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Terry Pratchett is one of the best-read authors in the English language, a much-loved writer of comic fantasy fiction, but he has recently said that due to early-onset Alzheimer’s disease that he can no longer write dedications when signing books. Other well-known personalities diagnosed with Alzheimer’s include former US President Ronald Reagan, Irish novelist Iris Murdoch, former British Prime Minister Harold Wilson and Spanish leader Adolfo Suárez.

It has been estimated that 26.6 million people worldwide had Alzheimer’s in 2006 and that this number may quadruple by 2050 due to increased longevity of life. Given that the majority of those affected are to be found in the developed world this amounts to a potentially large customer base for pharmaceutical firms.

There are very few pharmaceutical remedies available to combat Alzheimer’s despite this potential customer base. In fact, only four medications have been granted licenses by the regulatory bodies in the US and Europe to treat the cognitive cause of Alzheimer’s disease. Of these, three are acetylcholinesterase inhibitors and the other, memantine, is an NMDA receptor antagonist. None of these drugs has an indication with regard to the delay or halting of the disease’s progression.

“Only four medications have been granted licenses by the regulatory bodies in the US and Europe to treat the cognitive cause of Alzheimer’s disease.”

Despite the scale of the potential problem that Alzheimer’s disease poses, not all major international pharmaceutical companies are seeking to develop treatments for the condition. For example, GlaxoSmithKline (GSK) spokesperson David Outhwaite says that GSK has no Alzheimer’s drugs in development.

As a problem associated with advanced countries it is no surprise that development of drugs aimed at treating Alzheimer’s is not a priority for the often state-controlled pharmaceutical companies of the developing countries.

However, this situation is not the case with all the big pharmaceutical companies. AstraZeneca, Jansenn, Pfizer and Novartis among others have products in various stages of development.

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Reducing symptoms

There are few drugs available to sufferers of Alzheimer’s but those that do exist include the cholinesterase inhibitors donepezil, galantamine and rivastigmine and the NMDA receptor antagonist memantine. The cholinesterase inhibitors work by reducing the destruction of acetyllchoine, a characteristic of Alzheimer’s disease, and thereby increase acetyllchoine levels in the brain. This is thought to maintain the transmission of information between certain brain cells and can therefore reduce some of the symptoms of the disease, such as memory loss, apathy and anxiety, although it cannot reverse its effects.

Around 50–60% of people using these drugs show a small improvement or stabilisation of their condition. However, the National Institute for Health and Clinical Excellence (NICE) has ruled that these drugs are not cost effective in the early stages of Alzheimer’s and should only be given to people in moderate stages of the illness.

Memantine, also known as Ebixa, is thought to work by affecting the brain chemical glutamate which is involved in memory and learning. Completed studies show that just over half the people taking memantine display some slowing down of the development of Alzheimer’s but this has only been demonstrated so far in those with severe dementia. As with the cholinesterase inhibitors NICE has issued guidelines restricting its use due to concerns over cost effectiveness.

New developments

It seems unlikely that either the cholinesterase inhibitors or memantine offer an effective way forward in the treatment of Alzheimer’s disease but recent developments may be more positive. These are gamma-secretase modulators (GSM) and HDAC inhibitors.

“It seems unlikely that either the cholinesterase inhibitors or memantine offer an effective way forward in the treatment of Alzheimer’s disease.”

There is no positive proof of these hypotheses as tests cannot be carried out on living subjects, but some scientists say that Alzheimer’s works due to brain cells being damaged by “plaques” of protein. The gamma-secretase modulators (GSMs) reduce the production of a protein fragment that is prone to building up and prevents the fragments accumulating by a number of different mechanisms.

Of particular interest to scientists is that the GSMs work by acting on the protein, not the enzyme that forms the proteins that make up the plaques. It also seems that not only do they work on the enzyme but on the amyloid beta itself.

Jacksonville Mayo Clinic Department of Neuroscience’s Professor Todd Golde, who has been carrying out research in this area, says that this has implications for disorders other than Alzheimer’s as it broadens the notion of what drugs can do.

This development may prove to be extremely valuable commercially, but given the massive expense of clinical trials it is too early to speculate.

Promising trials

High costs – the most important factor in the development of commercially viable drug treatments – have not deterred a number of major pharmaceutical companies from entering this arena with its potentially massive rewards. Novartis spokesperson Ulrike Engels says that CAD 106, an active immunotherapy in early-phase clinical development for the treatment of Alzheimer’s disease, is expected to be submitted for marketing authorisation in 2012 or soon after.

Novartis says that CAD 106 offers potential to advance the treatment of Azheimer’s. Pfizer too has new products in the pipeline, including Dimobon in Phase III, which, like many other products aimed at Alzheimer’s has also been shown to be effective against Huntingdon’s disease, another neurodegenerative condition. However, how much potential these drugs may have the company cannot say.

New effective pharmaceutical treatments for Alzheimer’s are without doubt some way in the future and will almost certainly remain expensive, beyond the grasp of much of the population if trends continue. But they do appear promising in that they seem likely to offer a degree of protection from the disease.

“New effective pharmaceutical treatments for Alzheimer’s are some way in the future and will almost certainly remain expensive.”

In addition to pursuing the development of new pharmaceutical treatments, AstraZeneca is also committed to making early diagnosis a reality, spokesperson Christopher Sampson says.

Working in conjunction with the Karolinska Institutet in Sweden and the Banner Alzheimer’s Institute in the US, AstraZeneca has submitted a US investigational new drug application for its AZD2184 biomarker.

The AZD2184 biomarker is a positron emission tomography (PET) radioligand that binds selectively to amyloid and allows the plaque to be measured in real time using a PET scan.

This innovative technology may offer a promising approach for the early diagnosis of Alzheimer’s disease in patients, as well as the assessment of the severity of Alzheimer’s disease and the effectiveness of new drugs that aim to reduce amyloid plaques. As with all diseases it may be that early diagnosis will prove to be the most cost-effective and customer-friendly technique to combat Alzheimer’s.