Micronutrients in the Prevention of Dementia

In addition to normal, age-related deterioration in brain function, the risk of a pathological decline in mental and intellectual abilities increases with age. Typical of such diseases – collectively called dementia, although there are several sub-forms – is deterioration in memory capacity, cognitive performance, language and practical skills. As a consequence, those affected can no longer perform everyday tasks. The most common forms of dementia are Alzheimer’s disease, a form in which harmful proteins (plaques) accumulate in the nerve cells of the brain, and vascular dementia, characterized by narrowing of the blood vessels due to atherosclerosis. Since dementia cannot at present be cured, early recognition and prophylaxis are extremely important. In addition to regular physical exercise and mental activity, a balanced and micronutrient-rich diet can help prevent the onset and combat the progression of dementia.

For dementia prophylaxis, consumption of specific foods is less important than the regular intake of a balanced mixture of nutrients, some of which seem to play a particularly important role. Research has provided evidence that excessive con- sumption of saturated animal fats can increase the risk of developing the disease, while polyunsaturated fatty acids may have a protective effect. A sufficient intake of B vitamins supports the function of the nerve cells in the brain and combats the occurrence of harmful metabolic products. The latter includes aggressive oxygen radicals, which appear to be implicated in the occurrence of neural damage and which could be neutralized by the antioxidant micronutrients. A Mediterranean diet, for example, offers many elements of a neuroprotective diet. The large pro- portion of vegetables, fruit and fish ensures a high intake of vitamins, secondary plant substances, minerals, trace elements and omega-3 fatty acids.

Omega-3 fatty acids

The human brain consists to 60% of fatty acids, the largest proportion of which (an estimated 20–30%) is made up of the omega-3 fatty acid docosahexaenoic acid (DHA). In the cells of the brain and spinal cord (central nervous system) DHA is chiefly incorporated into the phospholipids of the plasma membranes and the membranes of cell organelles (e.g. mitochondria). The phospholipids of the nerve endings in the gray matter of the brain are especially rich in DHA, which makes DHA crucially important for the development, maintenance and function of the central nervous system. Based on numerous experimental, epidemiological and clinical studies, it is believed that the type of fatty acids (omega-3 or omega­-6 fatty acids) to be found in the phospholipids of the cell membranes depends greatly on the composition of fatty acids in the diet (1). Hence a high intake of DHA effects an increase in the proportion of DHA in the plasma membranes by dis- placing the omega-6 fatty acid arachidonic acid and therefore increases the internal mobility of the mem- brane (membrane fluidity). This in turn has an effect on the activities of membrane proteins – for example receptors,enzymes, transport proteins and ion channels – and on the availability of neurotransmitters, on membrane permeability and on intercellular interactions (2). DHA, as an essential element of the myelin sheath that surrounds the axons of the neurons, is also necessary for the electrical insulation of the nerve tracts. In this way DHA helps ensure correct transmission of information (nerve impulses) and thus supports learning, memory and cognitive performance of the brain (3).

Clinical studies have shown that cognitive function in older people with above-average intakes of DHA was better than in peers with lower intakes (4). In one randomized controlled study, targeted consumption of fish oil (2.2 grams per day) containing DHA and EPA (eicosapentaenoic acid), as compared with placebo, led to a significant improvement in (executive) brain functions like cognitive flexibility, working memory and activity planning in older people not suffering from dementia (5). Deterioration of these types of cognitive performance is part of the pre-clinical stage of Alzheimer’s disease (6). Moreover, an increased intake of omega-3 fatty acids appears to have positive long-term effects on the structure and volume of certain regions of the brain rich in neurons (the cerebral cortex, including “white” and “gray” matter), which are responsible for memory and learning processes as well as control of muscles and sensory organs (5). The results of observational studies indicate that an adequate intake of fatty fish and the omega-3 fatty acids they contain (in particular DHA) could help prevent the development of a pathological, progressive loss of tissue from the cerebral cortex and reduce the risk of Alzheimer’s disease (7, 8). Regardless of the promis- ing findings described, clinical studies have not yet provided evidence for a protective effect of DHA and EPA on the progression of Alzheimer’s disease and dementia in patients at a relatively early stage of the disease (9, 10).

The exact causes of Alzheimer’s disease are not yet known. An accumulation of neurotoxic aggregates of a particular protein (tau protein) in the neurons, as well as external deposits of a protein-polysaccharide com- plex (amyloid-beta), can be detected in Alzheimer’s patients. It is assumed that DHA could combat the for- mation of amyloid-beta plaque by directly and indirectly preventing the conversion of the amyloid-beta precursor protein (APP) to the neurotoxic end product (11). Further, experimental studies recently provided evidence that a particular lipid mediator molecule (resolvin D1), which is synthesized from DHA in the body, increases the activity of immune cells (macrophages) that dissolve existing amyloid-beta plaques in nerve cells (12).

In addition to their positive effects on cells and functions of the central nervous system, omega-3 fatty acids have also been linked to positive effects on vascular health (13, 14). In epidemiological and clinical studies the following effects have been demonstrated for EPA and DHA: an improvement in plasticity and increase in flexibility of the red blood cells (erythrocytes) through the integration of omega-3 fatty acids into the cell wall, with a consequent improvement in blood flow. Furthermore, blood pressure reduction due to vasodil- ation, mediated by an influence on the lining of the blood vessel walls (endothelium) has been shown. Other effects that combat the onset of atherosclerosis and thrombosis are: a fall in blood triglyceride and LDL cholesterol levels, inhibition of coagulation, and anti-inflammatory effects. Improving vascular health and blood flow in general also improves cognitive performance and reduces the risk of vascular dementia, in which neurons of the cerebral cortex are increasingly destroyed through atherosclerotic vascular changes (15, 16). More recent experimental studies have provided evidence that functional disorders of the blood vessels in combination with an increase in the production of reactive oxygen species by mitochondria can also contribute to the onset of Alzheimer’s disease (17).

Antioxidant micronutrients

The brain is very vulnerable to the oxidative damage that can be caused by free oxygen radicals. The sub- stantial consumption of oxygen by the brain (20% of total consumption), together with a relatively low concentration, compared to other tissues, of intrinsic antioxidant enzymes means that there is an increased risk of oxidative stress. Experimental studies increasingly indicate that an accumulation of free radicals causes damage to membrane lipids, proteins and DNA, which can contribute to the demise of neurons in the brain and to atherosclerotic vascular degeneration and hence in the longer term to the onset of neurode- generative diseases like dementia (18). Increased production of free radicals in the brain could also be triggered by the amyloid-beta peptide characteristic of Alzheimer’s disease, by the trace elements iron, copper and zinc, and by raised homocysteine levels. It is assumed that the brain reacts more sensitively to oxidative damage as it ages, for instance, because of deteriorating antioxidant defense mechanisms, and that the production of energy decreases due to mitochondrial dysfunction (19). Reducing oxidative stress and protecting mitochondria could therefore represent important objectives in the prevention and treatment of all forms of dementia. This has been particularly well researched in the context of Alzheimer’s disease (20).

In addition to the antioxidant enzymes produced by the body itself, micronutrients with antioxidant activity consumed in the diet could also help reduce oxidative stress in the brain. Most studies conducted with Alz- heimer’s patients show that they have lower vitamin C and vitamin E levels (21). It is thought that larger amounts of the vitamins are used due to disease-related oxidative stress. The fat-soluble vitamins E and A, as well as beta-caw rotene could protect the phospholipid membranes of the neurons against oxidative da- mage, which appears to be linked to the incidence of Alzheimer’s disease (22). Vitamin E in particular app- ears to have the ability to interrupt existing radical chain reactions in the phospholipid membranes (lipid peroxidation). Water-soluble vitamin C could prevent free radicals from coming into being and therefore protect against the damage to elements of the fluid interior of cells that they cause.Clinical studies indicate that combined administration of vitamin C plus vitamin E for at least three years is associated with a reduc- tion in relative prevalence and incidence of Alzheimer’s disease (23). There are indications that vitamin A, beta-carotene, vitamin E and vitamin C can all prevent the formation of neurotoxic amyloid-beta deposits (24). The potentially vasculoprotective effects of antioxidant micronutrients mean that they could potentially help prevent vascular dementia. Evidence of this was supplied by studies with vitamins E and C (25). The trace elements zinc and selenium also play an important part in brain metabolism. Zinc is important as a cofactor for antioxidant enzymes (oxidoreductases), strengthening the production of a neuron growth factor (brain-derived neurotrophic factor) and functioning as a neuroreceptor cofactor (26). The best known func- tion fulfilled by selenium is as an essential element of the enzyme glutathione peroxidase, which is especially important in antioxidant defense (in particular of lipid peroxidation) (27). Studies on the connection between zinc or selenium and the incidence of dementia are very limited and contradictory. One large cohort study was able to show that people with a low blood selenium status display an increased risk of cognitive impair- ment (28). 

Vitamin D

In addition to its many other functions, vitamin D appears to be able to influence the central nervous sys- tem. Vitamin D receptors have been discovered in several neuron-rich key regions of the brain (29). More- over, it has been shown that the brain contains enzymes which promote the local synthesis of calcitriol (the active form of vitamin D3). According to experimental studies the vitamin could potentially combat the deve- lopment of dementia due to its multifaceted modes of action by influencing anti-inflammatory, vasculoprotective and neuroprotective processes (30).

Epidemiological studies indicated that an inadequate supply of vitamin D could represent a risk factor for the loss of cognitive functions and the incidence of dementia (31, 32). In one prospective observational study over 30 years with 10,000 participants, participants who developed Alzheimer’s disease or vascular dementia during this time were shown to have inadequate blood levels of vitamin D (33). Furthermore, specific genetic characteristics, which express themselves as reduced vitamin D receptor activity, contribute to an increase in the risk of developing Alzheimer’s disease (34).

A meta-analysis showed that Alzheimer sufferers exhibited low levels of vitamin D in observational and in- terventional studies (35). There are, moreover, indications that in Alzheimer sufferers vitamin D apparently aids the immune cells (macrophages) in the removal of the neurotoxic amyloid-beta plaques that are typical of this disease (36).

For the prevention of dementia, scientists recommend blood vitamin D concentrations of at least 30 ng/mL, which can be achieved with sufficient exposure to sunlight, an adequate intake in the diet, or through dietary supplementation of at least 800 IU per day (35). One clinical study showed that raising the level of vitamin D can have a particularly positive effect on mental abilities that control thinking and activity (37). Impairment of such so-called executive functions is often observed in the preclinical stage of Alzheimer’s disease.

B vitamins

Almost 50% of all apparently healthy older people exhibit raised blood levels of homocysteine, an amino acid formed in protein metabolism. Experimental findings indicate that high levels of homocysteine in the blood destroy cells that line the interior walls of the blood vessels (endothelium), encourage the formation of thromboses and raise LDL cholesterol levels – all factors that promote the incidence of atherosclerosis and cardiovascular disease (38). More recent studies point to neurotoxic effects in the brain (39). It was also possible to show that patients with vascular dementia and Alzheimer’s disease frequently had high levels of homocysteine, which thus represents a risk factor for dementia (40). Several studies reported that targeted administration of folic acid, vitamin B6 and vitamin B12 lower homocysteine levels and thereby reduce the risk of cerebrovascular disease (41). Both epidemiological and clinical studies have shown that low levels of homocysteine and a good supply of vitamins B6, B9 and B12 are associated with a reduced risk of deve- loping Alzheimer’s disease, and that dietary supplementation with B vitamins could lead to lower homocy- steine levels and reduce the risk of Alzheimer’s disease and its early symptoms (42–44). According to one observational study, raised homocysteine levels are a risk factor that can predict the occurrence of Alz- heimer’s disease at least seven years prior to the appearance of obvious clinical symptoms. Besides this, the targeted raising of vitamin B12 levels led to a clear reduction in the risk for Alzheimer’s disease (45).

Special diets

For some time much research has been dedicated to discovering to what extent a particular type of diet can prevent the onset of dementia. Studies have come to contradictory conclusions. It is especially difficult to identify the potentially protective properties of individual active ingredients in complex combinations of food- stuffs or nutrient mixtures.

Regular consumption of black and/or green tea, as is usual in many Asiatic countries, has been linked to prophylaxis prior to the degeneration of mental abilities and the onset of dementia in several epidemiological studies (46, 47). Specific substances in the tea (e. g. catechins or L-theanine) could have a neuroprotective effect (48). Catechins are the best studied (in particular epigallocatechin-3-gallate, EGCG). As polyphenols with antioxidant activity, they could combat cognitive function disorders by reducing oxidative stress(49).

A Mediterranean diet, consisting mainly of fruit and vegetables, cereals, bread, potatoes, nuts, poultry, fish and olive oil and a moderate consumption of alcohol (wine) could contribute to the prevention of demen- tia. Numerous epidemiological studies indicate that considerably fewer cases of mild cognitive dysfunction, vascular dementia and Alzheimer’s disease occurred with lifelong consumption of a Mediterranean diet than with other forms of diet, which are more strongly typified by consumption of red meat and milk products (50).