What is Alzheimer's disease?

Alzheimer’s disease

What is Alzheimer’s disease?

Alzheimer’s disease (AD) is the most common causative brain disease first characterised by Alois Alzheimer in 1907, his findings were the changes in the brain tissue of a women who had died of an unusual mental illness, when a post mortem commenced, abnormal clumps known as senile or neuritic plaques and tangled bundles of fibres known as neurofibrillary tangles (NFTs) were found. These plaques and tangles in the brain are considered as neuropathological hallmarks of AD. AD is classified under Dementia, Delirium, and Amnestic disorders (Crimson & Eggert 1994).

Dementias are neuropyschiatric disorders defined by widespread symptoms of memory loss, deficits in cognition, and behaviour. Dementias result from the underlying disease, and are not part of normal ageing. Delirium differs from dementia in that it develops over a short period of time, and involves an acute change in the level of consciousness in addition to decline in cognition. The severity, prognosis, and treatment of dementia are dependent entirely on the underlying cause, and accurate diagnosis. AD is becoming increasingly prevalent, and is the most common cause of dementia.

The disease usually begins after the age of 65, and risk of AD goes up with age. While younger people also may have AD, it is much less common. It is important to note, however, that AD is not normal part of ageing. AD affects more than 3% of the 65-74 year old age group and more then 45% of those over the age of 85 years (Hier, 1997). AD affects two times as many women as men, and although genetic inheritance is the primary mode of transmission, several environmental factors may also contribute (Crimson & Eggert 1994).

Memory deficits are the most frequently observed symptom, usually accomplished by disorientation, language difficulties, impairment of judgement, and emotional and behavioural disturbances (Hasegawa, 1998).

AD begin to lose nerve cells slowly where the initial symptom is mild forgetfulness and confusion are little different from those found in normal ageing. But gradually more nerve cells die off the symptoms significantly intensifies. Areas of which the brain are severely affected include the hippocampus that is a centre for memory, and the cerebral cortex, these are involved in many vital thought processes, including higher reasoning. The damage of nerve cells then results in a subsequent drop in levels of certain neurotransmitters, in particular acetylcholine (Evans, 2001).

Neuritic Plaques and Neurofibrillary Tangles

When analysing the brain of a diagnosed AD patient, two main neuropathological markers of the disease are evident at the microscopic level, β-amyloid senile plaques; and neurofibrillary tangles (NFTs). The plaques are formed from insoluble clumps of β-amyloid protein, which gather in the spaces between the nerve cells, while the tangles are found inside of the nerve cells and consist of a hyperphosphorylated version of a protein known as tau, this prevents them from binding to tubulin and instead causes them to join together to make tangles inside the nerve cells which could eventually kill the cell. The two types of protein deposits are central to the development of AD (Evans 2001).

NFTs disrupt the neurons resulting in the inhibition of nervous impulses. In other words, the neurons are unable to transmit messages, and the affected individual is unable to respond to environmental stimuli, therefore losing control of the myriad functions characteristic of senile dementia. NFTs are made up of filament masses characterised by a paired helical structure within the neuronal cytoplasm. The paired helical structures are made up of abnormally phosphorylated tau protein. Tau protein regulates the dynamic instability of the microtubules in the cell, and is possibly associated with the polarity and bundling of microtubules. This phosphorylation causes the tau protein to associate with itself instead of binding with the microtubules, thus resulting in paired helical structures. Although NFTs are best known as indicators of AD, they also found in the brain of a person afflicted with other neurological disorders, such as encephalopathic Parkinson’s disease (Crimson & Eggert 1994).

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Senile plaques are much larger and more complex structures than NFTs. A senile plaque is a complicated lesion consisting of degenerating nerves with a core consistent of insoluble β-amyloid protein (βAP) which forms the plaques that are made from enzymes which act on the β-amyloid precursor protein (BAPP). This consists of between 695-770 amino acids that are long and normally push through the membrane of a selection of cells within the human body. BAPP is coded for by a gene on chromosome 21, it’s been found that people with an alteration on this gene are at risk of developing an early-onset form of AD. Chromosome 14 and 1 are two other genes which have been linked to early-onset of AD, these genes code for two proteins (prensenilin 1 & 2) which form complexes/compounds with other proteins; the complexes also cut membrane-bound proteins like BAPP (Evans, 2001).

β-amyloid protein Composed of 39-49 amino acids, this protein has an instinctive tendency to form insoluble aggregates. Simply stated, the protein precipitates out of the cell fluid and solidifies causing an interruption of the normal tissue function. The abnormal neutrites surrounding the central core originate from both axons and dendrites. Senile plaque seems swollen and is made up of the same material as NFTs. There is a direct relationship between the number of senile plaques and both the severity of the clinical impairment and the decreased neurotransmission of acetylcholine. Because acetylcholine is associated with memory loss, it is believed that the senile plaques are a major cause of short-term memory loss in AD.

Nerve cells close to the plaques appear to be swollen and deformed, which are surrounded by inflammatory cells called microglia theses are part of the brains immune system. There are high density of plaques in the hippocampus and cerebral cortex found in AD patients. The densities of NFTs found in the brains of patients who suffer from AD are related closely to the severity of the dementia in AD, although their presence in the brain is again not exceptional to AD (Evans, 2001).

It’s been known that the plaques and the tangles are closely involved in the nerve cells being destroyed; which are also a target for drug therapy. Refer to the diagram on the many factors involved in AD (Evans, 2001).

Genetic causes

It used to be thought that early-onset cases of AD were genetic, whereas the more common later-onset cases were sporadic (Crimson & Eggert 1994).

There are two types of AD, a familial AD (FAD) and the sporadic AD. The early-onset cases can be attributed to alterations on chromosome 1, 14, 21. Chromosomes 21 is encoded on the β-amyloid precursor protein (BAPP), a small number of early-onset, familial AD cases been known to be associated with mutations in the BAPP, which results in the over production of βAP (Cordell, 1994). The common and most aggressive early-onset cases are to mutations of an Alzheimer’s gene located on chromosome 14, which produce presenilin 1(PS-1) (Rockville, 1996). Similar in structure to presenilin 1 is a protein produced by a gene on chromosome 1 called presenilin 2 (PS-2), which is responsible for early-onset AD. Both PS-1 and PS-2 encode for membrane proteins that might be involved in BAPP processing. It is possible to make predictive testing that indicates which individual will eventually develop the inherited AD.

Another genetic linkage susceptibility to late-onset AD is influenced by apolipoprotein E genotype. Apoliprotein E (APO E) functions as a carrier for cholesterol in the bloodstream and central nervous system and also involved in cellular repair and regeneration. In the brain, APO E is produced by astrocytes and is important in distributing cholesterol for repair of neuronal membranes and myelin. Therefore the production is increased following damage of neuronal tissue (Mirra, 1997). The gene, which produces APO E, is situated on chromosome 19 in a region previously linked/associated with late-onset AD. There are three main alleles of APO E, known as APO E2, E3, and E4. Humans inherit one copy of the APO E gene from each parent. APO E3 is the most common type (90% of individuals have at least one copy), with E2 and E4 occurring less frequently (Behl C. 1999). Inheritance of the E4 allele increases the risk for developing AD compared to those with E2 and E3 (Evans, 2001).

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APO E binds to the BAP deposits located in neuritic plaques and cerebral vessels in the brains of AD patients and is also associated with NFT’s. However the exact role of APO E in the genesis of AD is unclear a protein known as low density lipoprotein (LRP), a receptor for APO E which usually transports cholesterol, and processing release of APP. LRP is found in neuritic plaques (Rockville, 1996). LPR worked with proteins such as α-2-macroglobulin and APO E. This implied that people who had the E4 allele of APO E might have a less efficient system for transporting BAP out of their brains, allowing it to build up and form plaques (Evans, 2001).

Links between the APO E allele and AD pathology have been demonstrated, it has been concluded that APO E genotyping does not give adequate sensitivity or specificity to used alone as a diagnostic test for AD (Mayeux et al., 1998).

The association of APO E with AD is not causative and should thus be considered rather as a risk or predisposition factor (Behl C. 1999). For short version refer to journal cholesterol modulation* and update on AD recent finding journal

Inflammatory mediators

Inflammatory mediators and other immune system constituents are present near areas of plaque formation, which means that the immune system plays an active role in the parthenogenesis of AD. Antichymotrypsin (ACT) and α-2-macroglobulin are acute phase proteins both in the serum and within amyloid plaques of patients with AD. These flammatory mediators have been known to increase BAP toxicity and aggregation.

Current pharmacologic treatments /approaches

Pharmacological treatments for AD are normally suggested only for patients who already have been diagnosed with mild to moderate AD. There are studies been carried out for people who have not yet have the disease but are at risk of developing it. Where investigation into the effectiveness of acetylcholinesterase inhibitors (AChE) like donepezil in individuals with mild cognitive impairment (O’Hara et al 2000). Neurobiologic features such as the build up amyloid and the reduction in ACh, and feasible/possible impairments in immune and inflammatory mechanisms have aided the development of current pharmacological approaches (Small 1998).

There are four therapeutic approaches to AD that can be identified. These are to (1) relieve behavioural symptoms associated with dementia, including depression, agitation, and psychosis (2), relieve cognitive dysfunction to improve memory, language, praxis, attention, and orientation (3), slow the rate of illness progression, thereby preserving quality of life and independence, and (4) delay the time of onset of illness.

Refer to figure, which shows pharmacotherapeutic treatment algorithms for AD.

Cholinesterase Inhibitors

The treatment of AD has progressed since the late 1970’s to a transmitter replacement strategy, based on the facts of a significant deficit acetylcholine (ACh) content in structures such as the Nucleus Basalis of Meynert, the hippocampus and associative cortical areas. This deficit is linked with severe reduction in choline acetyl-transferase activity and relative sparing of post-synaptic muscarinic (M1) receptors (Gauthier 1997). Acetylcholinesterase (AChE) is the main enzyme in the brain, which is responsible for the catabolism of synaptic ACh. Inhibition of AChE with cholinesterase inhibitors (CI) increases the half-life of ACh in the synapse, thus increasing/augmenting the receptor mediated post-synaptic signal (Giacobini 1998). Table 1

Source: Gauthier 1997.

CI delays the intrasynaptic degradation of ACh, thereby presumably prolonging its chemical and functional effects. CI has been the most widely studied experimental treatment for Alzheimer's disease and is currently the only approved symptomatic treatment. CI is a group of drugs used to treat symptoms in individuals with mild to moderate AD.

The best developed approach to treatment aims at correcting the insufficiency of ACh which is associated AD. AChE inhibitors include first-generation compounds such as physostigmine and tacrine and second-generation compounds such as donepezil, rivastigmine, galantamine and metrifonate. These compounds increase the concentration of ACh and the duration of its action in synapses by inhibiting the AChE enzyme, which metabolises ACh. AChE inhibitors are currently the most successful drugs used to improve the transmission of ACh, which could also be more beneficial compared to direct activation of cholinergic receptors.

Tacrine (Cognex) was the first AChE inhibitors licensed for the treatment of mild to moderate AD in 1993. AChE inhibitors reduce the action of the enzyme that removes ACh from the brain, thus maintaining levels of this neurotransmitter in AD patients (Evans 2001). It is a centrally active aminoacridine and is a reversible cholinesterase inhibitor. Use of AChE compounds by the oral route could be moderately limited by problems with bioavailability and adverse gastrointestinal side effects. This problem can be overcome by transdermal administration of AChE (Daniel & Hier 1997). The most important determinant of response to tacrine identified is the adequate dosing which was unlikely to respond to AChE therapy. Or additionally, the use of tacrine has been limited by its relatively short half-life that necessitates dosing at four times per day. Treatment with tacrine, however resulted in only modest improvements in cognition (Sirvio 1999). Tacrine has a low bioavailabilty compared to second-generation CI such as donepezil and rivastigmine, and has a worse side effect Tacrine is fraught with significant side effects including gastrointestinal distress, and asymptomatic, reversible elevations of serum transaminase levels caused by direct hepatotoxicity.It is currently used in the United States as a last-line agent because of a high incidence of hepatotoxicity, and of its significant side effects that severely limited the ability of patients to adhere to the treatment.

The use of tacrine has been replaced by the advent of safer, more tolerable CI’s.

Donepezil is a highly selective, non-competitive, reversible, second generation is a piperidine, CI with specificity for inhibition of AChE. Donepezil is a highly selective AChE inhibitor with a long duration of action

Second-generation cholinesterase inhibitors: Donepezil, formerly known as E2020, is a reversible acetylcholinesterase inhibitor that has dose-dependent activity showing greater selectivity for acetylcholinesterase and a longer duration of inhibitory action than tacrine or physostigmine, as well as greater specificity for brain tissue than peripheral tissue. Encouraging preliminary studies led to the completion of multicenter, placebo-controlled studies examining donepezil at doses of 5 and 10 mg/day versus placebo for 15 and 30 weeks, respectively, as well as another 30-week trial conducted in Europe (15,16). Results of these studies showed statistically significant benefit in both of the primary outcome measures (cognitive function and global clinical impressions), which was somewhat greater at 10 mg/day. Donepezil has been reported to be safer and more tolerable (especially in terms of gastrointestinal distress) than tacrine. Donepezil was approved by the Food and Drug Administration (FDA) in November 1996 for a number of reasons: Its efficacy is generally equivalent to that of tacrine, it is not associated with hepatotoxicity or elevated transaminase levels, and it is thought to have fewer cholinergic side effects than tacrine. The ease of its once-daily dosing may result in improved patient compliance. It also has reduced potential for drug-drug interactions and may be taken with food. Because of donepezil's improved tolerability and because therapeutic doses are achieved quickly, rather than taking months, substantially more patients are expected to experience benefit with donepezil than with tacrine.

Further information about donepezil also suggests that, as with some other cholinergic agents, improvement gained with early treatment is sustained with ongoing therapy (17). Studies are under way to assess donepezil's effectiveness over the long term as well as in patients with more severe dementia or comorbid medical conditions; results should help illuminate its usefulness in a broader patient population.

References:

Cordell B, (1994), B-amyloid formation as a potential therapeutic target for Alzheimer’s disease. Annual review pharmacology Toxicology, Vol 34, 69-89.
Rockville MD (1996), National institute on aging. Progress report on Alzheimer’s disease.
Evans J, (2001). New paths to Alzheimer’s drugs, Chemistry in Britain, 47-51.
Mirra SS, (1997). Alzheimer’s disease and other dementia: Neuropathological considerations. Progress in Alzheimer’s disease and similar conditions, 21-34.
Behl. C (1999). Alzheimer’s disease and oxidative stress: Implications for novel therapeutic approaches. Progress in Neurobiology, Vol 57, pp. 301-323.
Mayeux, R., Saunders, A. M., Shea, S., Mirra, S., Evans, D.,Roses, A. D., Hyman, B. T., Crain, B., Tang, M.-X. and Phelps, C. H. (1998) Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. N. Engl. J. Med. 338, 506-511.
Daniel B. Hier M.D., 1997. Alzheimer’s disease. Elsevier science Inc. Vol 47

pp 84-85.

Crimson M.L. 1994. First drug approved for Alzheimer’s disease. Ann pharmacotherapy, Vol 28 pp 744-751
Gauthier S. 1997. Treatment strategies for Alzheimer’s disease. Clinical review. McGill Journal of Medicine, Vol 3, pp 149-152.
Giacobini E. 1998. Pharmacokinetic and Pharmacologic considerations in: Pharmacotherapy of Alzheimer’s disease.
O’Hara R, Mumenthaler M.S., and Yesavage J.A., 2000. Update on Alzheimer’s disease: recent findings and treatments. West J Med. Vol 172, pp 115-120.
Small G.W., 1998. Treatment of Alzheimer’s disease: current approaches and promising developments. AM J Med: Vol 104, pp 32-38.
Sirvio J. 1999. Strategies that support declining cholinergic neurotransmission in Alzheimer’s disease patients. Gerontology. Vol 45, pp 3-14.