Prevention of Alzheimer’s disease: Putative nutritive factors

Authors


Dr Takashi Asada, MD, Department of Neuropsychiatry, University of Tsukuba, Tennodai 1-1-1, Tsukuba city, Ibaraki 3-5-8575, Japan. Email: tasada@md.tsukuba.ac.jp

Abstract

During the last decades, researchers have found several risk factors for the development of Alzheimer’s disease (AD) and other dementing illnesses. Among them, lifestyle-related factors such as exercise and nutrition have received increasing attention. Only recently, several encouraging studies, both in animal experiments and human clinical trials, have been reported. These studies inspire us to develop effective interventions including lifestyle changes that might prevent the onset of human AD. In order to provide sound interventions against the development of AD, it is indispensable to evaluate in detail the putative risk factors for AD, especially modifiable lifestyle-related factors. Thus, in this article, we review recent findings regarding nutrition as a possible prevention against AD. The main issues dealt in this review are as follows: dietary fat including omega-3 fatty acids (EPA, DHA); diabetes (glucose, insulin); antioxidants (vitamin C & E); Ginkgo biloba and the Mediterranean diet.

INTRODUCTION

Dementing illnesses, including Alzheimer disease (AD), are major sources of morbidity and mortality that affect more than several hundred millions of persons in the increasingly aging society of developed and developing countries. Efforts to develop strategies to delay and prevent the onset of the potentially devastating illnesses are now ongoing worldwide.

The pathology of AD is complex and involves numerous pathways including defective beta-amyloid (Aβ) protein metabolism, abnormalities of glutamatergic, adrenergic, serotonergic and dopaminergic neurotransmission. The pathways are said to involve inflammatory, oxidative and hormonal pathways.1 Even though the precise cause of AD is unknown, it is clear that genetic factors play a major role. However, the four genes that have been identified so far are linked to less than 10% of total AD cases, and there are numerous familial cases that are not linked to any of the genes. On the other hand, non-genetic factors also play extremely important roles in the pathophysiology of AD, epigenetic components of neurons such as mitochondria, proteasomes and post-translation protein modifications (processing of amyloid precursor protein to Aβ and hyperphosphorylation of tau), rather than nuclear genes, are primary targets for the actions of diverse groups of neurotoxins.2

During the last decades, researchers have found several risk factors for the development of AD and other dementing illnesses. Among them, lifestyle-related factors such as exercise and nutrition have received increasing attention. Some longitudinal studies and randomized trials have suggested that exercise enhances cognitive functioning of elderly individuals, whereas other studies have failed to observe such benefits.3–6

Only recently, several encouraging studies have been conducted. A recent investigation has demonstrated that exercise and environmental enrichment lead to reduction in amyloid deposit in AD-like transgenic mice.7 Additionally, the administration of docosahexaenoic acid (DHA) also succeeded in reducing amyloid deposits in similar mice.8 Furthermore, it has been reported that the benefit of donepezil in delaying the progression of mild cognitive impairment (MCI) to AD was evident during 1-year follow-up.9 All of these studies inspire us to develop effective interventions including lifestyle changes that might prevent the onset of human AD.

In order to provide sound interventions against the development of AD, it is indispensable to evaluate in detail the putative risk factors for AD, especially modifiable lifestyle related factors. Thus, in this article, we will review recent findings regarding nutrition as possible method of AD prevention. The main issues dealt with in the review and their putative mechanisms are shown in the Table 1.

Table 1.  Nutritive factors associated with Alzheimer’s disease and their putative mechanisms
Dietary fat: Omega-3 fatty acids (EPA, DHA)
neural function including neurotransmission, membrane fluidity, ion channel and enzyme regulation and gene expression
Diabetes: Glucose, Insulin
1 glucose regulatory mechanisms can also affect amyloid precursor protein (APP)
2 the insulin degrading enzyme can break down Aβ as well as insulin
3 insulin also reduces intracellular accumulation of Aβ by accelerating APP trafficking
Antioxidants: Vitamin C, E, beta-carotene
to reduce reactive oxygen species (ROS) causing the neuronal degeneration in AD
Ginkgo biloba
putative antioxidant properties and to reduce the aggregation of the Aβ
Mediterranean diet
Others
Green tea, melatonin, miscellaneous

DIETARY FACTORS FOR ALZHEIMER’S DISEASE

It has been well known that caloric restriction (CR) extends the lifespan of rodents and increases the resistance of neurons to degeneration. Animal studies suggest that this mechanism is mediated by decreased glucose, attenuated free radical generation, alteration of vasculature and reduction of glial activation. In addition, CR decreases Aβ peptide generation and neuritic plaque deposition in the brains of AD model mouse.10

A large number of AD researches have focused on individual dietary components, the efficacy of certain dietary patterns on the protection of AD remain uncertain. However, epidemiological studies have shown that people of similar ethnic origins yet living in different environments can have significantly different risks of dementia and AD.11 For example, immigrants from Okinawa Japan in Brazil have much higher incidence of dementia when compared with Japanese living in Okinawa.12 Among several dietary components, diet and fat intake seem to be important when comparing the lifestyles of population screened for AD. Thus we start by reviewing these aspects.

Dietary fat

The results of studies regarding these issues have produced conflicting results. One study has found that the more fat consumed in a meal, the greater the risk of developing AD.13 On the contrary, a famous Rotterdam study showed that a high total intake of saturated fat and cholesterol was not associated with an increased risk of dementia.14

With respect to diet and fat intake, we must consider the differences in the types of dietary fat. Namely, it appears that saturated and polyunsaturated fats have apparently opposite effects on cognitive performance. In animal experiments, feeding high levels of saturated fat can result in learning and memory impairments,8 in contrast high levels of polyunsaturated fatty acids result in better cognitive function. Thus, we first review the possible AD preventive role of omega-3 fatty acids.

Omega-3 fatty acids

Epidemiological evidence suggests that dietary consumption of the long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), commonly found in fish or fish oil, may modify the risk for dementing illnesses including AD. It is clear that DHA is the predominant n-3 fatty acid found in the brain and that EPA plays an important role as an anti-inflammatory precursor.15

Although omega-3 fatty acids are present in plant-based sources such as alpha-linolenic acid (ALA), here we focus mainly on the animal-derived long chain n-3 polyunsaturated fatty acids (EPA, DHA). The pathway for the metabolic conversion of ALA to DHA involves the sequential utilization of delata-6, 5- and 4-desaturateses along with elongation reactions (Fig. 1). The conversion of ALA to EPA and DHA is limited in humans and has been estimated to be anywhere from less than 1% to 6%.16 Interestingly, DHA can also be retroconverted to EPA at rates of about 10% in humans.17

Figure 1.

The metabolic conversion of alpha-linolenic acid to docosahexaenoic acid.

EPA is found primarily in cholesterol ester, triglycerides and phospholipids. DHA is found primarily in phospholipids, and is highly concentrated in the cerebral cortex, retina and testes. In fact, DHA makes up a large proportion of the brain’s lipids, and is the predominant n-3 fatty acid found in brain. The structural predominance of DHA in the brain suggests functional significance.18 Both DHA and EPA can be linked with many aspects of neural function, including neurotransmission, membrane fluidity, ion channel and enzyme regulation and gene expression.15

It has been said that the present western diet is deficient in n-3 fatty acids compared to that on which our genetic patterns were established. This deficiency is explained in terms of decrement in consumption of fish and wild game, and also the increment of the consumption of plant-derived oils, which contain large amounts of n-6′s and minimal n-3′s. Some common vegetable oils, including soybean, canola and flax seed oil, are concentrated sources of ALA in the diet, while fatty fish, such as halibut, mackerel, herring, and salmon are concentrated sources of EPA and DHA. Other sources of dietary n-3 fatty acids are nuts, seeds, fruits, vegetables, egg yolks and meat15 (Table 2).

Table 2.  Foods abundant in omega-3 fatty acids (Modified from Young G et al.15)
Food itemEPADHAALA
  1. The omega-3 fatty acid content, in grams per 100 g food serving, of a representative sample of commonly consumed fish, shellfish, fish oils, nuts and seeds, and plant oils.

Fish (raw)
 Anchovy, European0.6 0.9
 Mackerel, Pacific and jack0.6 0.9Trace
 Salmon, Atlantic, farmed0.6 1.3Trace
 Trout, rainbow, farmed0.3 0.7Trace
 Tuna, fresh, bluefin0.3 0.9
Shellfish (raw)
 Oyster, Pacific0.4 0.3Trace
Fish oils
 Cod liver oil6.911.0 0.9
 Herring oil6.3 4.2 0.8
Nuts and seeds
 Butternuts, dried 8.7
Plant oils
 Flaxseed53.3

In the USA, it has been recommended that EPA and DHA be consumed at an intake of 0.65 g/day, which is a 4-fold increase from the current level of consumption of 0.1–0.2 g/day.19 Even in Japan, where seafood has traditionally been consumed at very high levels, the ration of n-6 to n-3 fatty acids is increasing as diets become more Westernized, particularly among young people.20

It has long been suggested that AD is associated with brain lipid defects. Blood levels of omega-3 fatty acids of individuals with existing AD have been investigated. One study suggests an inverse association between cognitive decline and ratio of n-3/n-6 fatty acids in red blood cell membranes.21 Similarly, several studies demonstrated the decreased blood levels of omega-3 fatty acids in AD patients, however, the reason for it is unclear. There are three known studies in which AD or other dementia patients have been supplemented with long-chain omega-3 fatty acids (EPA and/or DHA). All of the three reported from Japan showed the efficacy of their interventions.15

More recently, epidemiological studies have suggested that high fish and/or omega-3 fatty acid consumption is inversely associated with cognitive impairment, cognitive decline and/or development of dementia such as AD.22–24

On the other hand, diabetes as an AD risk factor has attracted attention from researchers because of the following reasons.25 First, glucose regulatory mechanisms can also affect amyloid precursor protein (APP).26 Second, the insulin degrading enzyme can break down Aβ as well as insulin.27 Third, insulin also reduces intracellular accumulation of Aβ by accelerating APP trafficking.28 Adding further links between diabetes and AD is other study that has found that type II diabetes is associated with a low unsaturated : saturated fat intake ratio.29 Several researchers reported that saturated and trans-fatty acids increase insulin resistance, whereas mono- and poly-unsaturated fats decrease resistance and offer protection against diabetes.29,30 In obese and diabetic individuals, there is a marked decrease in the clearance and metabolism of cholesterol-rich lipoproteins from plasma. Additionally, it has been reported that individuals with type II diabetes who posses ApoE ɛ4 allele have twice the risk of developing AD as compared with non-diabetic with ApoE ɛ4.31 Taking these findings together, it appears that abnormalities in glucose metabolism may have some effects on cognitive performance.

Antioxidants

Oxidative stress and mitochondrial dysfunction have been speculated to be linked to AD, and in fact, there is increasing evidence that oxidative stress and apoptosis are closely linked physiological phenomena and are implicated in the pathophysiology of AD. Consequently, increased generation of reactive oxygen species (ROS) is a possible explanation for the neuronal degeneration in AD.32

Some reactions of the mitochondrial electron transport chain with molecular oxygen generate a number of potent ROS, which cause damage to mitochondrial components and initiate degenerative processes. Such toxic reactions contribute significantly to the aging process and form the central dogma of ‘the free radical theory of aging’. ROS are generated through the process of oxidation by a variety of sources from the environment and normal cellular functions. ROS include free radicals, non-radical oxygen species and reactive lipids and carbohydrates. Oxidative damage to DNA can occur by many routes including the oxidative modification of the nucleotide bases, sugars or by forming cross-links. Such modification can lead to mutations, pathologies, cellular aging and death.33 Oxidation of proteins appears to play a causative role in AD. It has been shown that the enhancement of acetylcholinesterase activity induced by Aβ is mediated by oxidative stress,34 and that vitamin E can have an important role in the maintenance of acetylcholine synaptic levels, thus preventing or improving the cognitive and memory functioning of AD patients.35

The production of ROS can occur very early in the AD process, even before the appearance of the Aβ plaques and neurofibrillary tangles, leading to tissue damage via several different cellular pathways. Therefore, treatment with antioxidants might act to prevent propagation of tissue damage and improve both survival and neurological outcome.

Many researchers have attempted to identify an association between antioxidant intake and a reduced incidence of dementia, and in fact several of them have found such a link. For example, a study, lasting 6 years found that the use of antioxidative supplements or high intake of vitamin C along with vitamin E was associated with lower risk of AD (rate ratios 0.82 for the both).35 However, other researchers have found no association between the risk of AD and either supplemental or dietary intake of carotenes and vitamins C and E.36 Furthermore, in a separate study of 2459 middle-aged, Japanese–American men, the researchers concluded that midlife dietary intake of antioxidants does not modify the risk of late-life dementia.37 There are few studies of the role of ROS in mild cognitive impairment (MCI). An exceptional study found a marked reduction of the main components of the endogenous antioxidants defense system in AD patients, and noted that since MCI represents a condition of increased risk for AD, use of antioxidants in MCI could be important for prevention of AD.38 If oxidative damage occurs as one of the earliest pathophysiological events in AD, an increased intake of antioxidants in individuals with MCI could be theoretically helpful in lowering the risk of conversion to dementia. However, data from a three-year clinical trial that assessed the effect of vitamin E in persons with MCI failed to show a significant effect on prevention of the progression to AD.9

Several researchers have found that supplementation with both vitamin C and E is superior to that with either vitamin alone in AD patients. It appears that the initiation of free radical chain polymerization is a crucial early event in AD pathogenesis, thus antioxidant therapy may be beneficial only if given before or in the very early stage of the course of AD process.39,40

A related question is whether vitamin E administration helps to prevent AD, and on this point the data are mixed. Epidemiological studies assessing the effect of vitamin E in healthy individuals have yielded conflicting results. The Medical Research Council/British Heart Foundation Heart Protection Study, a randomized trial in which patients with vascular risk factors were allocated to receive a combination of vitamin E, vitamin C and β-carotene or placebo for 5 years, did not detect any differences in the frequency of cognitive impairment between groups.41 Although several epidemiological studies have shown a delay in the onset of AD in individuals taking vitamin E supplements or that from diet, other studies failed to find this association.39 Intake of supplements or dietary vitamin C has not been shown to decrease the risk of AD except in one study with borderline significance, but another study suggested that only the combination of supplements of vitamin C with vitamin E had a protective effect.42

Ginkgo

Ginkgo biloba comes from a single type of tree, and its seeds are most commonly employed in traditional Chinese medicine. An extract of Ginkgo biloba (EGb 761), has been available in Europe as a herbal extract since the early 1990s. The postulated mechanism of action of Ginkgo is purported to have an antioxidant effect that leads to the destruction of free radicals implicated in cell damage and to increased cerebral blood flow through platelet activation factor inhibition and nitric oxide pathways. In addition to putative antioxidant properties, the extract of ginkgo has been reported to reduce the aggregation of Aβ.43 It also reverses age-related losses in brain alpha 1-adrenergic, 5-HT1A (serotoninergic) and muscarinic receptors, protects against ischemic neuronal death, preserves the function of the hippocampal mossy fiber system, increases hippocampal high-affinity choline uptake, inhibits the down-regulation of hippocampal glucocorticoid receptors, enhances neuronal plasticity and counteracts the cognitive deficits that follow stress or traumatic brain injury.44 The ginkgo extract does not improve cognitive function in healthy elderly individuals.45 Several authors have concluded that Ginkgo biloba appears to be a useful and sensible supplementary medication to treat AD. Although there is a possible improvement of cognitive function, activities of daily living and mood in those with AD, recent results of trials have been inconsistent.46 Ginkgo is rarely prescribed by physicians; nonetheless, it remains a popular remedy and is widely available in drugstores, supermarkets and health food stores without a prescription. As a side-effect, the prolongation of bleeding time has been reported, and there are some case reports of intracerebral hemorrhage.

Mediterranean diet

From a therapeutic aspect, it has been reported that a typical Mediterranean diet, which has received increasing attention in recent years because of converging ecologic, analytical-observational and interventional evidence relating it to lower risk for cardiovascular disease, several forms of cancer and overall mortalities. The Mediterranean diet is characterized by high intake of vegetables, legumes, fruits and cereals; high intake of unsaturated fatty acids (mostly in the form of olive oil), but low intake of saturated fatty acids; a moderately high intake of fish; a low-to-moderate intake of dairy products (mostly cheese or yogurt); a low intake of meat and poultry; and a regular but moderate amount of ethanol, primarily in the form of wine and generally during meals.

Recently, a community-based prospective study in New York conducted intervention study using the Mediterranean diet and showed the following findings:6 higher adherence to the diet was associated with lower risk for AD (hazard ratio, 0.91; 95% confidence interval, 0.83–0.98; P = 0.015) and compared with subjects in the lowest diet tertile, subjects in the middle tertile had a hazard ration of 0.85 (95% confidence interval, 0.63–1.16) and those at the highest tertile had a hazard ratio of 0.60 (95% confidence interval. 0.42–0.87) for AD (P for trend = 0.007). Thus this study indicates that higher adherence to the diet is associated with lower risk of AD development.

CONCLUSION

Taking all of the findings described above, the nutritive intervention to delay and prevent AD is the challenge. For this purpose, we should conduct trials using some foods and supplements on individuals without any signs of dementia, or those with MCI, over a long period of time.

Ancillary