Exploring the role of vitamin E in Alzheimer’s disease : an epidemiological and clinical perspective

摘要

Vitamin E, the main non-enzymatic lipophylic antioxidant in the human body, has a major role inprotecting the brain from damage mediated by free radicals. The term vitamin E encompasses eightnatural congeners (forms): four tocopherols and four tocotrienols, named α, β, γ, and δ. Mostinvestigation of vitamin E in relation to dementia and Alzheimer´s disease (AD) has focused primarilyonly on α-tocopherol, with conflicting findings. However, increasing knowledge regarding the biologicalproperties of vitamin E provides a strong biological rationale that other forms of vitamin E, beyond justα-tocopherol, may play a role in AD pathogenesis.The aim of the present project is to investigate the relation of all eight natural vitamin E forms with mildcognitive impairment (MCI) and AD in older adults, by combining both an epidemiological and a clinicbasedapproach.Study I. Plasma levels of all eight natural vitamin E forms, and markers of vitamin Eoxidative/nitrosative damage (α-tocopherylquinone, 5-nitro-γ-tocopherol), were investigated in subjectswith AD, MCI, and normal cognition (CN) in a clinical-based, multi-centre European study(AddNeuroMed Project). Compared to CN subjects, AD and MCI cases had lower plasma levels of totaltocopherols, total tocotrienols and total vitamin E. Both MCI and AD cases had 85% lower odds to be inthe highest tertile of plasma total tocopherols and total vitamin E, and they were, respectively, 92% and94% less likely to be in the highest tertile of total tocotrienols than the lowest tertile. Further, bothdisorders were associated with increased plasma indices of vitamin E oxidative/nitrosative damage(ratios α-tocopherylquinone/α-tocopherol and 5-nitro-γ-tocopherol/γ-tocopherol).Study II. Within the AddNeuroMed Project, analysis which integrated plasma levels of vitamin E formswith structural magnetic resonance (MRI) parameters, derived from automated regional analysis, wasused to differentiate AD and MCI cases from CN individuals, and to predict MCI conversion to AD. Theanalysis of MRI and vitamin E data alone provided an accuracy of 83.2% and 92.8% respectively, forAD versus CN, and of 58.1% and 87.8% for MCI versus CN. The integrated analysis of plasma vitaminE and MRI data enhanced the accuracy, which were 98.2% for AD versus CN and 90.7% for MCIversus CN. This combination of data also correctly identified 85% of the MCI who converted to clinicalAD at one year follow-up and 67% of the non-converters.Study III. The association of plasma levels of eight natural vitamin E forms with the incidence of ADwas examined in a Swedish population-based prospective study (Kungsholmen Project) of oldest-oldindividuals (age 80+), using six-year follow-up data. Subjects with higher concentrations of totaltocopherols, total tocotrienols or total vitamin E had approximately a 50% reduced risk of developingAD in comparison to subjects with lower plasma levels (highest versus lowest tertile).Study IV. The association of serum levels of all eight natural vitamin E forms and markers of vitamin Eoxidative/nitrosative damage, with the incidence of cognitive impairment (MCI or AD) was investigatedin a Finnish population-based prospective study (CAIDE) of older adults (age 65+), using eight-yearfollow-up data. The odds of cognitive impairment was reduced for subjects in the medium tertile of γ-tocopherol serum levels, relative to those subjects in the lowest tertile [odds ratio and 95% confidenceinterval: 0.27(0.10-0.78)]. Subjects with a higher serum value for the index of γ-tocopherol nitrosativedamage (5-nitro-γ-tocopherol/γ-tocopherol ratio; high and middle versus lowest tertile) were about threetimes more likely to develop cognitive impairment.Conclusions. α-tocopherol is the only vitamin E form currently used to define vitamin E dietaryrequirements, and it is the only congener tested in randomized controlled trials in subjects with AD andMCI. The results of this project provide evidence that suggests that the other natural forms of vitamin Ecan also be important in cognitive impairment and AD in older adults. Thus, all natural vitamin E formsshould be considered when studying the association of this micronutrient with cognitive impairment andAD. These findings also suggest that some aspects of vitamin E supplementation in preventing andtreating AD should be re-examined. This should include the timing of intervention, the composition ofsupplementation, and the assessment of plasma levels of all vitamin E forms. The latter can help identifysubjects who could benefit from vitamin E supplementation, and monitor in-vivo biological response totreatment.