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Alzheimers disease (AD) is a progressive cognitive disorder, which commonly inflicts the elderly. There are currently several genetic markers that can guide detection and early diagnosis, including the presence of mutated APP, PS1, and PS2. Early detection may prompt individuals to self-treat with nutrition, complementary and alternative medicine, due to ease of access and potential cost savings. There are currently multiple natural products that may be useful in alleviating cognition disorders such as AD, including bacopa, melatonin, ginkgo, ginseng, coenzyme Q10, and huperzine A. Bacopa is an herb which has been used for centuries to assist in learning and possesses multiple mechanisms of actions to exert its effects. Melatonin is a well-tolerated neurohormone which serves as an antioxidant. Ginkgo has been used in all types of memory loss and exhibits antioxidant as well as anti-inflammatory properties. Ginseng may safely and effectively modulate choline release and reuptake in the hippocampus. Coenzyme Q10, a coenzyme naturally made in the body which is depleted in AD patients, may protect mitochondria and reduce brain atrophy. Huperzine A is an acetylcholinesterase inhibitor which has already been approved for use in China. Since its development was conducted in a foreign country, it lends itself to being subject to the environmental and health standards and potentially trade-impeding regulations that may restrict supply into certain countries including the United States. The proper selection of a natural product or alternative therapy can successfully improve memory and AD treatment, a strategy that can benefit from the incorporation of physical exercise, cognitive training, and socialization.
Keywords: nutrition, complementary and alternative medicine (NCAM), management of Alzheimer's disease, treatment of Alzheimer's disease, Alzheimer's disease, bacopa, melatonin, gingko, ginseng, coenzyme Q10, and huperzine A
Alzheimer's disease (AD) is the most common single cause of dementia in our ageing society. It is estimated that 5.3 million Americans of all ages have Alzheimer's disease, including 5.1 million people aged 65 and older. According to the Alzheimer's Association, there are 500,000 Americans younger than 65 with dementias, with 40% estimated to have Alzheimer's. Every 70 seconds, someone in America develops Alzheimer's, which means by mid-century, someone will develop the disease every 33 seconds. Traditionally thought of as an untreatable degenerative condition, recent advances in drug therapy have challenged this view. (Brookmeyer et al., 2000).
The disease is characterized by an insidious decline in cognitive and non-cognitive function. Classically, short and long-term memory is impaired and language skills, concentration and attention are often affected. This results in impaired ability to learn and retain new skills as well as the loss of existing ones. Non-cognitive function is the global term used to describe problems such as depression, agitation, personality changes, delusions and hallucinations. These factors have a significant impact on patient behavior and a very real impact on the quality of life for both patients and caregivers. Diagnosis of AD is clinically based, and using the NINCDS-ADRDA criteria, a diagnosis of probable or possible AD can be made. Definitive diagnosis relies on pathological confirmation, which in the majority of cases is rarely completed. With the development of AD specific treatments, definition of AD from other types of dementia is very important. (Sonnen et al., 2008).
Alzheimer's disease is associated with significant losses in cholinergic neurons and decreased concentrations of the neurotransmitter, acetylcholine, which is significantly involved in learning and memory processes. It is also hypothesized that AD is caused by deposition of amyloid beta-peptide (Abeta) in plaques in brain tissue and the CNS. For the most part, medications for AD are indicated for the management of mild to moderate Alzheimer's dementia. (McLean et al., 1999). From a pharmacology standpoint, prescription drugs and in the context of this report, complementary and alternative herbal remedies exert their effects via some modulation of the integrity of neurotransmitters and effect of the amyloid precursor protein and the reactive beta amyloid (Figure 1-4).
Fig. 1. The binding of Ach and depolarization of the postsynaptic membrane. The release of the Neurotransmitter depolarizes the presynaptic membrane causing the brief opening of the Calcium channels that allows extracellular calcium ions to enter the synaptic knob. Their arrival triggers the release of ACh through exocytosis. The binding of Ach and depolarization of the postsynaptic membrane. The binding of Ach to sodium channels causes them to open and allows sodium ions to enter. If the resulting depolarization of the postsynaptic membrane reaches threshold, an action potential is produced. (Source: Katzung et al Basic and Clinical Pharmacology, McGrawHill, 2009 copyright).
Most medications whether they are natural or not do not alter the long-term progress of Alzheimer's disease, but have been shown to delay the time to institutionalization, which may be cost-effective. Medications should be discontinued when dementia becomes unresponsive to therapy and progressively severe, as the efficacy of these agents diminishes due to loss of intact cholinergic neurons.
Fig. 2. Sites of drug action. (Source: Katzung et al Basic and Clinical Pharmacology, McGrawHill, 2009 copyright).
Mutations in several genes have been associated with the development of Alzheimer's disease (AD). Firstly, mutated APP, which codes for the Amyloid precursor protein normally involved in the formation of neurons, can lead to the production of amyloid beta peptide. (Ulbricht and Seamon, 2010). When these proteins are released from the cells, they accumulate in the brain and form amyloid plaques characteristic of AD. There are more than 25 various mutations that exist for APP, and they may all lead to neuronal death and progression of the disease. Additionally, PS1, which codes for presenilin 1 protein, plays a crucial role in metabolizing membrane and secretory proteins, can be mutated and disrupt normal brain functioning. (Naruse, 1998). Mutation of PS2, which codes for presenilin 2 and is normally involved in the apoptosis process, can lead to a toxic buildup of amyloid beta peptide characteristic of the disease. Due to the attribution of the development of AD to specified genes, in the future genetic testing may be used as a diagnostic tool for AD.
As AD is a progressive disease, detection of the mutated genes early-on in its course may assist in disease management. Some have projected using blood tests to detect Beta amyloid, though it remains to be reviewed by the FDA. (Kolata, 2011). The results of testing may lead the patient to reflect on the options that are available to him to help delay disease onset and promote health. (Beery and Williams, 2007). As it is easily accessible and far less expensive than Western drugs, patients may rely on self-treatment with complementary and alternative medicine to help maintain cognition. There is currently a variety of natural products available to help improve memory and cognition, many of which have been proven to be efficacious in preventing decline of the disease. (Ulbricht and Seamon, 2010). Controlling the disease at an early stage may have implications on the payers involved, and result in cost savings in the long-run.
Fig. 3. The production of Beta amyloid plaque. (Source: http://ghr.nlm.nih.gov/gene/APP).
Natural products useful in the management of Alzheimer's disease
Natural Products are described as areas of CAM that include a variety of herbal medicines (also known as botanicals), vitamins, and minerals. Herbal or botanic medicines reflect some of the first attempts to improve human condition. Interest in and use of CAM natural products have grown considerably in the past few decades. The concept that the mind is important in the treatment of illness is integral to the healing approaches of traditional Chinese medicine as well as Ayurvedic medicine, which is a whole medical system that originated in India. It aims to integrate the body, mind, and spirit to prevent and treat disease. Therapies used include herbs, massage, and yoga. While there are many theories about what exactly causes the cognitive defects associated with Alzheimer's disease, different treatments target different theories. The goal of treatment is usually to decrease symptoms, improve functioning, and delay the progression of the disease (Williams et. al., 2011). People who show no significant improvement when taking conventional drugs may benefit from NCAM.
Bacopa, also known as Brahmi, is an Ayurvedic herb that has been used for centuries to aid in learning. It is considered a nootropic agent, a class of agents that improve cognition, since it aids in regenerating neural tissue. It also alters and improves acetylcholine and glutamate levels in addition to modulating muscarinic receptor binding.(Ulbricht and Seamon, 2010). Numerous mechanisms of action have been proposed for Bacopa to help in managing Alzheimer's, characterized by the loss of cholinergic activity in hippocampus. Firstly, studies show that it can restore frontal and cortical muscarinic and cholinergic receptor activity, thereby improving the mental quotient, memory span and concentration abilities of demented individuals. Additionally, Bacopa improves protein activity and synthesis, especially in the brain cells. These are important properties needed for intelligence, memory, learning, grasping power and the sharpening of short and long-term memory.
Fig. 4. Location and Function of mGluRs. (Source: Katzung et al Basic and Clinical Pharmacology, McGrawHill, 2009 copyright)
Bacopa has also showed to have important antioxidant activity in many brain parts including the hippocampus, striatum and frontal cortex, which suppresses neuronal oxidative stress. By scavenging free radicals, which removes dangerous byproducts, it can potentially improve mental deficiencies, Alzheimer's disease, learning skills, and anxiety. It may also have protective effects against DNA damage in astrocytes and fibroblast cells. This suggests that it has an important role in AD and may be useful in delaying the progression of this disease to an extent.
Melatonin (N-acetyl-5-methoxytrypamine) is a natural non-toxic neurohormone endogenously produced by the pineal gland. Unfortunately, melatonin secretion and synthesis declines sharply with age and is profoundly decreased in age-matched AD patients, especially AD patients who are homozygous for APOE4. Melatonin provides mitochondrial support by significantly inhibiting the formation of neurotoxic amyloid ß-sheets indicating a possible preventative benefit. Melatonin acts as an antioxidant through endogenous electron donation, which does not have the same potential for a pro-oxidant side effect. In a study conducted in identical twins, one of the twins was given 6mg while the other twin was not given melatonin. This study showed that after 36 months the melatonin-treated patient had less memory loss. (Brusco et al., 1998). Another study that consisted of 10 patients with mild cognitive impairment showed great mood and memory improvement after six days of 6mg daily melatonin consumption. (Jean-Louis et al., 1998).
Ginkgo biloba is a Chinese medicine that has been extracted from leaves of the ginkgo biloba tree and is believed to have multiple effects which improve brain function. Ginkgo contains flavonoid and terpenoids constituents that serve as free radical scavengers and have been shown to reduce oxidative stress in human models. (Ulbricht and Seaman, 2010). There is some evidence that ginkgo inhibits the formation of beta-amyloid, a protein that forms amyloid plaques in the brains of people with Alzheimer's disease. Ginkgo biloba may increase cerebral circulation and protect the brain against age-related losses of cholinergic neurons in addition to increasing the uptake of acetylcholine in the hippocampus.
Fig. 5. Ginkgo biloba tree (source: http://nccam.nih.gov/)
When used orally and appropriately, ginkgo leaf extracts have been used safely in trials lasting from several weeks to up to 6 years. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia was conducted in the USA to assess the efficacy and safety of ginkgo extract in Alzheimer disease and multi-infarct dementia. The 52-week parallel-group multicenter study analyzed mildly to severely demented outpatients with Alzheimer disease or multi-infarct dementia, without other significant medical conditions. Patients were assigned randomly to treatment with the ginkgo exact of 120 mg/d or placebo. From the 309 patients included in an intent-to-treat analysis, 202 provided valuable data for the 52-week end point analysis. In the intent-to-treat analysis, the ginkgo extract group had an ADAS-Cog score 1.4 points better than the placebo group (P=.04) and a GERRI score 0.14 points better than the placebo group (P=.004). The same patterns were observed with the evaluable data set in which 27% of patients treated with ginkgo extract achieved at least a 4-point improvement on the ADAS-Cog, compared with 14% taking placebo (P=.005); on the GERRI, 37% were considered improved with the ginkgo extract, compared with 23% taking placebo (P=.003). No difference was seen in the CGIC. (Le Bars et al., 1997).
Ginseng is an herb and of which several of its components have been used for millennia for the treatment of a variety of conditions including age-related memory decline. American ginseng is a neurological protestant; it improves memory and learning and has been shown to improve ADHD.Â
American ginseng extract has been shown to improve brainstem neuronal activities, free radical quenching activity and cerebral circulation, which contribute to its neuro-protective and anti-aging effects. Orally, American ginseng is used as an adaptogen, for increasing resistance to environmental stress, as a general tonic, preventing the effects of aging and improving stamina. Research suggests that the applicable part of American ginseng is the root. American ginseng contains triterpene saponins, more commonly called ginsenosides. The six most abundant ginsenosides in American ginseng are Rb1, Rb2, Rc, Rd, Re, and Rg1. American ginseng contains higher amounts of Rb1, Re, Rc, and Rd relative to other ginsengs, and lesser amounts of Rb2 and Rg1. Rb1 and Rg1 in ginseng root may modulate acetylcholine release and reuptake and the number of choline uptake sites, especially in the hippocampus. They also increase choline acetyltransferase levels in rodent brains (Ulbricht and Seaman, 2010).
Fig. 6. Ginseng. (source: USDA, NRCS. The PLANTS Database http://plants.usda.gov, 2011 copyright).
When used orally and appropriately over short-term, American ginseng has been safely used for up to 4 weeks. In a randomized, double-blind, placebo-controlled, crossover trial (N = 32, healthy young adults) the acute mood, neurocognitive and glycemic effects of three doses (100, 200 400 mg) of Cereboost (P. quinquefolius standardised to 10.65% ginsenosides) were assessed. The result was that there was a significant improvement of working memory (WM) performance associated with P. quinquefolius. Corsi block performance was improved by all doses at all testing times. There were differential effects of all doses on other WM tasks which were maintained across the testing day. Choice reaction time accuracy and 'calmness' were significantly improved by 100 mg. The preliminary study conclusion identified robust working memory enhancement following administration of American ginseng. These effects are distinct from those of Asian ginseng and suggest that psychopharmacological properties depend critically on ginsenoside profiles. These results have ramifications for the psychopharmacology of herbal extracts and merit further study using different dosing regimens and in populations where cognition is fragile.
Ubiquinone, also known as Coenzyme Q-10, is a coenzyme that is made naturally in the body and is essential for mitochondrial energy production. Studies have shown that levels of CoQ10 are altered in Alzheimer's disease and that brain energy levels are dramatically reduced in dementia-related diseases. Therefore, it is helpful in the treatment of a variety of neurodegenerative diseases such as Alzheimer's. As an antioxidant, CoQ10 neutralizes harmful free radicals, thereby alleviating Alzheimers manifestations (Boo et al., 2009). CoQ10 can be used as a part of a comprehensive, integrative approach (along with vitamins B, E, and K, and lipoic acid) to improve mitochondrial function in Alzheimer's disease. In one animal study, CoQ10 counteracted mitochondrial deficiencies in rats that had been treated with beta-amyloid and also destabilized amyloid plaques.
CoQ10 may have other neuroprotective qualities such as the reduction of apoptosis, extension of life, reduction of brain atrophy, promotion of energy production, and protection of ischemia. It has been found to be safe and well tolerated at doses as high as 3600mg/day, even though maximum plasma levels are reached at a dose of 2400mg/day. (Young et al., 2007). A two year double blinded study was performed to evaluate its efficacy on 450 mild to moderate AD patients given a synthetic variant of CoQ called Idebenone at 90 and 120 mg doses. Both showed great improvement from the placebo group, yet the higher dose group was associated with improved outcomes. (Gutzman et al., 1998). Another randomized, double-blinded, placebo-controlled study conducted in 300 mild to moderate AD patients done over a six month period, comparing tehh efficacy of 30 and 90 mg doses of idebenone. This showed that patients who took 90mg of idebenone performed better on various cognitive tests compared to the placebo group. (Weyer et al., 2003).
The alkaloid Huperzine was extracted from a club moss called Huperzia serrata. It has originally been used in Chinese folk medicine to treat a variety of conditions and has been approved for use for the symptomatic treatment of Alzheimer's disease in China. Significant effects were noted in AD patients, both in terms of quality of life and memory retrieval. This is due to the fact that it shows high specificity towards acetylcholinesterase (AChE) and potently inhibits it, while at the same time lacks potentially complicating muscarinic effects. (Figure 1). (Kozikowski and Tuckmantel, 1999). It has higher oral bioavailability and penetrates the blood brain barrier more easily than other AChE inhibitors. (Drugs in R&D). Following oral administration of huperzine, acetylcholine (Ach) levels increase in the frontal and parietal cortex, which may constitute a therapeutic advantage since that is precisely the anatomical location where Ach is lacking in patients with Alzheimer's disease. (Wang et al., 2006).
Fig. 7. Huperzia Serrata moss plant. (source: USDA, NRCS. The PLANTS Database http://plants.usda.gov, 2011 copyright).
Adding on a new dimension, it has also been demonstrated that huperzine may prevent neuronal cell death caused by glutamate, a neurotransmitter that plays an important role in memory and learning. The neurons found in AD patients' brains may be deprived of glucose, leading to glutamate overstimulation, which causes calcium influx and subsequent cell death. (Kozikowski and Tuckmantel, 1999). Huperzine may also antagonize the N-methyl D-aspartate (NMDA) receptor, which binds glutamate and is involved in synaptic plasticity. (Haviv et al, 2007). In rat studies, huperzine has shown to decrease the level of lipid peroxidation and increase antioxidant activity. By inhibiting the formation of reactive oxidative species, it may possess anti-apoptotic properties. (Wang et al., 2006).
In a placebo-controlled, double-blind 202 person randomized trial conducted in China, huperzine A was found to be safe and efficacious in the management of Alzheimers. One hundred participants were in the huperzine group, who received 400 micrograms of the product per day for 12 weeks, while the placebo group, which contained 102 participants, received the placebo once daily. In comparison with baseline data, there was a 4.6 point improvement in cognition, as assessed by the ADAS-cog test in the huperzine group. (p=0.00). There was also a 2.4 point increase in the ability to execute activities of daily living (ADL) with a 10-32% increase in the huperzine group. (p=0.001). (Zhang et al. 2002). A meta-analysis of four randomized trials displayed that oral administration of huperzine A led to significant improvements in ADL and mini-mental state examination (MMSE). In all, huperzine has shown to be well-tolerated and effective in the improvement of cognition and ADL. (Wang et al, 2009).
Huperzine and the food supply chain
Since huperzine A was studied and produced in China, its quality and applicability standards may not be up to par with that of more developed countries, rendering it as part of the food supply chain. Though it has been approved for use by Chinese agencies, there may be safety concerns when importing it to another country. The World Trade Organization (WTO) has instituted sanitary and phytosanitary (SPS) measures that allows for international harmonization and safe food trade. (Aruoma, 2008). The adoption of these practices may result in the use of more foreign natural products, especially those that aid in treating diseases such as AD.
They involve the action of various stimuli on muscles, nerves or sensory end organ, and evoke an activity. They include cognitive training, physical exercise and socialization, and have been shown to facilitate cognitive functioning (Wollen, 2010). Research has shown increased recognition and use of psychosocial interventions for dementia resulted in an increase in high-quality research and restrictions in the use of drug therapies for Alzheimer's disease in the UK. (Spector et al., 2009). Cognitive stimulation therapy (CST) uses a brief group treatment for people with mild-to-moderate dementia, based on the theoretical concepts of reality orientation and cognitive stimulation. The therapy consisted of 14 sessions of themed activities twice a week over a 7-week period in a multicenter, randomized controlled trial. There were significant benefits in cognition and participant-rated quality of life when compared CST versus no treatment. These benefits in cognition were also compared to those gained through medication, and they proved to be cost-effective.
AD and Physical exercise
Physical exercise increases blood supply to the brain and regulates chemicals such as insulin that are necessary for a healthy brain functioning (Wollen, 2010). In a recent review of studies on exercise, learning and memory were improved. Vascular function and metabolism also improved. There was a reduction in inflammation and an elevation of mood and age related memory loss. Information processing, brain volume, synaptic plasticity increased as well as increases in brain -derived neurotrophic factor and dendritic spines. Exercise aided neurogenesis and enhanced the glutamatergic system while reducing cell death (Wollen, 2010).
In an article by Arkin, 2007, 24 mild- to moderate-stage Alzheimer's disease patients (AD Rehab group) were evaluated through socialization. Socialization experiences consisted of supervised volunteer work and cultural or recreational activities. Changes in global functioning and neuropsychological test performance were tracked and compared to those of a similar group of untreated patients from the Consortium for the Establishment of a Registry for Alzheimer's Disease (CERAD). A measure of global functioning on 5 or 6 of the cognitive and language measures were compared with the CERAD sample. The results showed a slower rate of decline for the AD Rehab group. Psychological factors that might either improve or worsen AD have generally been overlooked because the emphasis has been on medications to threat the problem (Wollen, 2010). However, it has been estimated that less than 20 percent of AD patients have moderate response to approved drugs and that they offer little or no neuroprotection. They are effective only for a short period and produce serious side effects as well as being expensive. (Arkin, 2007).
Increases blood to brain; improves vascular function; aids sleep; reduces inflammation; elevates mood; increases brain volume; increases synaptic plasticity; aids neurogenesis; reduces cell death; benefits some cognitive processes.
None if done within one's physical capabilities; little research specifically on AD patients.
Improves many cognitive functions
More research indicated
Preserves cognitive functioning; may improve mood
Table 1. Comparative advantages and disadvantages of the various stimulatory therapies for patients with AD. (Arkin, 2007).
As there is a limited quantity and effectiveness of pharmaceutical agents available for the treatment of AD, and the prevalence of AD is on the rise, especially in elderly population, there is an increasing need for the utilization of natural products and alternative therapies to help manage this condition. While bacopa, melatonin, gingko, ginseng, and coenzyme Q10 have all been shown to improve memory in a relatively safe fashion, future studies are necessary to assess their efficacy in AD in particular. In light of the fact that HupA has been used for centuries in Chinese folk medicine successfully, the molecule definitely has potential for use in patients with various memory disorders. Furthermore, stimulatory therapies, which are relatively harmless, can enhance memory, and is recommended to be incorporated into the regimen of individuals with memory impairment.
Exercising the use of alternative medicine remains an integral part of medical decision making, and is ultimately the choice of the patient and his or her caretakers. Potential risks versus benefits should be weighed and discussed with health care providers prior to integrating the use of complementary and alternative medicine. Ideally, it would be preferable to consider genetic factors, the extent of neurochemical dysfunction, as well as other comorbidities when tailoring individualized therapy for a patient. Though future research is still necessary in regard to the integration of non-conventional medicine in treatment of AD, familiarity with the multiple options available can optimally guide patient therapy, resulting in improved health outcomes.