Abstract: Alzheimer’s Disease (AD) is the most common cause of dementia worldwide, characterized as a progressive and irreversible neurodegenerative disease. It is probably caused by complex interactions among multiple genetic, epigenetic and environmental factors. The pathophysiology of AD is largely represented by the neurotoxic events triggered by the proteins like β-amyloid cascade and the hyper phosphorylation of microtubule associated tau proteins and other copathogens in neurons. These processes lead respectively to the formation of neurotic plaques and neurofibrillary tangles which are the pathological hallmarks of the disease. Last 20 years extensive study was done to search (through the internet, books, journals and software’s) available data to elaborate the current update on Alzheimer’s disease. The available data related to etiology, pathophysiology, molecular pathway, traditional cure and available treatment of AD were discussed throughout this study. This study will provide an enough data to various academicians regarding current pharmacological, non-pharmacological interventions, ethnopharmacological treatments and other relevant data related to AD. Due to in availability of proper cure for this disorder and much of the treatment available has been able only delay the progression of the disease or provide symptomatic relief for a short period of time. So much more targeted approach should be discovered to resolve the complications. Arise due to tau proteins and further study on amyloids in underway.
INTRODUCTION
Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder scientifically categorised as change in cognition and impairment of memory leads to difficulties in day to day working1. Alzheimer’s disease is the most common form of dementia in the last 60 years. The percentage of persons with Alzheimer disease has been recorded by a factor of two fold increase every 5 years of age, so, it may be frequent as the person gets old. By 2050, the number of cases in US2 is predicted to rise to13.2 million. An IndoUS studies assessed prevalence of Alzheimer disease in a settingof rural India. Few health care systems will be able to cope with this development. These review highlights of the most informative developments in AD study and raises major unresolved issues.
The cognition decline in AD is directly proportional to loss of neurons in specific brain regions3. Although, AD clearly causes loss of neurons in specific brain regions (e.g., of pyramidal cells in lamina II of the entorthinal cortex and in the CA1 region of the campus) much of the overall loss of brain volume appears to be due to the shrinkage, loss of brain volume appears to be due to the shrinkage and loss of neuronal processes. Progressive decreases in cortical thickness can be detected in multiple brain regions by brain Magnetic Resonance Imaging (MRI) in AD patients, correlate with the cognitive decline and predict conversion from Mild Cognitive Impairment (MCI) to AD4,5. The introduction of functional MRI (fMRI) in AD has revealed the alteration in neuronal activities or decreases the risk of disease prognosis in patients. The change in connectivity will remain in default mode due to hyperactivation of the hippocampus during execution of memory tasks5,6.
Another reason is to overstimulation of specific neuronal populations which is so called excitotoxicity and neurodegeneration in AD and related conditions. It is interesting in this regard that AD is associated with an increased incidence of epileptic seizures which is most evident in patients with early-onset forms of the disease7.
Loss of synapses and dendritic spines correlates better with the cognitive decline in AD than loss of neurons8. The different neuronal cultures showed the synaptodendritic refraction and found same with transgenic mice when exposed to AD causing factors9 (Fig. 1).
Taken together, these studies suggest that aberrant neural network activity, dysfunction and loss of synapses and degeneration of specific neuronal population are the main substrates of cognition decline in AD.
| Fig. 1: | Multifactorial basis of Alzheimer’s disease pathogenesis |
As outlined below, it is likely that these abnormalities are caused by copathogenic interactions among diverse factors and pathways (Fig. 1).
Multifactorial etiology of AD: The AD is very likely caused by complex interactions among multiple genetic, epigenetic and environmental factors.
Genetic factor’s mutations in three genes-amyloid precursor protein (APP): Presenilin PS1 and PS2 cause early-onset (<60 years) Autosomal dominant AD10 which probably accounts for less than 1% of AD cases11. Then mutations affect processing of APP which leads to altered production of different Aβ peptides and their ratio10. Down’s syndrome patients carrying an extra copy of chromosome 21 on which the APP gene resides, develop early-onset dementia with pathological hallmarks of AD in their brains12, consistent with the idea that over expression of APP cause early-onset AD. Moreover, increased APP gene expression caused by genetic variations on the promoter sequence may be a risk factor for late-onset AD with levels of APP expression correlating inversely with age of disease onset13.
Apolipoprotein (Apo) E4: It (used here to refer to either the ApoE ε4 allele or the protein it encodes) has been genetically linked to late-onset (>60 years) familial and sporadic AD which accounts for most AD cases and has a gene-dose effect on increasing the risk and lowering the age of onset of the disease14,15. Recent genome-wide association studies (GWASs) identified that ApoE4 is a major gene associated with the age-related cognitive decline in humans16 which is in line with a longitudinal study showing that age-related memory decline in non-demented ApoE4n carriers diverges from that of non-demented non carriers before the age of 60 years17. Thus, ApoE4’s detrimental effect on cognition occurs before the typical signs of AD arise. In contrast, ApoE2 may protect against AD in some populations15.
Epigenetic factor: Epigenetic mechanism may also play a role in AD pathogenesis18. Studies on human post-mortem brain samples and peripheral leukocytes as well as transgenic animal models have shown that aging and AD are associated with epigenetic dysregulation at various levels including abnormal DNA methylation and histone modifications19. Pharmacological inhibition of DNA methylation in the hippocampus after learning task impaired memory consolidation in mice18 and promotion of histone acetylation improved learning and memory in a mouse model of AD and increased learning-related gene expression in aged wild-type mice20,21, suggesting epigenetic regulation of learning and memory in health and memory in health and disease.
Environmental factor: Aging is the most important known non genetic risk factor for late-onset AD. Potential environmental risk factors for late-onset AD include head injury, low educational levels, hyperlipidaemia, hypertension, homocystinemia, diabetes mellitus and obesity22-25.
Pathophysiology and therapeutic targets for treatment of AD
Aβ and Other APP products: The Aβ peptides derived from APP are the main constituent of amyloid plaques26,27. Over expression of APP in humans through duplication of its gene or trisomy of chromosome 21 causes early-onset of AD28. The catalytic subunit of the γ-secretase protein complex that releases Aβ peptide from its precursor is formed by PS1 or PS2. Autosomal dominant mutations in APP, PS1 or PS2 that alter APP processing and the production or self-aggregation and accumulation of Aβ, promoting aggregation and accumulation of Aβ in the brain causes early-onset AD10. Neural expression of mutant human APP (hAPP) either alone or in combination with mutant PS1 in transgenic rodents causes several AD like alterations which is explained below29-32. The immediate early gene arc which directly binds to PS1 to regulate γ-secretase trafficking is required for neuronal activity-dependent Aβ production33. Results obtained in diverse experimental models suggest that insoluble Aβ fibrils found in amyloid plaques and monomeric Aβ are less pathogenic than soluble, nonfibrillar assemblies of Aβ such as Aβ dimers, trimers and larger oligomers.
ApoE4: The major impact of ApoE4 on AD risk is clearly not understood and less attention, it has received in the field as compared to APP, Aβ, tau and inflammation. The ApoE4 was identified as a genetic risk factor for AD, in vitro and in vivo studies have explored its structural properties and functions in neurobiology, its cellular source-dependent physiological and pathophysiological activities within the brain and its Aβ-dependent and independent roles in AD pathogenesis.
ApoE: Polymorphisms and functions in neurobiology: The ApoE is a polymorphic protein with an important and diverse role in neurobiology. It occurs in three common isoforms (ApoE2, ApoE3 and ApoE4) in humans and differs from one another by single-amino acid substitution9,34-36. The ApoE3 stimulates the neurite outgrowth and ApoE4 inhibits it34-36. In addition, ApoE modulates glutamate receptor recycling in neurons with ApoE3 stimulating and ApoE4 inhibiting this process37.
Cellular source-dependent roles of ApoE4 in AD: Pathogenesis cellular derived ApoE has distinct roles in both physiological and pathophysiological pathways34-36. Astrocytes have long been recognized as the primary source of ApoE in the brain and expression of ApoE in astrocytes is increased during aging and in response to estrogen and activation of liver X receptor or NF-κB34-36. In vitro and in vivo studies suggest that astrocyte-derived ApoE has isoform-specific effects on Aβ clearance or deposition38, a neurite outgrowth39 and behavioural performance.
Aβ-dependent roles of ApoE4 in AD: Pathogenesis in vivo, ApoE is associated with amyloid plaques and in vitro lipid-free ApoE3 and ApoE4 can form stable complexes with Aβ Peptides, with ApoE4 forming complexes more rapidly and effectively34,38. Studies in ApoE-deficient mice expressing mutant hAPP demonstrate that ApoE is actually required for the formation of fibrillar amyloid plaques. In hAPP transgenic mice, human ApoE stimulates Aβ clearance. The ApoE2 and ApoE3 clear more Aβ than ApoE440,41 which may be related to ApoE isoform-dependent effects on astroglial degradation of Aβ deposits. A recent study demonstrated that C-terminally truncated ApoE4 which is found in AD brains, inefficiently clears Aβ and acts in concert with Aβ to elicit neuronal and deficit in transgenic mice42.
Aβ-independent roles of ApoE4 in AD: Pathogenesis in addition, neural stem cells in adult mice express ApoE and ApoE4 impairs adult hippocampal neurogenesis which might also contribute to ApoE4-associated learning and memory deficit. Since, there is no Aβ accumulation in any of these ApoE4 mouse models, these data strongly suggest an Aβ-independent role of ApoE4 in causing a neuronal and behavioural deficit in vivo43,44.
ApoE4-induced impairment of GABAergic interneurons: The ApoE4 knock in mice show an age-dependent decrease in hilar GABAergic interneurons which correlates with the extent of ApoE4-induced impairments of adult hippocampal neurogenesis and with learning and memory deficits. Dysfunction of the GABAergic system may also contribute to cognitive impairment in humans. The AD patients have decreased GABA and somatostatin levels in the brain and CSF and these alterations are more severe in ApoE4 carriers45.
Tau and other copathogens AD: It is associated not only with the abnormal accumulation of amyloid plaques but also with that of NFTs. The NFTs form intracellularly and are made up of primarily of aggregated tau bearing abnormal posttranslational modifications, including increased phosphorylation and acetylation46-48. Tau function primarily to stabilize the microtubules and that are an aggregation in AD causes deficits through a loss-of-function mechanism49. When it is abnormally modified and assumes pathogenic confirmations, tau becomes enriched in dendritic spines where it can interfere with neurotransmission50. Interestingly, tau reduction prevents Aβ from causing a neuronal deficit in cell culture and hAPP transgenic mice49. Thus, while Aβ acts upstream of tau, its adverse effects depend in part on tau. Moreover, tau reduction also prevents ApoE4-dependent neuronal deficits in vitro and in vivo45, pinpointing tau as a key mediator or enabler of both Aβ and ApoE4-dependent pathogenesis.
Approaches for treatment of AD
Approved drugs
Acetyl cholinesterase inhibitors (AChEIs): Degeneration of cholinergic neurons and decrease in Ach levels in neocortex, hippocampus and basal forebrain plays a major role in the pathophysiology of AD. Various therapeutic approaches are proposed to elevate cholinergic transmission like increasing the amount of ACh precursors, blocking hydrolysis with AchE inhibitors, stimulating nicotinic and muscarinic receptors or using or using cholinomimetic substances. Animal and human data suggest that AchEI is the most efficacious drugs for increasing Ach levels in brain and ameliorating symptoms of AD51. The AchEIs are approved for the treatment of mild to moderate AD52.
The AchEIs include donepezil, rivastigmine, galantamine and tacrine-all approved by the U.S. Food and Drug Administration (FDA) for treating AD. The AchEIs have a modest beneficial effect on cognition and memory53 (Table 1).
DonepezilIs: A reversible inhibitor of AchE with a long plasma half-life of 70 h. It is not hepatotoxic54. In vitro studies show that donepezil offers neuro protection by reducing glutamate excitotoxicity, diminishing βA toxicity and consequently increasing cell longevity55. Donepezil show atrophy of the hippocampus in humans which suggests a neuroprotective effect56.
Rivastigmine: It is a reversible AChEI with higher affinity for brain Ach than peripheral Ach. It inhibits both butyrylcholinesterase and AchE57. It has a plasma half-life of 2 h. Rivastigmine is started at a dose of 1.5 mg BD, then increase to a maximum dose of 6 mg BD. Rivastigmine has demonstrated significant treatment effect on the cognitive (thinking and memory), functional (activities of daily living) and behavioural problems that are commonly associated with AD58.
| Table 1: | Clinical pharmacology of cholinesterase inhibitors useful for reducing the signs of Dementia51-55 |
Galantamine: It is a reversible and selective AChEI having 50 times more selectivity for human AchE than for human butyrylcholinesterase. Galantamine also acts as a nicotinic receptor agonist in the brain59. In an animal model, galantamine also increased dopaminergic neurotransmission in the hippocampus60, a brain area and particularly important in memory. A Meta-analysis of 10 randomized, placebo-controlled, double-blind studies concluded that galantamine either improved or prevented the decline of cognition and activities of daily living61.
NMDA receptor antagonist: Glutamate is an excitatory neurotransmitter and acts on a variety of receptors. The NMDA is one such receptor. The NMDA receptor on activation causes potentiating of neuronal activity but in AD, excessive glutamatergic excitotoxicity causes apoptotic cell death and defects in cognition and memory62.
Memantine: An NMDA receptor antagonist has been recently approved by FDA for the treatment of moderate to severe AD, it is found to interfere with the glutamate excitotoxicity63. A study reviews the molecular mechanism of memantine action and the basis for memantine used in AD. Excitotoxic cell death is mediated by over activation on NMDA glutamate receptors which results in excessive ca2+ influx through the receptor associated in the channel. Memantine acts as an uncompetitive and low affinity open channel blocker.
Experimental drugs
Immunization
Anti-amyloid therapy: Anti-amyloid strategies comprise pharmaceutical compounds with distinct mechanisms of action, namely drugs that (i) Facilitate the clearance, (ii) Inhibit the production and (iii) Prevent the aggregation of Aβ64. Many pharmacological compounds have been developed to tackle the "amyloid cascade" with the prospect of reducing the Aβ burden in the brain of mild to moderately demented AD patients65 (Fig. 2, Table 2).
Classification of anti-amyloid therapy: Both active and passive immunization targets the reduction of intracerebral of Aβ load by eliciting humoral response against the Aβ peptide, facilitating its clearance from the brain by immune-mediated mechanisms76. Highly encouraging findings were presented by preclinical studies with transgenic mice with high Aβ load, submitted to active and passive immunization; these strategies proved effective reducing the amount of Aβ in the mouse brain which was supposedly associated with improvements on behaviour and cognition (Fig. 3).
| Fig. 2: | Stages of (Aβ) β-amyloid production with possible targets for treatment44 |
| Table 2: | List of compounds used to target the β-amyloid and act as anti-beta-amyloid treatment in AD |
| DAPT: [N-(3, 5-Diflourophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester | |
First generation of immunotherapeutic agents for AD: These agents were based on the active immunization of AD patients with the actual Aβ peptide77. Therefore, this strategy induces an IgM response to generate antibodies against pathogenic Aβ which further mobilize microglia to clean plaques through phagocytosis64,76. Also, the immune response prevents Aβ deposition by removing the excess of soluble Aβ forms from the circulation76.
Second generation of active anti-Aβ Immunotherapeutic agent: It was designed to minimize the risk of eliciting such secondary inflammatory responses or vasogenic oedema by stimulating soluble Aβ derivate immunogens. These vaccines elicit the immune response to raise antibodies against Aβ monomers and oligomers. Studies with the vaccine CAD 106 at phase 1 indicated that it was able to reduce Aβ accumulation in cortical and subcortical brain regions by binding to Aβ aggregates and blocking cellular toxicity with no evidence of micro haemorrhage, vasogenic oedema or inflammatory reactions subsequent to activation of T-cells67. Conversely, passive immunotherapy is based on the intravenous administration of full monoclonal antibodies or antibody fragments from specific exogenous origins which directly target Aβ64.
Several passive immunotherapeutic agents have been evaluated by RCTs over the past years, namely bapinuzumab, solanezumab, gentenerumab, ponezumab and crenezumab. These monoclonal antibodies have high affinity to antigenic determinant epitopes of Aβ, binding either to soluble forms or in plaques, being further recognized by B and T-cells to promote its clearance from the brain.
| Fig. 3: | Stages of anti-amyloid therapy64,76 |
In addition, monoclonal antibodies may delay Aβ burden or stop its accumulation within the brain70,77.
Other anti-amyloid strategies have been addressed by clinical trials: Preliminary studies support that the production and accumulation of Aβ. It can be down regulated by the specific γ-secretase inhibitor's like avagacestat and semagacestat69,71.
Semagacestat: A non-selective γ-secretase inhibitor has been examined as potential treatment for AD patients78. Unfortunately, preliminary results showed no efficacy.
Avagacestat: It has been considered as a potentially inhibitor of Ab40 and Ab42 formation with selectivity for effects on APP relative to Notch proteins which interfere with cell proliferation, differentiation and apoptosis. In a study enrolling healthy subjects, this compound exerted a potent selective γ-secretase inhibition with decreased CSF Ab levels as well as the inhibition of the human notch proteins79.
Inhibition of β-secretase: It is another potential mechanism of disease modification in AD given the major role of this enzyme in the amyloidogenic cleavage of the Amyloid Precursor Protein (APP). The BACE-1 (β-site amyloid precursor protein cleaving enzyme 1) produces two peptides (Aβ40 and Aβ42) and its inhibition with specific compounds precludes the excess of amyloid and its accumulation into plaques80.
An inhibitor of β-secretase (GRL-8234) was recently investigated in young transgenic mice with decreased soluble β-amyloid in the brain tissue and with rescued behaviour performance72.
Tau-oriented strategies: Its critical role in pathogenesis of AD, drug development may also target the production, processing (phosphorylation) and aggregation of Tau protein81 (Table 3).
Nicotinic receptor agonist: Another approach to enhance cholinergic function is to administer nicotinic receptor type’s α4β2 and α7 are localized in areas of the brain associated with dementia and memory loss.
| Table 3: | Different drugs which act through tau oriented strategies in AD |
A selective partial α7 nicotinic receptor agonist 4 OH-GTS-21 is shown to have protective action on cholinergic neurons but not protective for the amyloid over expressing transgenic mice84. A study reported that chronic treatment with RJR-2403 and 17β-estradiol had marked antiamnesic effect in middle-aged ovariectomized rats with experimental Alzheimer type dementia85. A novel compound α-7 nicotinic receptor agonist EVP-6124 is currently in phase II (www.clinicaltrials.gov/NCT01073228). More study is needed to unravel the full potential of nicotinic Ach agonists.
PPAR γ agonists: Peroxisome Proliferator Activated Receptors (PPAR) are a family of nuclear receptors and play an important role in lipid peroxidation, cellular proliferation and differentiation86. The PPAR γ agonists inhibit inflammatory gene expression, alter Aβ homeostasis and exhibit neuroprotective effects87. They also induce apoptotic cell death in glioma cells. A study demonstrated the effect of 15-30 mg of pioglitazone daily in patients with mild AD. The pioglitazone group improved agitation and regional cerebral blood flow in the parietal lobe. The study demonstrated that pioglitazone exhibited cognitive and functional improvement88. It may offer a novel strategy to the already existing treatment paradigm. However, several issues like metabolic effects, genomic effects of PPAR γ agonists need to be addressed.
Antihypertensive drugs
Angiotensin-converting enzyme inhibitors (ACEIs): This reduced inflammation and mental decline in AD patients89 by 50%. Mild-to-moderate AD subjects with blood pressure had a fewer cognitive decline when given an ACE inhibitor that crossed blood-brain barrier (perindopril or captopril) than when given an ACE inhibitor that did not (enalpril or imidapril) or a calcium-channel blocker (nifedipine or nilvadipine)90. A recent study confirmed that ACEIs slow the progression of AD91.
Angiotensin receptor blockers: These block the action of angiotensin II by binding at AT1 receptor sites. They have been reported to reduce AD risk and slow its progression92.
Calcium channel blockers: This is another category of antihypertensive drugs. It may be that β-amyloid, mutations in presenilin proteins or other factors open channel that permit calcium to enter and damage cells93. If so, calcium-channel blockers might be expected to benefit AD patients.
Anti-inflammatory drugs (NSAIDs): Alzheimer’s disease is characterized by neurotic plaques and neurofibrillary tangles. Along with them, there is also evidence of inflammation in the form of cytokines and microglial activation94,95. These observations led to a series of clinical trials with NSAIDs to ascertain their role in Alzheimer’s disease. The mechanism by which NSAIDs affect the pathology of AD is by inhibition of cytokines, decreased platelet aggregation and decrease release of factors which prevent free-radical damage94. A recently published study has tested the effect of NSAID use for more than 5 years on AD. It reported that long-term use of NSAIDs was protective against AD. Maximum effect was seen with the use of Ibuprofen96. The drug treatment reduced the expression of the proinflammatory enzyme COX-2 and iNOS and β-secretase97. Two other studies also demonstrate that ibuprofen reduces microglial activation and cytokine production in transgenic mice over expressing APP98.
Hormones: Insulin has many roles in normal cell functioning. Nasal administration of insulin improved several cognitive measures in subjects with early AD or mild cognitive impairment. Nasal administration allows insulin to reach the brain quickly without affecting insulin levels elsewhere in the body. Nasal administration has also improved verbal memory but only for persons with a specific genetic makeup (apolipoprotein E4 [ApoE ε4] allele)99. Insulin resistance can affect the brain as well as other organs making it difficult for the brain cells to acquire energy for cell maintenance and synaptic connections thus, cell death can occur100. Also, hyperinsulinemia has been found to increase inflammation and βA1-42 in healthy adults101.
Estrogen level: Various pharmacoepidemiological studies have reported that AD is more common in postmenopausal women than men102. These occurrences have led to the hypothesis that estrogen loss in postmenopausal women may contribute to the development of AD. Estrogen is known to reduce the risk of developing dementia. Estrogen is known to modulate ApoE gene, increase the metabolism of APP, protects against oxidative stress and causes direct modulation of neurotransmitters103. Observation data link use of hormone therapy to reduction in Alzheimer’s risk but experimental evidence from clinical trials demonstrates that estrogen increases the incidence of dementia. Several studies are of the view that hormone therapy initiated closer to the time of menopause may reduce the incidence of Alzheimer’s dementia.
Melatonin is a naturally-occurring hormone that is produced in decreasing amounts with age. Melatonin is a powerful antioxidant provides mitochondrial support, protects against tau tangles and reduces βA toxicity. Melatonin readily crosses the BBB and enters all cell structures. A small case study showed 6 mg melatonin daily improved mood and memory over 6 days for 10 patients with mild cognitive impairment104.
Vitamins and minerals: Vitamins B low levels of vitamin B12 and folate appear to be associated with an increased rate of cognitive decline105,106. In addition, for a study of 107 normal individuals, those with low-normal vitamin B12 had the greatest 5 years loss of brain volume. The AD patients typically have high levels of homocysteine107. Researchers have examined the possibility that lowering homocysteine would be therapeutic. A combination of vitamin’s B12 and B6 and folate lowering homocysteine both in normal seniors and in those with mild-to-moderate AD108 but had no effect on cognition. Homocystein levels appear to correlate with aging but not with cognition109.
Vitamin A has received attention because it is essential for learning, memory and cognition because vitamin A levels in the brain decline with age and is lower still in individual with AD110. A metabolic product of vitamin A, retinoic acid is known to slow cell death and offer protection from βA111.
Vitamin E is low in AD patients, a study that followed 3,718 individuals over 6 years examined dietary consumption (excluding vitamin E supplement intake which showed no side effect) of all four tocopherols (α, β, γ and δ) as determined by questionnaires.
Multiple nutrients: Since, AD patients often have multiple deficiencies and it makes sense to use multiple supplements. A study of 14 individuals with early AD found that a multiple formulations (400 μg folic acid, 6 μg vitamin B12, 30 IU vitamin E, 400 mg S-adenosylmethionine, 600 mg N-acetylcysteine and 500 mg acetyl-L-carnitine per tablet with a daily dose of two tablets) improved all measures of cognition although, the increase in memory was not statistically significant. The improvement persisted throughout the 12 months study112.
Lithium is a naturally-occurring mineral found in small amounts in many foods. Lithium increases the level of a neuroprotective protein called bcl-2 in the rat hippocampus and frontal cortex and inhibits glycogen synthase kinase 3β (GSK-3), which is implicated in increasing levels of phosphorylated tau and is bought to be factor leading to βA plaques and cell death113.
Nutrients: Phosphatidylserine (PS) is important in neurotransmission, mitochondria function and cell metabolism. It has also been implicated in the enhancement of a nerve growth factor. In vitro study demonstrates PS increases Ach and provides neuroprotection by inhibiting βA and inflammation114. Supplemental PS was originally derived from bovine brains and study using bovine PS typically found cognitive benefits.
Alpha-lipoic acid (ALA), a fatty acid found in all cells and in some foods is manufactured within the body. It is a powerful antioxidant that readily penetrates the BBB, chelates metals, reduces inflammation and increases Ach. The potential mechanism underlying these and other neuroprotective effects are reviewed elsewhere115.
Omega-3 fatty acids have many beneficial effects that make them investigative prospects for AD. A recent study followed 5,395 healthy adults on an average of 9.6 year to assess the relationship between dietary imega-3 intake and risk of developing AD. Dietary intake of omega-3s was the same for the 365 subjects who developed AD as for those who did not116.
Acetyl-carnitine (ALCAR) is derived from the amino acid L-carnitine studies synergistically with ALA to transport acetyl groups and fatty acids into the mitochondria for energy production. The ALCAR is a small molecule that penetrates the BBB and promotes the biosynthesis of Ach while clearing mitochondria of toxic fatty-acid metabolites117. Its effect on APP helps prevent the build-up of amyloid plaque and preserve synaptic function. The ALCAR also increases the nerve growth factor118.
The ALCAR has been found to produce cognitive benefits for AD patients a small double-blind study of seven probable AD patients and five placebo controls found that 3 g ALCAR daily resulted in less cognitive decline over the course to one year119.
Coenzyme Q10 (CoQ10; Ubiquinone)/Idebenone Coenzyme Q10 is essential for mitochondrial energy production. Mitochondrial dysfunction can result in generation of reactive oxygen species and oxidative stress. Many mitochondrial dysfunctions occur in AD brains including disruption of energy production, apoptosis deregulation, altered calcium homeostasis and others (reviewed elsewhere). For these reasons, mitochondria are viewed as promising therapeutic targets120.
Flavonoids and other plant constituents: HuperzineA (HupA) HupA is an extract from the Chinese moss Huperzia serrata that has been used for centuries in Chinese’s folk medicine to treat a wide range of disease. In vitro and animal studies found HupA preserves Ach longer than tacrine, galantamine or donepezil.
| Table 4: | Different plants for Alzheimer’s therapy reported with neuroprotective.131 |
The HupA reduces βA-induced neuronal degeneration in the hippocampus and cortex, decrease oxidative damage from cytotoxins and apoptosis induced by βA plaques, protects neurons from βA and free radicals and inhibits glutamate toxicity. A recent meta-analysis of four Chinese studies found 300-500 mcg HupA produced a marked improvement in cognition121-124.
Polyphenols: Curcumin is extracted from the plant curcuma longa (turmeric). Reviewers suggest curcumin may be a promising therapy for AD because it has atleast 10 neuroprotective properties including anti-inflammatory, antioxidant, inhibition of βA formation, clearance of existing βA, copper and iron chelation125. Curcumin readily penetrates the BBB but oral administration may produce barely detectable blood levels at doses of 2 g and low levels at 8 g126. The reasons for bioavailability problems appear to be low absorption, rapid metabolism, quick elimination, the inherent instability and hydrophobic nature of curcumin.
Resveratrol a polyphenols found in red wine, peanuts and other plants reduces oxidative stress, decreases inflammation, reduces βA, protects DNA, decrease cell death and modulates various other systems that protect cells127. Several studies have shown that moderate consumption of red wine reduces the risk of developing AD128. Resveratrol is similar to curcumin in that oral bioavailability is low because it is quickly metabolized and excreted. Attempts have been made to increase bioavailability by the use of quercetin, catechin, apigenin, fisetin, myricetin and kaempferol129. List of different plants used for Alzheimer’s therapy is given in Table 4.
Non-pharmacological or stimulatory therapies for AD: There are several non-pharmacological strategies which manage the functional and behavioural deterioration (www.gmhfonline.org). Physical exercise, cognitive training and socialization are generally thought to facilitate cognitive functioning134 in Table 5.
| Table 5: | Non-pharmacological studies used in AD |
CONCLUSION
This study was aimed to provide the current and informative data in a compiled frame to treat the AD. It can be concluded that rehabilitation in patients with Alzheimer’s disease should take a multi professional and multidisciplinary study with an emphasis on physiotherapy including enhanced or individually modified physical activity and muscle training.