Vitamin E and Cognitive Impairment: The Importance Of Looking At All Forms Of Vitamin E.

Article by Arnie Gitomer

Vitamin E and Cognitive Impairment

Focus: You have done some remarkable work on tocotrienols and the aging brain. But before we get to that, can you tell us about the scope of the multicenter AddNeuroMed Project that you are involved in?
Mecocci: AddNeuroMed is a multicenter European longitudinal study focused on the detection of biomarkers for Alzheimer’s disease (AD), which can assist diagnosis, prognosis, drug discovery and treatment monitoring. The project includes six countries (Finland, France, Greece, Italy, Poland and the UK). More than 700 older individuals were recruited. These subjects included those individuals over 65 years of age who were cognitively normal, those who suffered mild cognitive impairment, or they had actual dementia due to AD.
Focus: What are the symptoms of mild cognitive impairment?
Mecocci: The term mild cognitive impairment (MCI) describes a clinical syndrome which can be caused by several diseases. Among neurodegenerative diseases, AD is among the most common brain disorders causing MCI. MCI is a condition in which memory or other cognitive abilities (e.g., executive function, language, visuospatial skills) are slightly abnormal but they coexist with predominantly normal functions in the activities of daily living and absence of dementia. MCI is related to an increased risk of conversion to dementia. MCI is quite variable in the population at large, ranging from 6-30%, according to different studies. And Alzheimer’s disease ranges from 5-30%, depending on age.
Focus: In one of your studies, you found that lower levels of both tocopherols and tocotrienols are associated with cognitive impairment. Do you think levels are lower because of genetic vulnerabilities, such as less ability to utilize Vitamin E forms? Or is oxidative stress actually “using” up the Vitamin E?
Mecocci: Both are possibilities. Lower plasma levels of different vitamin E forms in subjects with AD and MCI could be due to changes in metabolism and/or dietary habits promoted by AD. However, clinical information about the study participants allowed us to exclude malnourishment in all subjects. Furthermore, in our population reduced levels of a- and ?-tocopherol were associated with increased indices of their utilization due to reaction with free radicals. This suggests that vitamin E depletion was due, at least in part, to increased utilization in oxidative/nitrosative stress (OS/NS) events.
Higher plasma levels of total tocopherols, total tocotrienols and total vitamin E were associated with a 50% reduced risk of developing Alzheimers Disease over six years follow-up. Overall, our data support the hypothesis of a causal role of deficiency of vitamin E forms in development and clinical expression of AD.
In support of this oxidative stress hypothesis, we did a longitudinal study, in which we examined plasma levels of all eight vitamin E forms in relation to the incidence of AD in Swedish octogenarians. In this study we found that higher plasma levels of total tocopherols, total tocotrienols and total vitamin E were associated with a 50% reduced risk of developing AD over six years follow-up. Overall, our data support the hypothesis of a causal role of deficiency of vitamin E forms in development and clinical expression of AD.
As for genetic mechanisms regulating bioavailability of different forms of vitamin E in humans, very few studies have been done so far to clarify this issue, and such studies mainly focus on genetic factors affecting plasma levels of vitamin E alpha-tocopherol. We still do not know which genes regulate plasma levels and tissue distribution and cellular use of the eight vitamin E congeners. The apolipoprotein E (APOE) gene has been suggested as potential candidate for this role. This gene is a well-known risk factor for late-life AD: people who are carriers of the allele e4 have an increased risk of developing AD than those who carry the alleles e2 or e3. Some studies suggested that APOE e4 can affect serum levels and cell delivery of lipids and a-tocopherol, promoting the retention of Vitamin E in plasma lipoproteins and Vitamin E deficiency in peripheral tissues (see for instance Mas et al., Dementia and Geriatric Cognitive Disorders, 2006). However, few studies have investigated this issue and conclusive data on the effect of the APOE genotype on tissue delivery of vitamin E congeners is still lacking.
Focus: How does vitamin E “damage” show up?
Mecocci: We found significantly higher levels of the ratio of a-tocopherylquinone/a-tocopherol and the ratio of 5-nitro-?-tocopherol/?-tocopherol in subjects with AD and MCI in comparison to cognitively normal controls. a-tocopherylquinone (aTQ) is the primary product of a-tocopherol oxidation, while 5-nitro-?-tocopherol (5-NO2-?-tocopherol) is a product of reaction between ?-tocopherol and reactive nitrogen species. Thus, both ratios reflect vitamin E depletion (specifically a- and ?-tocopherol) due to OS/NS. OS/NS levels have been proved to increase in central nervous system (CNS) and peripheral tissues, such as blood, of subjects with AD and MCI, and a great deal of evidence supports the putative role of OS/NS in the propagation of cellular injury. Cellular injury can lead to various kinds of damage observed both in brain aging and neurodegeneration. Levels of OS/NS can be also affected by different conditions, including lifestyle (such as smoking) and diseases (such as cancer, diabetes mellitus).
In another study we performed in the same cohort, we found a significant negative correlation between indices of vitamin E OS/NS and volumes of brain regions usually affected in AD (amygdala, hippocampus, entorhinal cortex, medial temporal lobe), meaning that higher indices of vitamin E oxidative/nitrosative damage were associated with increased brain atrophy.
Focus: Let’s talk about dietary sources of all the Vitamin E forms.
Mecocci: The main dietary sources of vitamin E are vegetable oils. All 4 tocopherols are found in wheat germ oil, almonds, sunflower and olive oil, which are mainly rich in a-tocopherol. ? -tocopherol is the major form of vitamin E in corn oil and soybean oil. Major food sources of all 4 tocotrienols are rice bran, barley, oats, and palm oil. Palm oil is one of the most abundant natural sources of tocotrienols. It contains a mixture of tocopherols and tocotrienols, and is used by the food industry (e.g., bakery products, breakfast cereals). a-tocotrienol is the predominant form of tocotrienol in oat and barley, while ß-tocotrienol is the major form of tocotrienol found in wheat. Rice bran oil, common in Asian countries, is a major natural source of ?-tocotrienol. Other dietary sources of vitamin E are animal fats, dairy products, fruit, and vegetables. a-tocopherol is the main form of vitamin E present in the European diet, while ?-tocopherol intake is higher than a-tocopherol in the USA diet. Since foods containing vitamin E usually contain more than one form, people who intake foods rich in vitamin E usually intake more than one form (often all eight congeners, although in different amounts, depending on the food composition). It is thus expected that plasma levels of different forms are positively correlated. The studies we conducted were the first to analyze all eight natural forms in human beings in relation to cognitive impairment. It would be premature at this stage to point at one specific form of vitamin E as a key compound to prevent or treat AD (we would then be making the same mistake that has been made with alpha-tocopherol).
The key conclusion that we have reached is that low plasma levels of tocopherols and tocotrienols are associated with the risk of cognitive impairment/AD 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 a-tocopherol therefore likely does 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 vitamin E family in preventing or slowing the onset and progression of age-related cognitive decline and dementia.
Vitamin E was discovered about 90 years
ago, but it has only been in the last few
years that researchers have started to focus on non-a-tocopherol forms in relation to human health.
Focus: In what way might the vitamin E isomers interfere with the cascade of events that lead to brain damage in Alzheimer’s?
Mecocci: 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. People with AD or cognitive problems are often consumers of a-tocopherol supplements, even though there is no evidence of a beneficial effect. In general, a-tocopherol is the most commonly used vitamin E supplement, due to the belief that this form of vitamin E may attenuate morbidity and mortality. However, current data on mortality and a-tocopherol supplementation at high doses emphasize that such a micronutrient, if unbalanced, may not be as harmless as previously thought. In fact, an increased risk of hemorrhagic stroke and mortality has been reported in users of high doses of alpha-tocopherol supplements. Additionally, in the last decade a large amount of studies showed that each form of vitamin E is functionally unique, but the possible role of different vitamin E forms in human health and disease is still not clear. Several studies are investigating the role of vitamin E forms in different disorders, including cancer, cerebrovascular and cardiovascular diseases. There are also clinical trials ongoing to test therapeutic effects of vitamin E congeners in these disorders.
We decided to focus on the entire vitamin E family to help explain its possible role in age related cognitive impairment and AD. We are aware that we need to take into account the “full picture” meaning that we need to keep in mind that people eat foods, not nutrients, and that they eat them in combination, not in isolation. Vitamin E is only one of the nutrients which might play a role in AD.
Vitamin E was discovered about 90 years ago, but it has only been in the last few years that researchers have started to focus on non-a-tocopherol forms in relation to human health. Many questions related to this issue still do not have a definite answer. Current developments in vitamin E research clearly indicate that members of the vitamin E family are functionally unique and not redundant with respect to their biological function. We hope to eventually determine the composition of vitamin E supplements best suited to AD prevention trials and to refine dietary recommendations for healthy cognitive aging.

Reprinted from Focus on Allergy Research Group
To see the original article, go to
http://www.allergyresearchgroup.com/focus/201311_mecocci.htm