ALZHEIMER’S DISEASE

What is Alzheimer's?

Alzheimer's disease is the commonest cause of dementia - a group of progressive conditions which involve memory loss (especially short-term memory), poor concentration, poor sense of time and space, difficulty in finding words or understanding other people, difficulty in perceiving and interpreting surroundings, mood changes and emotional upsets. As their condition worsens, people with dementia may get lost, engage in inappropriate behaviour or become unable to carry out simple everyday tasks. Eventually, they may show personality loss and become dependent on others. Alzheimer's disease accounts for 62 per cent of all cases of dementia. Vascular dementia, caused by damage in the brain following blockages in blood flow, accounts for a further 20 per cent.

It is difficult to diagnose Alzheimer's with certainty. Diagnosis is based on excluding other causes of dementia and on medical history. Computed Tomography or Magnetic Resonance Imaging scans of the brain show tissue loss over time, especially in the hippocampus (Figure 1), and, in advanced cases, brain shrinkage. However, these methods are not sufficient for a conclusive diagnosis. This is only possible after death, when microscopic examination of brain sections shows characteristic protein deposits inside brain cells (neurofibrillary tangles) and outside them (senile plaques).

Who does Alzheimer's affect and what does it cost?

Dementia affects as many as 5 per cent of people over 65, rising to 20 per cent over the age of 80. More than 400,000 people in the United Kingdom are estimated to suffer from Alzheimer's, some 80,000 of them with mild disease and the remaining 320,000 with moderate to severe disease. Aging of the population is expected to lead to a steady increase in the number of people affected by Alzheimer's, placing an increasing burden on their families and all parts of the healthcare system. Alzheimer's is, however, not simply a natural consequence of aging but a physical disease. A great deal has been learned in the past decade about factors that raise or lower the risk of the disease and about the biochemical basis of Alzheimer's, and this has resulted in a big increase in efforts to find better treatments.

The costs of caring for people with Alzheimer's disease are difficult to estimate. Costs also depend markedly on the stage of disease. The NHS bears relatively little of the cost of dementia, with local authorities and individuals (patients and their relatives) funding much of the care. Caregiving time and lost earnings for family carers make up the largest part of the costs, followed by the cost of professional carers. The total cost of providing care for Alzheimer's has been estimated at more than £6 billion per year, while expenditure on medicines for this condition in 2004/05 was approximately £60 million (about £1,000 per patient per year).

Present treatments and shortcomings

There is currently no cure for Alzheimer's. However, it has been known for some time that levels of a chemical messenger (a neurotransmitter) called acetylcholine (ACh) that acts in the brain (site 1, Figure 3) are reduced by 20-40 per cent in people with Alzheimer's, and medicines that prevent breakdown of ACh by inhibiting the enzyme acetylcholinesterase (AChE) can help with treatment of symptoms in those whose disease is not too far advanced.

Three AChE inhibitors are currently available in the United Kingdom: donepezil (Aricept, Eisai and Pfizer), rivastigmine (Exelon, Novartis) and galantamine (Reminyl, Shire). Clinical trials have shown that about 10-30 per cent of patients show an improvement with these medications compared with placebo treatment in one or more areas of measurement such as cognition, global functioning and daily activities. Gastrointestinal side effects (nausea, vomiting, diarrhoea) are the most common adverse reactions.

Memantine (Ebixa, Lundbeck), developed by Merz Pharma, is the fourth medicine to be made available for use in Alzheimer's. It is an inhibitor of the NMDA receptor in the brain, which responds to glutamate, another chemical messenger that is involved in memory and learning (site 6, Figure 3). Memantine has been shown to produce cognitive and behavioural improvement in the more advanced stages of Alzheimer's where AChE inhibitors may be less effective.

The use of these medicines has recently been called into question by a ruling from the Government's National Institute for Health and Clinical Excellence (NICE) that they do not meet criteria for cost-effectiveness and should be prescribed on the NHS only on a restricted basis (AChE inhibitors) or not at all (memantine). This conclusion has been strongly criticised by organisations representing doctors and patients, as it does not take into account the benefits of these medicines to patients and their carers/families that are not reflected in costs accruing to the NHS.

What's in the development pipeline?

Further research continues on AChE inhibitors. Novartis has a rivastigmine skin patch in Phase 3 development, which may be more suitable for use in people with Alzheimer's than tablets, which patients may forget to take. Eisai has conducted Phase 3 trials that showed that donepezil is also effective in those with severe Alzheimer's disease.

Huperzine-A is an agent developed from Chinese herbal sources that also inhibits AChE. Neuro-Hitech Pharmaceuticals is testing it in Phase 2 trials in the United States. The company is also developing a skin patch form, while DebioPharm has a form (ZT-1) of Huperzine-A in Phase 2 trials which is taken by mouth. This compound has also been claimed to have nerve-sparing properties as well as inhibiting AChE.

Also in the US, Torrey Pines Therapeutics is exploring Posiphen in Phase 1 trial. This compound has a dual action in Alzheimer's. In addition to being a selective AChE inhibitor, it has been shown to inhibit the formation of beta-amyloid precursor protein (site 4, Figure 3), which is the starting point for the formation of the characteristic amyloid plaques seen in the brain of patients with Alzheimer's. The company also has a compound (bisnorcymserine) in preclinical development that inhibits another ACh-metabolising enzyme.

AChE inhibitors help to prolong independent living and reduce the burden on carers, but they do not provide a long-term solution to the treatment of Alzheimer's. The eventual goal must be to develop medicines that modify the course of the disease.

Compounds which may do this can be grouped according to the sites at which they act (Figure 3). Medicines acting at site 2 mimic nerve growth factor (NGF) and are taken up at nerve endings, where they promote repair. Those acting at site 3 stimulate neuronal nicotinic (N) receptors and may also protect nerve cells. Those that act at site 4 prevent plaque formation by modulating its production or clearance, while others may act at site 5 to damp down the secretion of neurotoxic (nerve damaging) compounds by glial cells. One of these neurotoxic compounds is glutamate. This is an important neurotransmitter in the brain that acts via specific (NMDA and other) receptors (site 6) on certain neurones. However, high concentrations of glutamate are toxic and this toxicity is amplified by beta-amyloid protein. Beta-amyloid protein is normally removed from the brain by being transported through the blood-brain barrier, but this barrier is damaged in Alzheimer's disease and excess beta-amyloid protein accumulates in characteristic senile plaques in the brain.

Of the medicines in development that act in a nerve growth factor-like manner, or which stimulate production of NGF (site 2, Figure 3), the most advanced are Ebewe's cerebrolysin, which is in Phase 3 trial, and the oral agent SR 57746 (Xaliproden) from sanofi-aventis, also in Phase 3, which stimulates the production of naturally occurring NGFs. In addition, sanofi-aventis is researching another once-a-day oral compound of the same type (SR 57667, paliroden) which is now in Phase 2 trials. Another small molecule candidate with NGF-like properties is T-817MA from Toyama Chemical, now at Phase 1.

Compounds that activate some of the nicotinic ACh receptors in the brain (site 3, Figure 3) have been shown to improve cognition and memory. Such medicines are being developed by several companies. Abbott has ABT-089 in Phase 2 trial in patients with Alzheimer's and Targacept, in collaboration with AstraZeneca, has the compound TC-1734 (AZD 3480) at the same stage. Athenagen's GTS-21 is in Phase 1 trial and Memory Pharma has MEM 3454 at the same stage, while sanofi-aventis has SSR 180711 in Phase 1 development.

Much research has been directed towards developing medicines that can affect the formation and breakdown of amyloid protein plaques (site 4, Figure 3). Generation of beta-amyloid peptide from amyloid precursor protein is an early step in this process and agents that inhibit the enzyme gamma secretase would be expected to block this process and reduce plaque formation. Eli Lilly's gamma secretase inhibitor LY450139 is entering Phase 3 study, while Eisai is just starting Phase 1 trials with its agent E-2012.

Several other approaches are being taken to inhibiting amyloid plaque formation. Tramiprosate (Alzhemed, Neurochem) is a small molecule that binds to beta-amyloid peptide and prevents its deposition in plaque, as well as reducing its potential to damage nerve cells. A Phase 3 study with this agent has been started in patients with mild-to-moderate Alzheimer's. TransTech Pharma also has a candidate medicine that reduces beta-amyloid levels, and this has reached Phase 2 trial.

Other attempts to block or reverse plaque formation involve passive or active immunisation. Elan and Wyeth are studying an anti-amyloid beta monoclonal antibody (AAB-001, bapineuzumab) in Phase 2 trials. Other companies have similar antibodies at the Phase 2 (Eli Lilly) or Phase 1 stage (Roche), while Novartis and Cytos Biotechnology are collaborating on the Phase 1 development of a vaccine (CAD106) that will generate anti-amyloid antibodies. Elan and Wyeth also have an active immunity candidate (ACC-001) at Phase 1. Animal studies have shown that specific antibodies against beta-amyloid can dissolve pre-existing plaques and it is hoped that such an immunological approach may offer a real prospect of halting or even reversing the course of disease.

Non-steroidal anti-inflammatory drugs (NSAIDs) have shown signs of being able to reduce inflammation in brain cells in Alzheimer's (site 5, Figure 3) but some of this class of medications (Cox-2 inhibitors) have been found to have side-effects that make them unsuitable for long-term, high-dose use. R-flurbiprofen (Flurizan, Myriad Genetics) is an NSAID of low anti-inflammatory activity but with an ability to reduce levels of beta-amyloid through inhibition of gamma secretase. It has reached Phase 3 trial in earlystage Alzheimer's.

Another compound similar to memantine which also has inhibitory activity at NMDA-type receptors for the neurotransmitter glutamate (site 6, Figure 3) has reached clinical trials in Alzheimer's. Merz Pharma and Forest Labs have neramexane in Phase 3 trial.

Serotonin (5-HT) is another neurotransmitter that is thought to play a role in cognition and GlaxoSmithKline has 742457, an antagonist that is highly specific for 5HT₆ receptors, in Phase 2 study. Wyeth's lecozotan, a 5HT_1A receptor antagonist, is also at Phase 2, as is the 5HT₄ agonist (PRX-03140) from EPIX Pharma. It has been suggested that medicines affecting 5HT receptors may be helpful in addressing some of the behavioural and psychological symptoms of Alzheimer's, but development of these compounds is not yet far enough advanced for their value to have become clear.

Other neurotransmitter pathways are also being explored for their therapeutic potential. Muscarinic (M₁) receptors have also been implicated in memory and learning, and Torrey Pines Therapeutics has a selective M₁-agonist (NGX267) in Phase 1 development. An increased level of the dopamine- and noradrenaline-degrading enzyme monoamine oxidase-B (MAO-B) has been found in Alzheimer's, and several compounds that inhibit it are being investigated. Teva's ladostigil tartrate is a selective MAO-B inhibitor that also helps to protect nerves and inhibit AChE. It has reached Phase 2 trial, as has the company's other MAO-B inhibitor rasagiline, which is already available for use in Parkinson's disease. Of the other transmitters, UCB is exploring a GABA analogue (Piracetam) in Phase 3 trial for mild cognitive impairment, Saegis Pharma has a GABA_B receptor antagonist (SGS742) at Phase 2 for mild-to-moderate Alzheimer's, and sanofi-aventis is exploring the selective CB1 antagonist AVE1625, which has reached Phase 2 trial.

Lastly, there are some existing medications, indicated for other uses, that have shown preliminary evidence of being able to decrease the risk of developing Alzheimer's, and formal clinical trials are now in progress to evaluate their ability to affect the course of established disease. Several studies had indicated that the cholesterol-lowering statins may have such an activity, and Pfizer is conducting a Phase 3 study of atorvastatin (Lipitor), in mild-to-moderate Alzheimer's. Similarly, insulin resistance (seen in type 2 diabetes) has been found to correlate with the risk of developing Alzheimer's and glucose metabolism is known to be abnormal in those with the disease. A small study had shown that the insulin-sensitiser rosiglitazone XR (GlaxoSmithKline) produced a significant cognitive improvement in Alzheimer's patients lacking the apo-lipoprotein E-4 gene. GSK has started a Phase 3 study of rosiglitazone in mild-to-moderate Alzheimer's.

The longer-term future

Interest in developing new treatments for Alzheimer's remains intense, fuelled by recent discoveries about the disease processes, and a great number of alternative approaches are under investigation in earlier-stage clinical and preclinical trials by companies such as Pfizer (PF-4494700, Phase 2), Dainippon- Sumitomo (AC-3933, Phase 2), Memory Pharma (MEM1003, Phase 2), Accera Inc (AC-1202, Phase 2), Prana Biotech (PBT-2, Phase 1), AstraZeneca (AZD 1080, Phase 1) and others. With this degree of investment of research effort, future prospects for a treatment that can slow or halt the progress of Alzheimer's would seem encouraging.

FOR FURTHER INFORMATION CONTACT:

The Alzheimer's Society
Gordon House, 10 Greencoat Place
London, SW1P 1PH
Phone: 0845 300 0336 (Helpline)
Website: www.alzheimers.org.uk