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Thursday, May 14, 2009


C. G. JincyHH, Sujith Varma
National College of Pharmacy, Manassery, Calicut

Cite this:  C. G. Jincy, Sujith Varma, "THE COMPLICATIONS AND MANAGEMENT OF ALZHEIMER'S DISEASE", B. Pharm Projects and Review Articles, Vol. 1, pp. 543-591, 2006. (

Alzheimer's disease first characterized by Alois Alzheimer in 1907, is a gradually progressive dementia affecting both cognition and behaviour. This disease profoundly affect the family as well as the patient. (7)
Alzheimer's disease is a progressive brain disorder. The disease gradually progress and destroys the patients memory, lacking the ability to learn, communicate, carry out daily activities and to make judgement. (4)
    The only cure for Alzheimer's disease is to give support and care to improve the quality of life of the person. Once the disease is diagnosed, the care should be give right from the diagnosis to the end of life.






Mainly 4 major parts;


  • Brain stem
  • Cerebellum
  • Diencephalone
  • Cerebrum        Figure 1: Normal physiology of brain


  1. Brain stem.

    Brain stem consist of medulla oblongata, pons and mid brain.In medulla oblongata several nuclei are present which regulate the rate and force of heart beat and diameter of blood vessels. It also adjust the basic rhythm of breathing and controls reflexes for vomiting, coughing and sneezing. Pons also consist of several nuclei and tracts. It also helps to control breathing. Mid brain contain several axons which conduct nerve impulses from cerebrum to the spinal cord, medulla and pons.

  2. Cerebellum
    Cerebellum regulates posture and balance of the body and also plays a role in cognition and language processing.

  3. Diencephalon

    Diencephalon consist of thalamus, epithalamus, subthalamus and hypothalamus. Epithalamus secrete melanin. It is a pigment which provide characteristic color to the skin. Thalamus relays almost all sensory input to the cerebral cortex. Thalamus provides crude perception of touch, pressure, pain and temperature. Thalamus also includes nuclei involved in movement planning and control. Sub thalamus communicate with the basal ganglia to help control body movement. Hypo thalamus controls and integrate activities of autonomous nervous system [ANS] and pituitary gland and regulates emotional and behavioral patterns and circadian rhythms. Diencephalon controls body temperature and produces oxytocine and anti diuretic hormone.

  4. Cerebrum

    Cerebrum consist of sensory areas, motor areas, & association areas.
    Sensory areas interpret sensory impulses. Motor areas control muscular movement & association areas function in emotional and intellectual processes. Basal ganglia co ordinate gross, automatic muscle movements & regulate muscle tone. Limbic system functions in emotional aspects of behavior related to survival. (5)




    Direct analysis of neurotransmitter content in the cerebral cortex shows a reduction of many transmitter substances that parallels neuronal loss, there is a striking and disproportionate loss of acetyl choline. The anatomical basis of cholinergic deficit is the atrophy and degeneration of sub cortical cholinergic neurons, particularly those in the basal fore -brain that provide cholinergic innervation to the whole cerebral cortex. The selective deficiency of acetyl choline in Alzheimer's disease as well as the observation that central cholinergic antagonists such as atropine can induce a confusional state that bears some resemblance to the dementia of Alzheimer's disease has given rise to the Cholinergic hypothesis which proposes that a deficiency of acetyl choline is critical in the genesis of the symptoms of Alzheimer's disease. It is important to note that the deficit in Alzheimer's disease is far more complex involving multiple neurotransmitter systems including serotonin, glutamate and neuropeptides and that in Alzheimer's disease there is destruction of not only cholinergic neurons but also the cortical and hippocampal targets that receive cholinergic input. (4)


    Role of beta amyloid


    The presence of aggregates of beta amyloid is a constant feature of Alzheimer's disease. Beta amyloid was isolated from affected brains and found to be a short polypeptide of 42 to 43 amino acids. This information leads to the cloning of amyloid precursor protein [APP] a much larger protein of more than 700 amino acids which is widely expressed by neurons throughout the brain in normal individuals as well as in those with Alzheimer's disease. It is possible for abnormalities in amyloid precursor protein or its processing to cause Alzheimer's disease. (4)


    Figure 2: Prevalence of Alzheimer's disease
    A very small minority of Alzheimer's disease patients are under 50 years of age. However most are over 65. Only 5 to 6 percent of older people are afflicted by Alzheimer's disease or a related dementia but this means approximately 3 to 4 million Americans have one of these debilitating disorders. Alzheimer's disease affects two times as many women as men and although genetic inheritance is the primary mode of transmission, several environmental factors may contribute. (8)




    The exact etiology of Alzheimer's disease is not known. Scientists regard two abnormal microscopic structures called plaques and tangles as Alzheimer's hall marks. Amyloid plaques are clumps of protein that accumulate out side the brain's nerve cells. Tangles are twisted strands of another protein that form inside cells. There are several risk factors involved in the etiology of Alzheimer's disease. They are:


    1. Age


    The greatest known risk factor is increasing age and most individuals with the illness are 65 and older. After age 85 the risk reaches nearly 50%.

    2. Family history and genetics

    Research has shown that those who have a parent or sibling with Alzheimer's are 2 to 3 times more likely to develop the disease than those who do not. Head injury and overall brain health are other risk factors.The Genetic, environmental and infectious etiologies have been explored as potential cause of Alzheimer's disease.

    3. Genetics

    Almost all early onset cases of Alzheimer's disease can be attributed to alterations on chromosome number 1, 14 or 21.Approximately 5% of the cases of Alzheimer's disease are early onset. The majority and most aggressive early onset cases are attributed to mutations of an Alzheimer's gene located on chromosome 14, which produces a protein called presenilin1. Similar in structure to presenilin1 is a protein produced by a gene on chromosome1 called presenilin 2. Presenilin 2 is responsible for early onset of Alzheimer's disease . Both presenilin1 and presenilin2 encode for membrane proteins that may be involved in amyloid precursor protein processing. It has been suggested that presenilins are actually gamma secretase or that presenilins affect gamma secretase activity. As a group presenilins account for approximately 50% of all early onset Alzheimer's disease cases.Amyloid precursor protein [APP] is encoded on chromosome number 21. Only a small number of early onset, familial Alzheimer's disease cases have been associated with mutations in the Amyloid precursor protein gene, resulting in over production of beta amyloid protein. Genetic susceptibility to late onset Alzheimer's disease is thought to be primarily influenced by the apo lipoprotein [apo E] genotype. The gene responsible for the production of apo E is located on chromosome number 19 in a region previously associated with late onset Alzheimer's disease. Three major subtypes or alleles of apo E occur and are termed apo E2, apo E3, and apoE4. The apo E4 allele is a risk factor for development of Alzheimer's disease . About 40% of patients with late onset Alzheimer's disease have at least one copy of apo E4.

    4. Environmental factors

    A number of environmental factors have been associated with increased risk of Alzheimer's disease including stroke, alcohol abuse, small head circumference, repeated or severe head trauma, and lower levels of education. In particular, traumatic head injury in combination with the apo E4 genotype has been associated with an increased risk of Alzheimer's disease. (7)





    Figure 3: Normal brain and Alzheimer's brain

    Alzheimer's disease is characterized by marked atrophy of the cerebral cortex and loss of cortical and sub cortical neurons. The pathological hall marks of Alzheimer's disease are senile plaques which are spherical accumulation of the protein beta amyloid accompanied by degenerating neuronal processes and neuro fibrillary tangles composed of paired helical filaments and other proteins. Although small numbers of senile plaques and neurofibrillary tangles can be observed in intellectually normal individuals, they are far more abundant in Alzheimer's disease and the abundance of tangles is roughly proportional to the severity of cognitive impairment. In advanced Alzheimer's disease senile plaques and neurofibrillary tangles are numerous.They are most abundant in the hippocampus and associative regions of the cortex, whereas areas such as visual and motor cortices are relatively spared. This corresponds to the chemical features of marked impairment of memory and abstract reasoning with preservation of vision and movement. The factors underlying the selective vulnerability of particular cortical neurons to the pathological effects of Alzheimer's disease are not known. Other abnormal chemical changes associated with this disease include nerve cell degeneration in certain areas of brain and defect in the supply of blood to the brain. (4)
















    Figure 4: Neurofibrillary tangles and neuritic plaques

    Alzheimer's disease is defined by both neuro pathologic and clinical criteria. Neuro pathologically Alzheimer's disease destroys neurons in the cortex and limbic structures of the brain, particularly the basal fore brain, amygdale, hippocampus and cerebral cortex. These areas are responsible for higher learning, memory, reasoning, behavior and emotional control. There are four major alterations in brain structure are seen; cortical atrophy; degeneration of cholinergic and other neurons; presence of neuro fibrillary tangles; and the accumulation of neuritic plaques. Neurofibrillary tangles and neuritic plaques are considered the signature lesions of Alzheimer's disease. Clinically it will produce cognitive and non cognitive symptoms. (9, 10)

    Neuro fibrillary tangles are composed of paired helical filaments that aggregate in dense bundles, appearing microscopically like tiny flames filling the neuronal cell body. Paired helical filaments are formed from tau protein. Tau protein provides structural support to microtubules, the cells transportation and skeletal support system. When tau filaments undergo abnormal phosphorylation at a specific site, they cannot bind effectively to microtubules and the microtubules collapse. Without an intact system of microtubules, the cell cannot function properly and eventually dies. Overactivity of kinases such as microtubule affinity regulating kinase [MARK] or underactivity of phosphatases could theoretically produce or prevent break down of abnormally phosphorylated tau protein. (15)

    Neuritic plaques (also termed amyloid or senile plaques) are extra cellular lesions found in the brain and cerebral vasculature (amyloid angiopathy). Plaques are comprised of beta amyloid protein,and an entwined mass of broken neuritis (axon and dendrite projections of neurons). Many of these broken neurites combine neuropil filaments made up of the abnormally phosphorylated tau protein found in neurofibrillary tangles. Two types of glial cells, astrocytes and microglia are also found in plaques. Among other functions, glial cells secrete inflammatory mediators and serve as scavenger cells, which may be important in considering inflammatory processes in Alzheimer's disease. It was recently determined that a version of beta amyloid protein containing 42 aminoacids damages nerve cells. It is not clear that how beta amyloid protein causes neuronal damage. The possible way is the dysregulation in calcium and damage to mitochondria. This in turn may trigger inflammatory mediators.Taken as a whole,these data suggest beta amyloid protein deposition occurs early in the disease process rather than being simply an end product of neuronal death, and likely initiates the process of plaque formation and nerve cell destruction. (9,10)




        Evidence supporting significant involvement of the immune system includes the increased presence of acute phase proteins such as alpha1-anti chromotrypsin and alpha 2 microglobulin, both in the serum and within amyloid plaques of patients with Alzheimer's disease. Glial cells (microglial cells and astrocytes), cytokines (e.g, interleukin1 and interleukin6) and components of the classic compliment cascade are also markedly increased in plaque infested areas. These inflammatory mediators increase beta amyloid protein toxicity and aggregation . Chronic production of cytotoxic agents and free radicals by activated microglia can result in accelerated neurodegeneration.

    Microglial cells located around and within amyloid plaques are thought to release in flammatory mediators, which locally destroy neuronal tissue . Glial cells also function as phagocytes similar to macrophages and monocytes in the periphery. Another component of the compliment cascade, the membrane attack complex (MAC) is found associated with broken neurites and areas containing neurofibrillary tangles implicating membrane attack complex as promoting the vast neuronal destruction characterizing Alzheimer's disease.The acute phase protein and alpha 2 macroglobulin are also act as protease inhibitors and could influence proteolytic break down of amyloid precursor protein in to beta amyloid protein. Specific factors responsible for initiating the immune response are not known. One theory is that breaks in the blood brain barrier caused by trauma, leaky endothelial cells or other conditions, trigger an immune response to brain proteins previously unexposed to the periphery. Another possibility is that the immune system is activated by plaque precursors or byproducts of damaged cells, resulting in further destruction of adjuscent neurons. (7)



    Multiple neuronal pathways are destroyed in Alzheimer's disease. Damage occurs in any nerve cell population located in or travelling through plaque laden areas. Wide spread cell destruction results in a variety of neurotransmitter deficits. Most profoundly damaged are the cholinergic pathways, particularly a large system of neurons located at the base of the fore brain in the nucleus basalis of Mynert, a brain area believed to be involved in thought integration. Axons of these cholinergic neurons project to the frontal cortex and hippocampus, areas strongly associated with memory and cognition .The cholinergic hypothesis targets the cholinergic cell loss as the source of memory and cognitive impairment in Alzheimer's disease. Therefore it was presumed that increasing cholinergic function would improve symptoms of memory loss. This approach is flawed for two reasons. First cholinergic cell loss appears to be a secondary consequence of Alzheimer's pathology, not the disease producing event; second, cholinergic neurons are only one of many neuronal pathways destroyed in Alzheimer's disease. Simple addition of acetyl choline cannot compensate for the loss of neurons, receptors and other neurotransmitters consumed during the cause of the illness. (7)




    The presence of increased monoamine oxidase type B (MAO-B) concentrations may seem counter initiative considering the vast neuronal loss in Alzheimer's disease, unless one considers that MAO-B is also contained in glial cells whose populations are increased. Glutamate is a major excitatory neurotransmitter in the cortex and hippocampus. Many neuronal pathways essential to learning and memory use glutamate as a neurotransmitter, including the pyramidal neurons (a layer of neurons with long axons carrying information out of the cortex ), hippocampus and entorhinal cortex. Glutamate and other excitatory aminoacid neurotransmitters have been implicated as potential neurotoxins in Alzheimer's disease. If glutamate is allowed to remain in the synapse for extended periods of time, it can act as a toxin, destroying nerve cells. When excess glutamate is present in brain it causes neural injury and this condition is termed as excito toxicity. Although glutamate is required for normal brain function, the presence of excessive amount of glutamate can lead to excito toxic cell death. The destructive effect of glutamate are mediated by glutamate receptors like N- methyl D- aspartate type. Toxic effects are thought to be mediated through increased intracellular calcium and accumulation of free radicals. The presence of beta amyloid protein renders cells more susceptible to glutamate-mediated excito toxicity in vitro. Dysregulated glutamate activity is thought to be one of the primary mediators of neuronal injury after stroke as acute brain injury. (7)



    Estrogen promotes the growth and prevents the cell damage. Estrogen act as an anti oxidant. In culture estrogen protects hippocampal neurons exposed to glutamate and beta amyloid from cytotoxic and free radical damage. The risk of Alzheimer's disease in women who take estrogen replacement therapy is very high. (7)




    The symptoms of Alzheimer's disease are categorised into two; cognitive and non cognitive symptoms. Cognitive symptoms are present throughout the illness whereas behavioral or non cognitive symptoms are less predictable. (7)




    Memory loss
    Poor recall;
    Agnosia (inability to identify common objects);
    Losing items.


    Aphasia (unable to speak).


    Impaired perception of time;
    Direction;can not recognize family or self;
    Impaired calculation;
    Impaired judgement and problem solving






    Psychotic symptoms


    Non psychotic disruptive behaviour
    Physical and verbal aggression;
    Motor hyper activity; un cooperativeness; wandering;
    Repetitive mannerism/activities; combativeness. (7)




    A physician should be consulted about concerns with memory, thinking skills and changes in behavior. It is also important for a physician to determine the cause of memory loss or other symptoms. Some dementia like symptoms can be reversed if they are caused by treatable conditions, such as depression, drug interaction, excess use of alcohol or certain vitamin deficiencies.

    It can be diagnosed by performing mini-mental status exam which will helps in confirming defects in cognition.

    Other diagnostic methods include
  • Electro encephalogram
  • CT Scanning
  • MRI Scanning
  • Positron emission Tomography. (5, 7, 9, 10)




    STAGE 1


    No subjective or objective change in intellectual functioning.


    STAGE 2


    Complaints of loosing things or forgetting names of acquaintances. Does not interfere with job or social functioning. Generally a component of normal ageing.

    STAGE 3


    Cognitive decline causes interference with work and social functioning. Anomia, difficulty in remembering right word in conversation, and recall difficulties are present and noticed by family members. Memory loss may cause anxiety for patient.

    STAGE 4

    Patient can no longer manage finances or home making activities. Difficulty in remembering recent events. Begins to withdraw from difficult task and to give up hobbies .May deny memory problems.

    STAGE 5

    Patient can no longer survive without assistance. Frequently disoriented with regard to time (date, year, season). Difficulty in selecting clothing. Recall for recent events is severely impaired; may forget some details of past life (for eg; school attended or occupation). Functioning may fluctuate from day to day. Patient generally denies problems. May become suspicious or tearfull. Loses ability to drive safely.

    STAGE 6

    Patients need assistance with activities of daily living (e.g, bathing, dressing, and toileting). Patients experience difficulty in interpreting their surroundings, may forget names of family and care givers; forget most details of past life; have difficulty in counting backward from 10. Agitation, paranoia and delusions are common.

    STAGE 7

    Patient loses ability to speak (may only grunt or scream), walk and feed self. Incontinent of urine and feces. Consciousness reduced to stuper or coma. (8)



    Mainly five distinct approaches are there;

    • Cholinergic hypothesis
    • Hormone replacement approaches
    • Anti inflammatory approaches
    • Neurotrophic approaches
    • An approach to inhibit formation of amyloid and neurofibrillary tangfles.


According to the cholinergic hypothesis, memory impairment in patients with senile dementia of Alzheimer's disease results from a deficit cholinergic function. It was found in the postmortem analysis of Alzheimer's disease affected brains that the loss of cholinergic innervation of the hippocampus and cerebral cortex couples with the loss of cholinergic neurons in the basal fore brain. Therefore treatment for memory loss in Alzheimer's disease has mainly been focused on cholinergic hypothesis.

Three different approaches of enhancing cholinergic function include;

a) Increase the acetyl choline levels using acetyl cholinesterase inhibitors
b) Administration of acetyl choline precursors or acetyl choline releasing agents.
c) Inhibition of acetyl choline degradation and directly stimulating cholinergic receptors using cholinomimetics. (6)


A) Acetyl cholinesterase inhibitors

The enhancement of the central cholinergic function has been regarded as one of the most promising approaches for the treatment of Alzheimer's disease by means of acetyl cholinesterase inhibitors. Recent studies have shown that acetyl cholinesterase inhibitors interact with both peripheral and active site of enzyme. In addition to acetyl cholinesterase inhibition, it also act as potential inhibitor for formation of beta amyloid. Many research groups have reported over the last decade on compounds that inhibit acetyl cholinesterase as approaches to treat Alzheimer's disease. Tacrine [Tetra hydro amino acridine] was found to be a potent acetyl cholinesterase inhibitor or subsequently its derivatives such as Velnacrine and Surnacrine have been reported as acetyl cholinesterase inhibitor in the treatment of Alzheimer's disease. (6)

Tacrine shows side effects such as hepato toxicity and gastro intestinal upset. Dose:- Initially 10 mg q.i.d followed by 20-40 mg q.i.d for 4-6 weeks.
Side effects:- Hepato toxicity, Oto toxicity, Nausea, vomiting. (7)

Recently Tacrine based compounds showed invivo acetyl cholinesterase inhibition in rat cortex or whole brain. In addition to this many compounds have been reported as acetyl cholinesterase inhibitors such as aza analogues of Tacrine, New Tacrine –huperzine A hybrids. (4, 5, 7)

Later a number of compounds have been studied for this purposes viz. 4-amino pyridine , 4-aminoquinoline, &tetra hydro acridine and 9-(N-n-butyl amino) 1,2,3,4-tetra acridine. The results reveals that 4- amino pyridine and 4- aminoquinoline have very weak acetyl cholinesterase activity although their basicities were almost equal to that of tacrine. The N- butyl derivatives was not particularly active with the butyl chain hindering the interaction of the compound with the enzyme ,but tetra hydro acridine a much weak base was found to be as active as tacrine. (6)

Physostigmine has been reported to have memory enhancing effect in Alzheimer's disease. But it has short half life, variable bioavailability and narrow therapeutic index. Heptyl physostigmine a more lipophilic analogue is reported to be less toxic than physostigmine while retaining its in vitro acetyl cholinesterase inhibiting potency. 8-carba physostigmine has greater potency and reduced toxicity compared to physostigmine. Galantamine is a reversible inhibitor of cholinesterase and an allosteric modulator of nicotinic acetyl choline receptor. It is well tolerated during long term treatment and is under clinical evaluation for the treatment of Alzheimer's disease. Dose:- 4 mg b.i.d followed by 8-16 mg b.i.d for 4 weeks. Side effects include nausea, vomiting & diarrhoea. (2, 6)

The N-benzyl -4-[2-(N-benzoyl amino)-ethyl] piperidine, 1- benzyl 4-1[2-(N- phthalimido ethyl)]piperidine, 1- benzyl –[5,6-dimethoxy-1-indanon-2-yl) methyl] piperidine Hcl (Donpezil) have been reported by Sugimoto et al. to possess the acetyl cholinesterase inhibitory activity. (6)

(-)Huperin A originally obtained from the Chinese herb, Huperiza serrata,is a reversible inhibitor of acetyl cholinesterase, which is reported to have entered clinical trials for alleviation of Alzheimer's disease. A more powerful compound namely, huperine has been reported as more potent acetyl cholinesterase inhibitor, being a 40 fold more potent than donepezil and 180 fold potent than (-) huperine A. (6)

Donepezil and Rivastigmine have been marketed recently for the treatment of the cognitive symptoms of Alzheimer's disease. Dose of Donepezil:- 5 mg q. i. d followed by 5-10 mg q. i. d for 4-6 weeks. Dose of Rivastigmine:- 1.5 mg b.i.d followed by 3-6 mg b.i.d for 2 weeks. Side effects include nausea, vomiting, diarrhoea, decrease in weight, anorexia. Use of acetyl cholinesterase inhibitors in combination with vitamin E is generally considered for earlier stage of the disease. Vitamin E increases the brain catecholamine and reduces the oxidative damage to neurons thus reduces the progress of Alzheimer's disease. (2, 6, 7)


the recent past, a hexa hydro chromeno [4, 3-b] pyrrole derivative has been reported as acetyl cholinesterase inhibitor activity .An amino pyridazine analogue, minaprine has been reported to have acetyl cholinesterase inhibitory activity in homogenized rat striatum . An in vivo administration of minaprine to rats significantly increase acetyl choline level in the hippocampus and striatum. Further studies and optimization of minaprine led to the identification of 3-[2-(1-benzyl piperidin -4yl)ethyl amino ]pyridazine and 3-[2-(1-benzyl piperidin 4-yl)ethyl amino ] methyl -6- phenyl pyridazine. The 3-[2-(1-benzyl piperidin -4-yl)ethyl amino] pyridazine ,representing a 5000 fold increase in potency compared to minaprine. (6)


Recently a study on a series omega [N- methyl –N-(3- alkyl carbamoyl –o-phenyl)methyl] amino alkoxy aryl derivative an azoxanthone derivative reported an acetyl cholinesterase inhibitors which are more potent than tacrine but less than donepezil and showed acetyl cholinesterase inhibitory activity in rat cortex. (6)



The cholinomimetic effect of these compounds is based on increase in the amount of Acetyl choline precursor. Compounds that have such a cognition stimulating mechanism include exogenous choline, lecithin and phosphatidyl choline. Gliatilin and acetyl –L- carnitine (ALCAR) have been reported for the treatment of Alzheimer's disease from this class. (6)


Acetyl choline release modulator, linopyridine enhances the potassium evoked acetyl choline release from the rat cortex, hippocampus and caudate nucleus in vitro. Another mechanism of the stimulation of the acetyl choline is realized via antagonist of H3 histamine receptors. H3-histamine receptors, a subtype of histamine receptor is localized on pre synaptic terminals of histaminergic and non histaminergic neurons in the central and peripheral nervous system. Two drugs namely clobenpropit and thioperamide have been reported for the treatment of Alzheimer's disease. Clobenpropit is H3 histamine receptor antagonist whereas thioperamide is H3 histamine receptor agonist which belong to 4- substituted imidazole derivatives. (6)


A stimulation of acetyl choline release via the increase of the pre synaptic uptake of endogenous choline, formed due to the acetyl cholinesterase catalysed enzymatic degradation of acetyl choline considered to be an alternative to the receptor regulated acetyl choline release. MKC-231 has been launched for Alzheimer's disease from this class . It is an activator of the high affinity choline uptake the essential component of acetyl choline re-synthesis. (6)




Cholinergic agonist acting directly on muscarinic receptor may improve the cholinergic dysfunction seen in Alzheimer's disease. In Alzheimer's disease the basal fore brain muscarinic neurons that predominantly express the pre synaptic M2 receptors have been found in atrophy. However mainly the pre synaptic M1 receptors are highly concentrated in the cortex and hippocampus and their density is reported to be un altered in Alzheimer's disease. A preferential involvement of the M1 receptor in memory has been proposed. This suggest that M1 selective agonist may be useful. (6)



Estrogen replacement therapy in post menopausal women resulted in a 40- 50 % reduction in the risk of developing Alzheimer's disease. 17 beta estradiol protects neurons against oxidative damage induced by beta amyloid as well as other oxidants such as hydrogen peroxide and glutamate. Animal studies have shown that the administration of estrogen to estrogen deficient laboratory animal restores the number of neural synapsis causing beta amyloid to be more soluble. It also induces and increases the activity of choline acetyl transferase, the rate limiting enzyme for acetyl choline synthesis in both the basal fore brain and target area of cholinergic neurons. (6)



    Prostaglandins are implicated in the pathology of the Alzheimer's disease. Recently, it has been reported that non steroidal anti inflammatory drugs alleviate inflammatory changes in the brain of patients with Alzheimer's disease. Although NSAIDS would not be expected to modify the abnormal metabolism of beta amyloid, they could reduce the response of microglia to the protein. The neural damage in Alzheimer's disease may be due to the inflammatory reaction with consequent free radical and protease release than to the presence of amyloid precursor protein. Thus inhibition of inflammation may delay or even about the loss of neurons consequent on amyloid deposition. In a recent report ibuprofen and naproxen have been found to reduce the severity of Alzheimer's disease. (6)


Compounds namely propentofyline, citicoline, anapests and AIT -082 that have a neuroprotective and cognition-stimulating activity via stimulation of neurotrophic function in central nervous system. The main effect of propentofyline is the inhibition of the adenosine re-uptake system. This results in the accumulation of adenosine in CNS and consequent activation of adenosine receptors. Citicoline is an endogenous intermediate in the biosynthesis of structural membrane phospholipids and brain acetylcholine. Citicoline may improve memory via its neurotrophic effect. AIT-082 acts at the site of heme oxygenase to generate carbon monoxide and by activation of guanylyl cyclase induces a cascade of biochemical reaction through the second messenger system leading to the production of mRNA neurotrophins, it is currently in phase-III clinical trials. (6)



The proteolysis of the membrane APP results in the generation of the beta amyloid peptide that is thought to be caused for the pathology and subsequent cognitive decline in Alzheimer's disease. The amyloid approaches postulate that agents that decrease amyloid protein level in vivo would have promising therapeutic benefit in Alzheimer's disease. Amino acid derivatives, amine and urea analogs and hydroxyl –hexanamide deruivative have been shown to inhibit amyloid protein synthesis or its release. Apo lipoprotein E4 is found in both senile plaques and neurofibrillary tangles. Apo E4 interacts with and precipitates beta amyloid protein. The oxygen mediated complex formation was implicated. This suggest that anti oxidant may have therapeutic potential in Alzheimer's disease.

A major component of neurofibrillary tangles is tau, a family of microtubule associated protein which are important for the maintenance of the neuronal cytoskeleton. Neurofibrillary tangle associated tau is excessively phosphorylated which may result from neural calcium dysregulation. Before incorporation in neurofibrillary tangles, the abnormal phosphorylation of tau may lead to microtubules destabilization and cytoskeleton disruption resulting in impaired neuronal function and survival. Glycogen synthase kinase -3 (GSK-3) has been proposed as a possible phosphorylation enzyme for tau . Much recent report indicated that GSK-3 inhibitors viz. 3-anilino -4-aryl maleimides , 6-aryl-pyrazolo [3,4-b]pyridines, 6-hetero aryl pyrazolo [3,4-b]pyridines, 5-aryl-pyrazolo-[3,4-b]pyridazines, 1-(4-amino furazan -3-yl)-5-dialkyl amino methyl -1H-[1,2,3]triazols-4-carboxylic acid derivatives, pyrazolo pyramidines derivatives and 3-(7-azaindolyl)-4-aryl maleimides have therapeutic potential for treating Alzheimer's disease by protecting neuron from death induced by reduced PI-3 kinase path way activity . Statin derivatives such as simvastatin ,atorvastatin, have also showed promising anti Alzheimer activity which would be based on their ability to reduce a lipoprotein oxidation ,decrease inflammation, generation of radical oxygen species and reduce the cerebral beta amyloid level. (6)



  • Keep requests and demands of the patient simple and avoid complex tasks that might lead to frustration.
  • Avoid confrontation and differ requests that leads to frustration.
  • Remain calm, firm and supportive if the patient become upset.
  • Maintain a consistent environment and avoid un necessary changes.
  • Provide frequent reminders, explanations and orientation cues.
  • Recognize declines in capacity and adjust expectation for patient's performance
    • Being sudden declines in functions and emergence of new symptoms to professional attention. (7)

    Special care for Alzheimer's disease.
            These are separate areas for those patients in nursing home, assisted living residences and other care giving facilities. They have special architectural features and / or programmes tailored to the needs of the patients.

    Family care givers

    In order to reduce the burden the following techniques are helpful;
    Emotional support;

        Social support can help to reduce the stress and other care giving problems. Support groups, individual counseling and family counseling all fall into this category. Individual counseling has alleviated specific problems such as depression.




        The common services is Respite care services. These services are offered in home, in day care facilities, and even in institutions where patients stay a limited time usually a week or two.

    Knowledge and skills training;

    It depends on;

    • Care giver personality
    • Degree of care needed
    • Resources available to the care giver.

    Mainly two kinds of care giving strategies;
  1. Help the patients to maintain independence in daily activities as long as possible.
  2. Help to prevent the disturbing behaviors.


Maintaining independence has many advantages. The longer the patient can function independently, the better his or her quality of life and self esteem. It also helps to lower the level of stress. Behavioral management can help to alleviate many disturbing behaviors as well as reduce care giver stress.




Several twin studies have shown that when one twin develops Alzheimer's, the other twin is at increased risk but does not always develop the disease. Other studies suggest that even in cases where both twins develop Alzheimer's, the age where symptoms appear can defer significantly. These results suggest that even when there is a strong genetic influence, other factors can play a major role. Scientists have so far identified one gene that increases risk of Alzheimer's but does not guarantee an individual will develop the disorder. Research has also revealed certain rare genes that virtually guarantee an individual will develop Alzheimer's. The genes that directly cause the disease have been found in only a few hundred extended families world wide and are thought to account for a tiny percentage of cases. Experts believe the vast majority of cases are caused by a complex combination of genetic and non genetic influences.


A team of researchers led by Dale schenk at Elancorp, they tried to trick the immune system of mice to recognize amyloid proteins as a foreign substance that should be attacked. Deposits in the brain of a sticky protein called amyloid are one of the characteristics of Alzheimer's disease. If the same phenomenon can be repeated in humans, it will have a very important impact. The vaccine appears to ward off and even reduce the brain clogging deposits that are characteristics of the disease. If the maximal effect of this discovery to be obtained, it is needed to find out who has the disease and who is at risk much earlier. Most patients don't have any tell tale markers. The saponin obtained from Albezzia lebbek was found to be effective in improving cognition in various animals. (3)

Danggui-shoyao-san (DSS), a famous Chinese complex prescription has been widely used for gynecological and obstetrical purposes for a long time and recently it has gained much attention due to its therapeutic efficacy for senile dementia. In the present study the effects of aqueous extract of DSS on naturally aged mice were examined to investigate the pharmacological basis for its therapeutic efficacy on senile dementia especially Alzheimer's disease. The results showed that DSS significantly prolonged latency in a step through test and increased brain index so as to improve impaired cognitive function of aged mice after oral administration at doses of 250 &500mg/kg for three months. Using high performance liquid chromatographic technique with electrochemical detection, it was found that DSS has increased the content of monoamine neurotransmitters such as nor epinephrine, dopamine, and 5-hydroxy tryptamine in brains of aged mice. (1)

    Researchers found that people who drank three or more servings of fruit and vegetable juices per week had a lower risk of developing Alzheimer's disease. Fruit and vegetable juices per week will reduce the risk of developing Alzheimer's disease by 76%.

Researchers at Cardiff University created an antibody which is capable of blocking the production of beta amyloid and can be used as preventive treatment for people with a family history of Alzheimer's.


Alzheimer's disease is not a dangerous disease. It can be controlled if proper care and management is give to the patient right from the diagnosis of the disease till the death. As there is no specific cure aimed in minimising Alzheimer's disease. The primary aim should be to reduce the intensity of the symptoms that the patient suffers. The patient should be supported to bring back his ability to lead a normal life. The disease is fatal, the symptoms can be reduced with the help of medicaments along with proper physical as well as mental support for reducing the patient's hardship.



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Cite this:  C. G. Jincy, Sujith Varma, "THE COMPLICATIONS AND MANAGEMENT OF ALZHEIMER'S DISEASE", B. Pharm Projects and Review Articles, Vol. 1, pp. 543-591, 2006. (

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