Circulating metabolites and general cognitive ability and dementia: Evidence from 11 cohort studies  Sven J. van der Lee, Charlotte E. Teunissen, René Pool, Martin J. Shipley, Alexander Teumer, Vincent Chouraki, Debora Melo van Lent, Juho Tynkkynen, Krista Fischer, Jussi Hernesniemi, Toomas Haller, Archana Singh-Manoux, Aswin Verhoeven, Gonneke Willemsen, Francisca A. de Leeuw, Holger Wagner, Jenny van Dongen, Johannes Hertel, Kathrin Budde, Ko Willems van Dijk, Leonie Weinhold, M. Arfan Ikram, Maik Pietzner, Markus Perola, Michael Wagner, Nele Friedrich, P. Eline Slagboom, Philip Scheltens, Qiong Yang, Robert E. Gertzen, Sarah Egert, Shuo Li, Thomas Hankemeier, Catharina E.M. van Beijsterveldt, Ramachandran S. Vasan, Wolfgang Maier, Carel F.W. Peeters, Hans Jörgen Grabe, Alfredo Ramirez, Sudha Seshadri, Andres Metspalu, Mika Kivimäki, Veikko Salomaa, Ayşe Demirkan, Dorret I. Boomsma, Wiesje M. van der Flier, Najaf Amin, Cornelia M. van Duijn  Alzheimer's & Dementia: The Journal of the Alzheimer's Association  Volume 14, Issue 6, Pages 707-722 (June 2018) DOI: 10.1016/j.jalz.2017.11.012 Copyright © 2018 The Authors Terms and Conditions

Fig. 1 Flowchart of analyses. Study names: ERF, RS, WHII, NTR, SHIP-Trend, FHS, VUmc ADC, Finrisk97, DILGOM, EGCUT, and AgeCoDe. Abbreviations: AgeCoDe, German Study on Ageing, Cognition, and Dementia; DHA, docosahexaenoic acid; EGCUT, Estonian Biobank; DILGOM, Dietary, Lifestyle, and Genetic determinants of Obesity and Metabolic Syndrome; ERF, Erasmus Rucphen Family; FHS, Framingham Heart Study; Finrisk97, National FINRISK Studies 1997; LDL, low-density lipoprotein; NTR, Netherlands Twin Register; RS, Rotterdam Study; SHIP-Trend, Study of Health in Pomerania–Trend; VUmc ADC, VUmc Amsterdam Dementia Cohort; WHII, Whitehall II. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2018 14, 707-722DOI: (10.1016/j.jalz.2017.11.012) Copyright © 2018 The Authors Terms and Conditions

Fig. 2 Associations of metabolites with general cognitive ability. The standardized effect estimates on general cognitive ability of metabolites adjusted for age, sex, body mass index, and lipid-lowering medication use are shown. The estimates are shown for the discovery (red), replication (green), and the combined (yellow) analysis. Point estimates are shown as boxes with whiskers denoting the 95% confidence interval of the effect estimates. Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD, standard deviation. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2018 14, 707-722DOI: (10.1016/j.jalz.2017.11.012) Copyright © 2018 The Authors Terms and Conditions

Fig. 3 Association of metabolites with all-cause dementia and Alzheimer's disease. The standardized OR of metabolites with all-cause dementia (red) and Alzheimer's disease (blue) shown as point estimates with whiskers denoting the 95% confidence interval of the OR. Associations shown are adjusted for age (at entry), sex, and if available body mass index and lipid-lowering medication. Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; OR, odds ratio; SD, standard deviation. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2018 14, 707-722DOI: (10.1016/j.jalz.2017.11.012) Copyright © 2018 The Authors Terms and Conditions

Fig. 4 Association of metabolites with lifestyle factors. Lifestyle factors including smoking (current vs. past and never smokers), physical activity (yes/no), and dietary fish (oil) intake. Metabolites are grouped based on their association with general cognitive ability and subfraction of HDL. Colors represent standardized effects estimates. Green shows the lifestyle factor associated with an increase in the metabolite concentration, and red shows the lifestyle factor associated with a decrease in the metabolite concentration. Significance of the associations is shown *P < .05, **P < .001, and ***P < 1 × 10−5. Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; L, large particles; M, medium particles; S, small particles. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2018 14, 707-722DOI: (10.1016/j.jalz.2017.11.012) Copyright © 2018 The Authors Terms and Conditions

Supplementary Fig. 1 Comparing the effect estimates of the associations of metabolites with general cognitive ability over the three statistical models. Only replicated metabolites are shown. The standardized effect estimates are shown for model 1 (covariates: age, sex, BMI, and lipid-lowering medication), model 2 (covariates in model 1 and TC, HDL-C, LDL-C, triglycerides, and glucose), and model 3 (covariates in model 1 and APOEɛ4). The standardized effect estimates of metabolites with general cognitive ability shown as point estimates with 95% confidence interval whiskers. Abbreviations: APOE, apolipoprotein E; BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; TC, total cholesterol. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2018 14, 707-722DOI: (10.1016/j.jalz.2017.11.012) Copyright © 2018 The Authors Terms and Conditions

Supplementary Fig. 2 Metabolite associations with general cognitive ability by study. The standardized effect estimates adjusted for age, sex, BMI, and lipid-lowering medication of metabolites with general cognitive ability by study are shown. Discovery includes the ERF and the RS. The replication studies include the WHII study, NTR, the FHS, and the SHIP-Trend. Point estimates are shown as boxes with whiskers denoting the 95% confidence interval of the effect estimates. Abbreviations: BMI, body mass index; ERF, Erasmus Rucphen Family; FHS, Framingham Heart Study; HDL, high-density lipoprotein; LDL, low-density lipoprotein; L, large particles; M, medium particles; NTR, Netherlands Twin Registry; RS, Rotterdam Study; S, small particles; SHIP-Trend, Study of Health in Pomerania–Trend; WHII, Whitehall II. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2018 14, 707-722DOI: (10.1016/j.jalz.2017.11.012) Copyright © 2018 The Authors Terms and Conditions

Supplementary Fig. 3 Association with all-cause dementia and Alzheimer's disease adjusted for number of APOEɛ4 alleles. The standardized OR of metabolites with all-cause dementia (red) and Alzheimer's disease (blue) shown as point estimates with whiskers denoting the 95% confidence interval of the OR. Associations shown are adjusted for age (at entry), sex, body mass index (if available), lipid-lowering medication (if available), and number of APOEɛ4 alleles. Abbreviations: APOE, apolipoprotein E; HDL, high-density lipoprotein; OR, odds ratio. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2018 14, 707-722DOI: (10.1016/j.jalz.2017.11.012) Copyright © 2018 The Authors Terms and Conditions