Elsevier

Experimental Gerontology

Volume 48, Issue 12, December 2013, Pages 1428-1435
Experimental Gerontology

Serum levels of vitamin E forms and risk of cognitive impairment in a Finnish cohort of older adults

https://doi.org/10.1016/j.exger.2013.09.006Get rights and content

Highlights

  • Serum levels of various vitamin E forms are associated with reduced incidence of cognitive impairment in older adults.

  • Cholesterol modulates the association between vitamin E and cognitive impairment.

  • Assessment of all vitamin E forms might better reflect vitamin E status in humans.

Abstract

Background

Vitamin E includes eight natural antioxidant compounds (four tocopherols and four tocotrienols), but α-tocopherol has been the main focus of investigation in studies of cognitive impairment and Alzheimer's disease.

Objective

To investigate the association between serum levels of tocopherols and tocotrienols, markers of vitamin E oxidative/nitrosative damage (α-tocopherylquinone, 5-nitro-γ-tocopherol) and incidence of cognitive impairment in a population-based study.

Design

A sample of 140 non-cognitively impaired elderly subjects derived from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study was followed-up for 8 years to detect cognitive impairment, defined as development of mild cognitive impairment (MCI) or Alzheimer's dementia. The association between baseline serum vitamin E and cognitive impairment was analyzed with multiple logistic regression after adjusting for several confounders.

Results

The risk of cognitive impairment was lower in subjects in the middle tertile of the γ-tocopherol/cholesterol ratio than in those in the lowest tertile: the multiadjusted odds ratio (OR) with 95% confidence interval (CI) was 0.27 (0.10–0.78). Higher incidence of cognitive impairment was found in the middle [OR (95% CI): 3.41 (1.29–9.06)] and highest [OR (95% CI): 2.89 (1.05–7.97)] tertiles of the 5-NO2-γ-tocopherol/γ-tocopherol ratio. Analyses of absolute serum levels of vitamin E showed lower risk of cognitive impairment in subjects with higher levels of γ-tocopherol, β-tocotrienol, and total tocotrienols.

Conclusions

Elevated levels of tocopherol and tocotrienol forms are associated with reduced risk of cognitive impairment in older adults. The association is modulated by concurrent cholesterol concentration. Various vitamin E forms might play a role in cognitive impairment, and their evaluation can provide a more accurate measure of vitamin E status in humans.

Introduction

Alzheimer's disease (AD) is among the main determinants of dementia in older adults and is often preceded by a predementia phase of mild cognitive impairment (MCI) (Qiu et al., 2009). Oxidative and nitrosative stress (OS/NS) promoted by free radicals are important mediators of AD onset and progression, and oxidative/nitrosative damage can also be detected in individuals with MCI (Mangialasche et al., 2009, Valko et al., 2007).

Vitamin E, the main non-enzymatic lipophylic antioxidant in the human body, plays a major role in protecting the central nervous system (CNS) from free radical-mediated damage (Parks and Traber, 2000, Ricciarelli et al., 2007). The term vitamin E encompasses eight natural congeners: four tocopherols and four tocotrienols (α, β, γ, and δ) (Parks and Traber, 2000). All vitamin E forms act as antioxidants, and each congener has additional biological properties, often not shared by the other forms. Such properties, including anti-inflammatory activity and modulation of cell signaling, can be relevant for neuroprotection (Reiter et al., 2007, Sen et al., 2007).

Only α-tocopherol has been tested in AD and MCI treatments, and results have been inconsistent (Farina et al., 2012). However, reduced blood levels of various vitamin E forms have been reported in individuals with AD and MCI, together with increased indices of vitamin E oxidative/nitrosative damage, such as the ratios α-tocopherylquinone/α-tocopherol and 5-nitro-γ-tocopherol/γ-tocopherol (Mangialasche et al., 2012). α-Tocopherylquinone (αTQ) is the primary product of α-tocopherol oxidation (Niki, 2007), whereas 5-nitro-γ-tocopherol (5-NO2-γ-tocopherol) is a product of reaction between γ-tocopherol and reactive nitrogen species (RNS) (Williamson et al., 2002). Other studies have not confirmed the presence of reduced vitamin E levels in cognitively impaired subjects (Engelhart et al., 2005, Ravaglia et al., 2008). Similarly, longitudinal studies that investigated blood levels of various vitamin E forms in relation to the risk of cognitive decline/dementia have had conflicting results (Helmer et al., 2003, Mangialasche et al., 2010, Ravaglia et al., 2008, Sundelof et al., 2009), and only one study examined all eight natural vitamin E congeners (Mangialasche et al., 2010). Furthermore, there is some evidence that the association between vitamin E and cognitive decline/dementia is influenced by concurrent cholesterol levels (Mangialasche et al., 2010, Ravaglia et al., 2008), but data on this issue are scarce.

In this prospective, population-based study of a Finnish cohort of older adults (age 65 + years), we aimed to investigate the relationship between serum levels of all natural vitamin E congeners, markers of vitamin E oxidative/nitrosative damage (αTQ, 5-NO2-γ-tocopherol), and the risk of developing cognitive impairment.

Section snippets

Study population

The study population was derived from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study in Finland. It included a subsample of 140 subjects from the cohort of persons free of cognitive impairment at first re-examination in 1998. The CAIDE study has been described in detail elsewhere (Kivipelto et al., 2001). Briefly, as part of the North Karelia project and the FINMONICA study, CAIDE participants were examined at midlife in 1972, 1977, 1982, or 1987. A random sample of 2000

Main analysis

Subjects who developed cognitive impairment were more likely to be APOE ε4 carriers (p = 0.003) and to have lower education (p = 0.056) than subjects in the control group (Table 1). There were no significant differences between groups with regard to age, gender, baseline MMSE score, BMI, smoking status, alcohol use, history of cardiovascular/cerebrovascular conditions, use of lipid-lowering medications, or duration of follow-up (Table 1). Mean baseline serum levels of total cholesterol were lower

Discussion

Our results indicate an association between higher serum levels of vitamin E and reduced risk of cognitive impairment in older adults. Higher levels of γ-tocopherol, β-tocotrienol, and total tocotrienols seemed to protect against cognitive impairment, even after different adjustments for cholesterol. In addition, an elevated index of vitamin E nitrosative damage (5-NO2-γ-tocopherol/γ-tocopherol ratio, indicating consumption of γ-tocopherol in free radical reactions), was associated with

Conclusions

In conclusion, our results suggest that serum levels of tocopherols and tocotrienols are associated with the risk of cognitive impairment in older adults, which reinforces the hypothesis that each of the natural forms of vitamin E plays a unique role in human health. Evaluating only α-tocopherol might therefore not provide the most accurate measure of vitamin E status in humans. Larger studies with assessments of vitamin E forms at several points in time are warranted to clarify the role of the

The authors have no conflicts of interests.

Acknowledgments

The authors thank all CAIDE participants and members of the CAIDE study group for their cooperation and data collection and management, L. Lund from the Department of Chronic Disease Prevention, National Institute of Health and Welfare (THL), Helsinki, Finland, for help in sample management, M. Baglioni from the laboratory of the Institute of Gerontology and Geriatrics, University of Perugia, for the assessment of vitamin E, and Professor K. Hensley (University of Toledo Health-Sciences-Center,

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