were progressively adjusted for (1) age, (2) smoking status, body mass index, glycated hemoglobin, total cholesterol, and hypertension, and (3) ever use of hormone replacement therapy and age at menarche. We used two-sample Mendelian Randomization analysis to study whether there is a causal relationship between genetically proxied age at menopause and risk of stroke.ResultsA total of 204,244 women were included (7,883 from EPIC-CVD [5,292 from the sub-cohort]; 196,361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD 5.8) and pooled mean age at menopause was 47.8 years (SD 6.2). Natural menopause occurred in 77.6% of all women. Over a median follow-up of 12.6 years (IQR 11.8, 13.3), 6,770 women experienced a stroke. In multivariable adjusted observational analyses, the pooled hazard ratios per five years younger age at menopause were 1.09 (95% CI: 1.07, 1.12) for stroke, 1.09 (1.06, 1.13) for ischemic stroke, 1.10 (1.04, 1.16) for hemorrhagic stroke, 1.14 (1.08, 1.20) for intracerebral hemorrhage, and 1.00 (0.84, 1.20) for subarachnoid hemorrhage. The Mendelian Randomization analysis found no evidence for a causal relationship between genetically proxied age at menopause and risk of any type of stroke.ConclusionsEarlier age at menopause is associated with, but not causally related to the risk of stroke.Clinical PerspectiveWhat is new?This analysis involves over 200,000 postmenopausal women and more than 6,000 incident stroke cases and investigates the observational association between age at menopause and various subtypes of stroke. Furthermore, a Mendelian Randomization analysis was conducted to study whether associations are causal or not.Earlier age at menopause was statistically significantly associated with a higher risk of stroke and its subtypes ischemic stroke, hemorrhagic stroke, and intracerebral hemorrhage. We found no statistically significant relationship between earlier or later age at menopause and risk of subarachnoid hemorrhage.The Mendelian Randomization analysis suggested no causal effect of genetically proxied age at menopause and risk of any type of stroke.What are the clinical implications?Women with earlier age at menopause are at higher risk of stroke. The underlying reasons need to be further investigated.Our analysis suggested that earlier menopauseper sedoes not cause stroke. For prevention and adequate treatment of stroke in women, a better understanding of the specific role of menopause and the mechanistic background that leads to higher risk of stroke is needed.

BACKGROUND: Inflammatory, insulin and oestrogenic pathways have been linked to breast cancer (BC). We aimed to examine the relationship between pre-diagnostic dietary patterns related to these mechanisms and BC survival. METHODS: The diabetes risk reduction diet (DRRD), inflammatory score of diet (ISD) and oestrogen-related dietary pattern (ERDP) were calculated using dietary data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards models were used to assess associations between dietary patterns and overall mortality and competing risk models for associations with BC-specific mortality. RESULTS: We included 13,270 BC cases with a mean follow-up after diagnosis of 8.6 years, representing 2340 total deaths, including 1475 BC deaths. Higher adherence to the DRRD score was associated with lower overall mortality (HR1–SD 0.92; 95%CI 0.87–0.96). Greater adherence to pro-inflammatory diets was borderline associated with 6% higher mortality HR1–SD 1.06; 95%CI 1.00–1.12. No significant association with the oestrogen-related dietary pattern was observed. None of the dietary patterns were associated with BC-specific mortality. CONCLUSIONS: Greater adherence to an anti-diabetic and anti-inflammatory diet prior to diagnosis is associated with lower overall mortality among BC survivors. Long-term adherence to these dietary patterns could be a means to improve the prognosis of BC survivors., Instituto de Salud Carlos III FI19/00197, European Social Fund (ESF), AECC Scientific Foundation PRYES211366AGUD, World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue nationale contre le cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe Helmholtz Association German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) Federal Ministry of Education & Research (BMBF), Fondazione AIRC per la ricerca sul cancro Compagnia di San Paolo Consiglio Nazionale delle Ricerche (CNR), Dutch Ministry of Public Health, Welfare and Sports (VWS) Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds Netherlands Organization for Scientific Research (NWO), World Cancer Research Fund International (WCRF), Netherlands Government, Health Research Fund (FIS)-Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra Navarra, Catalan Institute of Oncology-ICO (Spain), Swedish Cancer Society Swedish Research Council, County Councils of Skkne, Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) 1000143 MR/M012190/1

There is existing evidence on the potential role of chronic inflammation in the pathogenesis of pancreatic cancer (PC) and on how risk may be modulated by dietary factors. Pro-inflammatory diets are suggested to be associated with increased risk of PC but, so far, evidence remains not conclusive. We examined the association between the dietary inflammatory potential and PC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which includes 450,112 participants.After a 14-year follow-up, a total of 1239 incident PC cases were included in this study. The inflammatory potential of the diet was estimated using an Inflammatory Score of the Diet (ISD). Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between the ISD and PC were estimated using multivariable Cox regression models, adjusted for known risk factors for PC.Participants with higher ISDs had a higher risk of developing PCs. In the fully adjusted multivariate model, the risk of PC increased by 11% (HR 1.11, 95% CI 1.02-1.22) for 1 point each standard deviation increase in the ISD score. Neither obesity nor any other known risk factor for PC showed statistically significant interactions.To the best of our knowledge, this is the first prospective study reporting a positive relationship between the inflammatory potential of diet and PC. Since early diagnosis and treatment of pancreatic cancer might be challenging, prevention remains the major hope for reducing the burden of this disease.

Background: Evidence is accumulating that immune cells play a prominent role in pancreatic cancer etiology but prospective investigations are missing. Methods: We conducted a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) study with 502 pairs of incident pancreatic cancer cases and matched controls. Relative counts of circulating immune cells (neutrophils and lymphocyte sublineages: total CD3+, CD8+, CD4+, and FOXP3+ regulatory T cells (Tregs) relative to nucleated cells, (white blood cells) were measured by qRT-PCR. ORs with 95% confidence intervals were estimated using logistic regressions, modeling relative counts of immune cells on a continuous scale. Results: Neither relative counts of immune cell types taken individually, nor mutually adjusted for each other were associated with pancreatic cancer risks. However, in subgroup analyses by strata of lag-time, higher relative counts of Tregs and lower relative counts of CD8+ were significantly associated with an increased pancreatic cancer risks in participants diagnosed within the first 5 years of follow-up. Conclusions: These results might reflect reverse causation, due to higher relative counts of Tregs and lower counts of CD8+ cells among individuals with more advanced stages of latent pancreatic cancer, who are closer to the point of developing clinical manifest disease. Impact: We have shown, for the first time, that increased relative counts of regulatory T cells and lower relative counts of CD8+, cytotoxic T cells may be associated with pancreatic cancer risk or relatively late-stage tumor development. See related commentary by Michaud and Kelsey, p. 2176

Neurofilament light chain (NfL) is an axonal protein that when measured in cerebrospinal fluid (CSF) serves as a biomarker of neurodegeneration. We aimed at investigating the association among CSF NfL, presence of Subjective Cognitive Decline (SCD) and hippocampal volume, and how CSF amyloid-β (Aβ) modifies these associations. We included 278 cognitively unimpaired participants from the Alfa+ cohort (78 SCD and 200 Controls). Linear models accounting for covariates (age, gender, and mood) were used to test the association between CSF NfL and SCD status, and between CSF NfL and bilateral hippocampal volumes. Interactions with Aβ were also explored. Individuals with SCD had higher CSF NfL and lower CSF Aβ42/40 than Controls. There was a significant interaction between SCD and CSF-Aβ42/40 levels. Stratified analyses showed a significant association between SCD and NfL only in Aβ+ individuals. Higher CSF NfL was significantly associated with lower hippocampal volume specifically in Aβ+ individuals with SCD. The presence of SCD in Aβ+ individuals may represent an early symptom in the Alzheimer's continuum related to incipient neurodegeneration. The research leading to these results has received funding from “la Caixa” Foundation (LCF/PR/GN17/1030 0 0 04) and the Alzheimer’s Association and an international anonymous char ity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2017-SGR-892. MS-C received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement No 752310, and currently receives funding from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I ). EMA-U is supported by the Spanish Ministry of Science, Innovation and Universities - Spanish State Research Agency ( RYC2018-026053-I ) and is recipient of the Alzheimer’s Association Research Grant ( AARC 2019-AARG 6 446 41). OG-R is supported by the Spanish Ministry of Science, Innovation and Universities ( FJCI-2017-33437 ). JDG holds a ‘Ramón y Cajal’ fellowship ( RYC-2013-13054 ). NV-T is funded by a post-doctoral grant, Juan de la Cierva Programme ( FJC2018-038085-I ), Ministry of Science and Innovation–Spanish State Research Agency. ASV is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship ( CP II 17/0 0 029 ). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (# 2018-02532 ), the European Research Council (# 681712 ), Swedish State Support for Clinical Research (# ALFGBG-720931 ), the Alzheimer Drug Discovery Foundation (ADDF), USA (# 201809-2016862 ), and the UK Dementia Research Institute at UCL. KB is supported by the Alzheimer Drug Discovery Foundation (ADDF), USA (# RDAPB-201809-2016615 ), the Swedish Alzheimer Foundation (# AF-742881 ), Hjärnfonden, Sweden (# FO2017-0243 ), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (# ALFGBG-715986 ), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236 )

It is unclear whether diet, and in particular certain foods or nutrients, are associated with lung cancer risk. We assessed associations of 92 dietary factors with lung cancer risk in 327,790 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) per standard deviation (SD) higher intake/day of each food/nutrient. Correction for multiple comparisons was performed using the false discovery rate and identified associations were evaluated in the Netherlands Cohort Study (NLCS). In EPIC, 2,420 incident lung cancer cases were identified during a median of 15 years of follow-up. Higher intakes of fibre (HR per 1 SD higher intake/day=0.91, 95%CI 0.87-0.96), fruit (HR=0.91, 95%CI 0.86-0.96), and vitamin C (HR=0.91, 95%CI 0.86-0.96) were associated with a lower risk of lung cancer, whereas offal (HR=1.08, 95%CI 1.03-1.14), retinol (HR=1.06, 95%CI 1.03-1.10), and beer/cider (HR=1.04, 95%CI 1.02-1.07) intakes were positively associated with lung cancer risk. Associations did not differ by sex and there was less evidence for associations among never smokers. None of the six associations with overall lung cancer risk identified in EPIC were replicated in the NLCS (2,861 cases), however in analyses of histological subtypes, inverse associations of fruit and vitamin C with squamous cell carcinoma were replicated in the NLCS. Overall, there is little evidence that intakes of specific foods and nutrients play a major role in primary lung cancer risk, but fruit and vitamin C intakes seem to be inversely associated with squamous cell lung cancer. This article is protected by copyright. All rights reserved.

Background: Obesity is a risk factor for endometrial cancer but whether metabolic dysfunction is associated with endometrial cancer independent of body size is not known. Methods: The association of metabolically defined body size phenotypes with endometrial cancer risk was investigated in a nested case–control study (817 cases/ 817 controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC). Concentrations of C-peptide were used to define metabolically healthy (MH, World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue nationale contre le cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, Helmholtz Association, German Institute of Human Nutrition PotsdamRehbruecke (DIfE), Federal Ministry of Education & Research (BMBF), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo, Consiglio Nazionale delle Ricerche (CNR), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds Netherlands Organization for Scientific Research (NWO), World Cancer Research Fund (WCRF-ERC) 232997, Netherlands Government, Health Research Fund (FIS)-Instituto de Salud Carlos III (ISCIII), Junta de Andalucia, Principality of Asturias, Basque Government, Regional Government of Murcia, Regional Government of Navarra, Catalan Institute of OncologyICO (Spain), Swedish Cancer Society Swedish Research Council, European Commission, County Council of Skane, County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017 C19335/A21351, UK Research & Innovation (UKRI), Medical Research Council UK (MRC), European Commission 1000143 MR/M012190/1

The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London-, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS)-Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra,-and the Catalan Institute of OncologyICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (C864/A14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (MR/N003284/1, MC-UU 12015/1 and MC UU_00006/1to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford). (United Kingdom). Open Access funding enabled and organized by Projekt DEAL., BACKGROUND: CA125 is the best available yet insufficiently sensitive biomarker for early detection of ovarian cancer. There is a need to identify novel biomarkers, which individually or in combination with CA125 can achieve adequate sensitivity and specificity for the detection of earlier-stage ovarian cancer. METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we measured serum levels of 92 preselected proteins for 91 women who had blood sampled ≤18 months prior to ovarian cancer diagnosis, and 182 matched controls. We evaluated the discriminatory performance of the proteins as potential early diagnostic biomarkers of ovarian cancer. RESULTS: Nine of the 92 markers; CA125, HE4, FOLR1, KLK11, WISP1, MDK, CXCL13, MSLN and ADAM8 showed an area under the ROC curve (AUC) of ≥0.70 for discriminating between women diagnosed with ovarian cancer and women who remained cancerfree. All, except ADAM8, had shown at least equal discrimination in previous case-control comparisons. The discrimination of the biomarkers, however, was low for the lag-time of >9–18 months and paired combinations of CA125 with any of the 8 markers did not improve discrimination compared to CA125 alone. CONCLUSION: Using pre-diagnostic serum samples, this study identified markers with good discrimination for the lag-time of 0–9 months. However, the discrimination was low in blood samples collected more than 9 months prior to diagnosis, and none of the markers showed major improvement in discrimination when added to CA125., World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, German Cancer Research Center (DKFZ) (Germany), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) (Germany), Federal Ministry of Education & Research (BMBF), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo, Consiglio Nazionale delle Ricerche (CNR), Netherlands Government, World Cancer Research Fund International (WCRF), Health Research Fund (FIS)-Instituto de Salud Carlos III (ISCIII) (Spain), Junta de Andalucia, Regional Government of Asturias (Spain), Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain), Regional Government of Navarra (Spain), Catalan Institute of OncologyICO (Spain), Swedish Cancer Society, Swedish Research Council, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK C864/A14136 C8221/A29017, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MR/N003284/1 MC-UU 12015/1 MC UU_00006/1 MR/M012190/1, Projekt DEAL

Vitamins and essential minerals are micronutrients that are essential for the normal functioning of the human body. However, they may lead to adverse health effects if consumed in excess. The concept of a tolerable upper intake level (UL) is a science‐based reference value, which was introduced to support policy‐makers and other relevant actors in managing the risks of excess nutrient intake. EFSA’s principles for establishing ULs for vitamins and minerals were originally developed by the Scientific Committee on Food in 2000. Since then, experience has been gained and the scientific field developed. This guidance from the EFSA Panel on Nutrition, Novel Foods and Food Allergens provides an updated framework to support EFSA’s UL assessments. It covers aspects related to the planning of the risk assessment (problem formulation and definition of methods) and its implementation (evidence retrieval, appraisal, synthesis, integration, uncertainty analysis). As in the previous framework, the general principles developed for the risk assessment of chemicals in food are applied (hazard identification, hazard characterisation, intake assessment, risk characterisation). Peculiar to nutrients are their biochemical and physiological roles and the specific and selective mechanisms that maintain the systemic homoeostasis and body burden of the nutrient. These must be considered when conducting a risk assessment of nutrients. This document constitutes a draft guidance that will be applied in EFSA’s assessments during a 1‐year pilot phase and be revised and complemented as necessary. Before finalisation of the guidance, a public consultation will be launched.

ObjectiveTo evaluate the hypothesis that proximity to parental age at onset (AAO) in sporadic Alzheimer disease (AD) is associated with greater AD and neural injury biomarker alterations during midlife and to assess the role of nonmodifiable and modifiable factors.MethodsThis observational study included 290 cognitively unimpaired (CU) participants with a family history (FH) of clinically diagnosed sporadic AD (age 49–73 years) from the Alzheimer's and Families (ALFA) study. [18F]flutemetamol-PET standardized uptake value ratios, CSF β-amyloid42/40 ratio, and phosphorylated tau were used as AD biomarkers. Hippocampal volumes and CSF total tau were used as neural injury biomarkers. Mental and vascular health proxies were calculated. In multiple regression models, we assessed the effect of proximity to parental AAO and its interaction with age on AD and neural injury biomarkers. Then, we evaluated the effects of FH load (number of parents affected), sex, APOE ε4, education, and vascular and mental health.ResultsProximity to parental AAO was associated with β-amyloid, but not with neural injury biomarkers, and interacted with sex and age, showing that women and older participants had increased β-amyloid. FH load and APOE ε4 showed independent contributions to β-amyloid load. Education and vascular and mental health proxies were not associated with AD biomarkers. However, lower mental health proxies were associated with decreased hippocampal volumes with age.ConclusionThe identification of the earliest biomarker changes and modifiable factors to be targeted in early interventions is crucial for AD prevention. Proximity to parental AAO may offer a timeline for detection of incipient β-amyloid changes in women. In risk-enriched middle-aged cohorts, mental health may be a target for early interventions.ClinicalTrials.gov identifierNCT02485730.Classification of evidenceThis study provides Class II evidence that in CU adults with FH of sporadic AD, proximity to parental AAO was associated with β-amyloid but not with neural injury biomarkers.

Introduction: The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood. Methods: We used NeuroToolKit and Elecsys® immunoassays to measure cerebrospinal fluid (CSF) amyloid-β (Aβ)42, Aβ40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and α-synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum. Results: CSF t-tau, p-tau, and neurogranin increase throughout aging only in Aβ-positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aβ status. We modelled biomarker changes as a function of CSF Aβ42/40, p-tau and p-tau/Aβ42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aβ42/40 ratio. This is followed by a steep increase in CSF p-tau; t-tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers. Discussion: Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum. The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004 and the Alzheimer's Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa‐17‐519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2017‐SGR‐892. MSC received funding from the European Union's Horizon 2020 Research and Innovation Program under the Marie Sklodowska‐Curie action grant agreement No 752310, and currently receives funding from Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018‐037478‐I). JDG is supported by the Spanish Ministry of Science and Innovation (RYC‐2013‐13054). NVT is supported by the Spanish Ministry of Science, Innovation and Universities—Spanish State Research Agency (FJC2018‐038085‐I). OGR is supported by the Spanish Ministry of Science, Innovation and Universities (FJCI‐2017‐33437). ASV is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029). EMAU is supported by the Spanish Ministry of Science, Innovation and Universities—Spanish State Research Agency (RYC2018‐026053‐I). CM was supported by the Spanish Ministry of Economy and Competitiveness (grant n° IEDI‐2016‐00690). KB holds the Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences, and is supported by the Swedish Research Council (#2017‐00915); the Swedish Alzheimer Foundation (#AF‐742881), Hjärnfonden, Sweden (#FO2017‐0243); and a grant (#ALFGBG‐715986) from the Swedish state under the agreement between the Swedish government and the County Councils, the ALF‐agreement. HZ is a Wallenberg Academy Fellow supported by grants from the Swedish Research Council (#2018‐02532), the European Research Council (#681712), and a grant (#ALFGBG‐720931) from the Swedish state under the agreement between the Swedish government and the County Councils.

The world's population is aging as a consequence of an increased global life expectancy. Identifying simple strategies to promote healthy aging (i.e., absence of major chronic diseases, preserved physical and cognitive functions, intact mental health, and good quality of life) have emerged as a major public health concern. Identifying biomarkers to better characterize the aging process is a research priority. Telomeres are repetitive DNA sequences at chromosome ends that prevent the loss of genomic DNA, protecting its physical integrity. Telomere length (TL) is considered a biomarker of aging: shorter telomeres are associated with a decreased life expectancy and increased rates of age-related chronic diseases. Telomere attrition has been shown to be accelerated by oxidative stress and inflammation. Since edible plants contain plenty of compounds with antioxidant and anti-inflammatory properties, it is plausible that their sustained consumption might help counteract telomere attrition. In this narrative review, we update evidence on the association between plant-rich dietary patterns and plant-based foods and TL. First, we summarize findings from observational studies on the association between TL and 1) adherence to plant-rich dietary patterns (mainly, but not only, focused on the Mediterranean diet); 2) consumption of seeds (mostly focused on nuts, grains, and coffee); and 3) intake of carotenoids, one of the plant-derived bioactives most studied in health and disease. Second, we summarize the main randomized controlled trials evaluating the effect on TL of dietary interventions involving either plant-rich dietary patterns or plant foods. Even though evidence from trials is very limited, several observational studies have reinforced the suggestive benefits of adherence to the Mediterranean diet (a plant-rich dietary pattern), consumption of seeds (and its derivatives), and dietary intake of carotenoids on TL, which further supports the research benefits of plant-rich dietary patterns and plant foods to promote health and longevity.

BackgroundCurrent evidence suggests that egg composition might have potential neuroprotective effects. Our aim was to determine the association between egg consumption and the risk of dementia in a Mediterranean population.MethodsThis study was carried out in 3 centers from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain Dementia Cohort, i.e., 25,015 participants aged 30–70 years, recruited in 1992–1996, and followed up for a mean of 21.5 years.ResultsA total of 774 incident dementia cases were diagnosed and validated, of which 518 were Alzheimer's disease (AD). Data on egg consumption were estimated using a validated dietary history questionnaire at recruitment. Cox proportional hazards models, adjusted for confounders, were used in the analyses. No association was observed between egg consumption and either total dementia [hazard ratio between extreme quartiles (HRQ4vs.Q1: 1.05; 95% CI 0.85–1.31; p-trend = 0.93)] or AD (HRQ4vs.Q1 0.93; 95% CI 0.72–1.21; p-trend = 0.50) risks. After dividing the population by adherence to the relative Mediterranean diet (rMED) score, a borderline inverse association was found between egg intake and both total dementia (HRQ4vs.Q1: 0.52; 95% CI 0.30–0.90; p-trend = 0.10) and AD (HRQ4vs.Q1: 0.52; 95% CI 0.27–1.01; p-trend = 0.13) risks within participants with low adherence to rMED score. However, no association was observed in participants with medium and high adherence to rMED score.ConclusionThis prospective study suggests that egg consumption is associated with a reduced risk of dementia, and specifically of AD, in the adult population with low adherence to rMED score; whereas it has no impact in subjects with moderate and high MD adherence.

Introduction Urban environmental exposures might contribute to the incidence of Alzheimer's disease (AD). Our aim was to identify structural brain imaging correlates of urban environmental exposures in cognitively unimpaired individuals at increased risk of AD. Methods Two hundred twelve participants with brain scans and residing in Barcelona, Spain, were included. Land use regression models were used to estimate residential exposure to air pollutants. The daily average noise level was obtained from noise maps. Residential green exposure indicators were also generated. A cerebral 3D-T1 was acquired to obtain information on brain morphology. Voxel-based morphometry statistical analyses were conducted to determine the areas of the brain in which regional gray matter (GM) and white matter (WM) volumes were associated with environmental exposures. Results Exposure to nitrogen dioxide was associated with lower GM volume in the precuneus and greater WM volume in the splenium of the corpus callosum and inferior longitudinal fasciculus. In contrast, exposure to fine particulate matter was associated with greater GM in cerebellum and WM in the splenium of corpus callosum, the superior longitudinal fasciculus, and cingulum cingulate gyrus. Noise was positively associated with WM volume in the body of the corpus callosum. Exposure to greenness was associated with greater GM volume in the middle frontal, precentral, and the temporal pole. Discussion In cognitively unimpaired adults with increased risk of AD, exposure to air pollution, noise, and green areas are associated with GM and WM volumes of specific brain areas known to be affected in AD, thus potentially conferring a higher vulnerability to the disease.

Background: Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer's disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown. Objective: We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors. Methods: The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer's continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071). Results: The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants. Conclusions: Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer's continuum. The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004 and the Alzheimer’s Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17–519007). Additional support has been received from the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan (PERIS) 2016–2020 grant# SLT002/16/00201) and the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2017-SGR-892. All CRG authors acknowledge the support of the Spanish Ministry of Science, Innovation and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. NV-T is funded by a post-doctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministry of Science and Innovation– Spanish State Research Agency. MS-C received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement No 752310, and currently receives funding from Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I). EMAU is supported by the Spanish Ministry of Science, Innovation and Universities—Spanish State Research Agency (RYC2018-026053-I). OGR is supported by the Spanish Ministry of Science, Innovation and Universities (FJCI-2017–33437). JDG is supported by the Spanish Ministry of Science and Innovation (RYC-2013–13054). KB is supported by the Swedish Research Council (#2017–00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809–2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466–236). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018–02532), the European Research Council (#681712), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-720931), the ADDF, USA (#201809–2016862), and the UK Dementia Research Institute at UCL.