Journals of Gerontology: Medical Sciences cite as: J Gerontol A Biol Sci Med Sci, 2016, Vol. 71, No. 5, 683–688 doi:10.1093/gerona/glv135 Advance Access publication August 18, 2015
Research Article
Plasma Carotenoids Are Inversely Associated With Dementia Risk in an Elderly French Cohort Catherine Feart,1,2 Luc Letenneur,1,2 Catherine Helmer,1,2,3 Cécilia Samieri,1,2 Wolfgang Schalch,4 Stéphane Etheve,4 Cécile Delcourt,1,2 Jean-François Dartigues,1,2 and Pascale Barberger-Gateau1,2 Centre INSERM U897-Epidemiologie-Biostatistique, INSERM, ISPED, Bordeaux, France. 2Centre INSERM U897-EpidemiologieBiostatistique, Univ. Bordeaux, ISPED, Bordeaux, France. 3Clinical Epidemiology Unit, INSERM CIC 1401, Bordeaux, France. 4DSM Nutritional Products, Kaiseraugst, Switzerland. 1
Address correspondence to Catherine Feart, PhD, Equipe Epidémiologie de la Nutrition et des Comportements Alimentaires, INSERM, U897, Université de Bordeaux, 146 rue Léo-Saignat, CS61292, F-33076, Bordeaux Cedex, France. Email:
[email protected] Received February 19, 2015; Accepted July 16, 2015 Decision Editor: Stephen Kritchevsky, PhD
Abstract Background: Although intake of fruits and vegetables has been associated with a decreased risk of dementia, studies focusing on nutrients underlying this association are lacking. Our objective was to analyze the relation between plasma carotenoids and the risk of dementia and Alzheimer’s disease (AD) in French elderly community dwellers. Methods: The study population consisted of 1,092 nondemented older participants, from the Three-City-Bordeaux cohort followed for up to 10 years (range: 1.8–10.8 years, median: 9.5 years). Dementia and AD were diagnosed by a committee of neurologists. The concentration of plasma carotenoids (beta-carotene, alpha-carotene, lycopene, lutein, zeaxanthin, and beta-cryptoxanthin) was determined at baseline. Longitudinal analyses of the association between each plasma carotenoid, either crude or expressed as a ratio to plasma lipids (total cholesterol + triglycerides), and the risk of dementia or AD were performed by multivariate Cox models. Results: During follow-up, 199 dementia cases, including 132 AD, occurred. After adjustment for sociodemographic data, diet quality, and clinical variables, including baseline cognitive performances, only higher lutein concentration, considered as a function of plasma lipids, was consistently significantly associated with a decreased risk of all-cause dementia and AD (hazard ratio = 0.808, 95% confidence interval = 0.671– 0.973, p = .024 and hazard ratio = 0.759, 95% confidence interval = 0.600–0.960, p = .021, respectively for +1 SD). Conclusion: This large cohort of older participants suggests that maintaining higher concentrations of lutein in respect to plasma lipids may moderately decrease the risk of dementia and AD. Key words: Carotenoids—Alzheimer’s disease—Dementia
Many epidemiological studies have suggested a possible protective role of nutrition against cognitive decline (1). In particular, adherence to diets rich in plant foods, that is fruits, vegetables, legumes, nuts, and cereals, such as the Mediterranean diet, is associated with lower risks of cognitive decline and dementia, including Alzheimer’s disease (AD) (2–4). This beneficial effect has been in part attributed to the high amount of nutritional compounds provided by fruits and vegetables, including vitamin C, polyphenols, and carotenoids. However, the contribution of each class of nutrients to the protective effects of plant foods on cognition is still poorly understood.
Carotenoids are ubiquitous colored pigments, found mainly in fruits and vegetables such as kiwi, carrots, and tomatoes or in green leafy vegetables (5). Regarding dietary carotenoid intake, longitudinal studies have generally failed to evidence a protective effect of beta-carotene on the risk of dementia or AD, and the pooled estimates were only borderline significant in a recent meta-analysis of five cohort studies (6,7). A recent study of 16,010 women reported a significantly lower cognitive decline with a greater consumption of lycopene and a more modest association with higher intakes of total carotenoids and lutein+zeaxanthin (8). This was in agreement
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[email protected].
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with the findings of an exploratory clinical trial suggesting a specific potential benefit of lutein and zeaxanthin on cognitive health (9,10). Biological data from cases–control studies persistently indicated that participants with dementia had lower circulating levels of carotenoids, whereas cross-sectional analyses provided mixed results (11– 15). Finally, longitudinal studies of the association between plasma carotenoid concentrations and cognitive decline are still scarce, showed conflicting results, and did not include dementia or AD as an end point (16,17). The present study investigated the relationship of plasma concentrations of various carotenoids with the incidence of all-cause dementia or AD over 10 years in a large population-based sample of French elderly persons.
Participants and Methods Study Overview The Three-City (3C) study is a prospective cohort study of vascular risk factors of dementia (18). The 3C study protocol was approved by the Consultative Committee for the Protection of Persons participating in Biomedical Research at Kremlin-Bicêtre University Hospital (Paris). All participants gave written informed consent. Four follow-up examinations were performed 2 (wave 1), 4 (wave 2), 7 (wave 3), and 10 years (wave 4) after baseline examination (1999–2000). Data collection included sociodemographic information, lifestyle, symptoms and medical complaints, medical history, medication use, blood pressure, tobacco use, anthropometrical data, neuropsychological testing, food frequency questionnaire, and blood sampling. The present study is based on baseline and Waves 1 to 4 data in Bordeaux, the only centre where the standard data collection was completed with measurement of carotenoids in plasma. The study sample comprises 1,092 participants, free of dementia at baseline, with at least one follow-up re-examination over 10 years (Figure 1). Between baseline and Wave 4, 151 participants deceased.
Diagnosis of Dementia Trained psychologists administered a battery of neuropsychological tests at each visit, including the Mini-Mental State Examination, the Isaac’s set test, and the Benton Visual Retention Test (19). The diagnosis of dementia was based on a two-step procedure (18). At each wave, the participants who were suspected of dementia were examined by a neurologist. Finally, an independent committee of neurologists reviewed all potential cases of dementia to obtain a consensus on the diagnosis and etiology (19).
Plasma Carotenoids Assessment Fasting blood samples were obtained at the baseline visit simultaneously to the baseline data collection. Blood was collected in heparinized vacutainers, centrifuged at 1,000g for 15 minutes, and stored (−80°C) until plasma carotenoids determination. Plasma concentrations of carotenoids were analyzed by routine high-performance liquid chromatography analytical methods developed at the R&D Analytical Research Center of DSM Nutritional Products Ltd (20). The most common carotenoids in humans, such as beta-carotene, alpha-carotene, lycopene (the sum of which represented total carotenes), lutein, zeaxanthin, and beta-cryptoxanthin (the sum of which represented total xanthophylls), were analyzed from 1,092 plasma samples. Because of technical failure, lutein and zeaxanthin plasma determinations were available for 1,083 participants (99.2%) only. Participants with a very low concentration of carotenoids
Figure 1. Study sample.
were attributed the quantification threshold value (Supplementary Methods).
Other Variables Baseline sociodemographic, clinical, genetic, and nutritional variables included age, gender, education, income, season of the blood drawing, vascular risk factors (BMI, hypercholesterolemia, smoking status, history of cardiovascular or cerebrovascular disease, hypertension, and diabetes), Apolipoprotein E ε4 (ApoE4) genotype, global cognitive functioning, depressive symptomatology, physical activity, alcohol consumption, and Mediterranean diet score (Supplementary Methods). Moreover, baseline plasma lipid levels (total cholesterol [TC] and triglycerides [TG]) were evaluated by routine enzymatic methods and used to correct plasma carotenoid concentrations. Indeed, carotenoid / (TC + TG) ratios were computed to better consider the effect of concurrent concentrations of lipids on the bioavailability of carotenoids (21,22).
Statistical Analysis Each plasma carotenoid concentration and carotenoid / (TC + TG) ratio was described by its mean and standard deviation among participants with incident dementia and control participants. We then estimated the associations between either crude carotenoids or carotenoid / (TC + TG) ratios and risk of allcause dementia over the 10 years by Cox proportional hazards model with delayed entry, and age as time scale. These analyses were adjusted for sociodemographic characteristics or clinical variables associated with incident dementia at p < .15 in crude univariate analysis. Season of blood drawing, BMI, TC, and
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alcohol consumption, previously associated with carotenoid concentrations, were considered as major adjustment variables (22). Analyses of the association between plasma carotenoid / (TC + TG) ratios and risk of incident dementia over 10 years were no longer adjusted for TC and TG in order to avoid overadjustment. These regression models were replicated focusing on the risk of incident AD over time. The relative risks of dementia or AD (hazard ratio [HR] and 95% confidence interval [CI]) for 1-SD increase of plasma concentration of carotenoids or carotenoid / (TC + TG) ratios were reported. Four kinds of sensitivity analyses have been performed (Supplementary Methods): (a) additional adjustment for Mediterranean diet score, (b) participants with low baseline cognitive performances were excluded, (c) additional adjustment for a baseline global cognitive composite score, and (d) carotenoids concentrations and carotenoid / (TC + TG) ratios were considered as categorical variables. Statistical interactions between plasma carotenoids or carotenoid / (TC + TG) ratios and ApoE4 were tested. The SAS statistical package (Version 9.2 SAS Institute) was used for these analyses.
Results The study sample consisted of 1,092 participants aged 74.4 years on average and who have been re-examined at least once over 8.8 years of follow-up on average (range: 1.8–10.8 years). The independent committee of neurologists validated 199 participants with
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incident dementia, among whom 132 participants had probable or possible AD. The sociodemographic characteristics and health status of the participants are described in Supplementary Table 1. As expected, participants with future diagnosis of dementia were significantly older than control participants, were less educated, were more often carriers of the ApoE4 allele, and had a worse general health status at baseline. In both incident cases of dementia and in control participants, two thirds of plasma carotenoids were composed of carotenes (mainly beta-carotene; Table 1). Lutein and beta-cryptoxanthin were equally represented among total xanthophylls. The concentration of total xanthophylls, but not total carotenes, was significantly associated with a reduced risk of all-cause dementia in crude univariate analyses (Table 1). Among xanthophylls, only higher lutein concentrations were related to a significantly decreased risk of dementia. These results were slightly strengthened when using the carotenoid / (TC + TG) ratios. After adjustment for sociodemographic, genetic, and clinical variables (Table 2), only a borderline, but not significant, inverse association was observed between plasma lutein and risk of dementia. Conversely, regarding the carotenoid / (TC + TG) ratios, increase of total carotenoids, beta-carotene, total xanthophylls, and lutein / (TC + TG) ratios were all associated with a significantly decreased risk of dementia in fully adjusted models. In sensitivity analyses additionally controlled for Mediterranean diet adherence, the strength of associations was slightly higher, leading to a significantly lower risk of dementia for each 1-SD increase of plasma lutein (Supplementary Table 2).
Table 1. Baseline Plasma Concentrations of Carotenoids and Carotenoid / (TC + TG) Ratios, and Lipids Levels, According to Future Diagnosis of Dementia, and Age-Adjusted Risk of All-cause Dementia by 1-SD Change Incident Cases of Dementia Yes (N = 199)
No (N = 893) Mean
SD
Plasma carotenoids (µg/L) Total carotenoids 1,105 578 Total carotenes 732 470 Alpha-carotene 98 84 Beta-carotene 398 315 Lycopene 240 167 Total xanthophylls 373 191 Lutein 166 87 Zeaxanthin 40 24 Beta-cryptoxanthin 167 132 Plasma carotenoid /(TC + TG) ratios (µg/mmol) Total carotenoids 160 84 Total carotenes 106 68 Alpha-carotene 14 12 Beta-carotene 58 46 Lycopene 35 24 Total xanthophylls 54 28 Lutein 24 13 Zeaxanthin 6 3 Beta-cryptoxanthin 24 19 Plasma lipids (mmol/L) TC 5.78 0.98 TG 1.22 0.58
Risk of All-cause Dementia*
Mean
SD
1,030 680 94 364 227 346 153 37 155
495 417 78 273 155 162 71 22 114
145 96 13 51 32 49 22 5 22
71 56 11 38 22 24 11 3 16
5.85 1.42
0.98 0.78
N cases / Total
HR
For 1 SD of plasma carotenoids 197/1,083 0.900 199/1,092 0.934 199/1092 0.943 199/1,092 0.890 199/1,092 1.044 197/1,083 0.857 197/1,083 0.842 197/1,083 0.885 199/1,092 0.914 For 1 SD of the ratio 197/1,082 0.853 199/1,091 0.897 199/1,091 0.919 199/1,091 0.858 199/1,091 1.001 197/1,082 0.813 197/1,082 0.801 197/1,082 0.850 199/1,091 0.884 For 1 SD of plasma lipids 199/1,092 1.044 199/1,092 1.311
Notes: CI = confidence interval; HR = hazard ratio; SD = standard deviation; TC = total cholesterol; TG = triglycerides. *Cox proportional hazard models with delayed entry, HR estimates for a 1-SD increase of studied parameters.
95% CI
p Values
0.774–1.046 0.806–1.084 0.814–1.092 0.759–1.043 0.904–1.207 0.737–0.997 0.724–0.981 0.759–1.031 0.789–1.059
.171 .371 .433 .151 .557 .046 .027 .117 .233
0.729–0.998 0.769–1.046 0.789–1.070 0.727–1.013 0.862–1.163 0.695–0.952 0.683–0.939 0.725–0.997 0.759–1.030
.047 .165 .279 .070 .988 .010 .006 .046 .113
0.912–1.196 1.173–1.465
.532
