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Disease focus: Alzheimer’s disease

Looking at the challenges, goals and developments for the pharma industry within specific disease and therapy areas
Alzheimer's disease

Alzheimer's disease is the most common cause of dementia, which affects 35.6 million people worldwide. First described by German neurologist Alois Alzheimer in 1906, it is a physical disease affecting the brain. Over its course, protein plaques and tangles develop in the structure of the brain, leading to the death of brain cells. People with Alzheimer's also have a shortage of the chemicals needed for transmission of messages within the brain.

Alzheimer's is a progressive disease, with three distinct stages: early, moderate and advanced. In the early stage, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small portion of sufferers, difficulties with language, perception, or execution of movements are more prominent than memory problems. The disease does not affect all memory capacities equally. Older memories of the person's younger life, learned facts and implicit memory are affected to a lesser degree than more recent ones.

Language difficulties are mainly characterised by a shrinking vocabulary and decreased word fluency, which lead to a general decline in oral and written language. In this stage, the sufferer is usually capable of adequately communicating basic ideas. Difficulties in performing fine motor tasks may be present but they commonly go unnoticed. As the disease progresses sufferers often continue to perform many tasks independently, but may need assistance or supervision.

In the moderate stage, progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions. Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated, so the risk of falling increases. Behavioural and neuropsychiatric changes become more prevalent. Common manifestations are wandering and irritability, leading to crying, outbursts of unpremeditated aggression or resistance to caregiving. Paranoia and other delusional symptoms can also appear. Sufferers also lose understanding of their disease processes and limitations.

Prevalence of dementia, population aged 30 and over, 2006
Prevalence of dementia (click image to enlarge)

In the advanced stages, patients are completely dependent on their caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. However, patients can often understand and return emotional signals. Muscle mass and mobility deteriorate to the point where sufferers are bedridden and they lose the ability to feed themselves. The disease is a terminal illness, with the cause of death typically being an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself.

London-based Alzheimer's Disease International's World Alzheimer Report 2010, states that the disease and other dementias cost 1 per cent of GDP (£386bn) and are set to accelerate in coming years. It predicts that the number of people with dementia will double by 2030 and more than triple by 2050.

No one cause
So far, no one single factor has been identified as a cause for Alzheimer's disease. It is likely that a combination of factors, including age, genetic inheritance, environmental factors, lifestyle and overall general health, are responsible. In some people, the disease may develop silently for many years before symptoms appear.

Age is the greatest risk factor for dementia. It affects one in 14 people over the age of 65 and one in six over the age of 80. However, it is not restricted to older people. For example, in the UK, there are more than 16,000 people under the age of 65 with dementia, although this figure is likely to be an underestimate.

Many people fear that they may inherit the disease and scientists are currently investigating the genetic background to Alzheimer's. There are some families where there is a very clear inheritance of the disease. However, in most cases, the influence of inherited genes for Alzheimer's disease in older people seems to be small.

The environmental factors that may contribute to the onset of Alzheimer's disease have yet to be identified. Research has shown that people who smoke, have high blood pressure, high cholesterol levels or diabetes are at increased risk of developing it. People who have had severe head or whiplash injuries also appear to be at increased risk.

Historic developments
There is currently no cure for Alzheimer's disease. However, drug treatments are available that can temporarily alleviate some symptoms or slow down their progression in some people. The first Alzheimer's drug trial, investigating tacrine, was held in 1987. It targeted the symptoms of the disease and became the first Alzheimer's drug to be approved by the US Food & Drug Administration (FDA). Twenty years on, more than 500 clinical trials have been conducted for identification of possible treatments. To date, the FDA has approved five drugs: tacrine (1993), donepezil (1996), rivastigmine (2000), galatamine (2001) and memantine (2003).

Chemical shortage
People with Alzheimer's have been shown to have a shortage of the chemical acetylcholine in their brains. The drugs donepezil hydrochloride, rivastigmine and galantamine work by maintaining existing supplies of acetylcholine. The side effects are usually minor but may include diarrhoea, nausea, insomnia, fatigue and loss of appetite. The drug memantine works in a different way and is the only drug that is recommended for people in both the moderate and severe stages of the disease. Its side effects may include dizziness, headaches, tiredness and hallucinations or confusion. These drugs are not a cure, but they may stabilise some of the symptoms for a limited period, typically 6-12 months or longer.


Age- and sex-specific prevalence of dementia in EU countries, 2006
Prevalence of dementia
(click image to enlarge)

Other drugs that have been used to control symptoms include haloperidol for aggression and agitation, olanzapine and risperidone for agitation, quetiapine for those suffering upset and carbamazepine, used to reduce symptoms such as aggression, wandering and hallucinations. In addition, antidepressants, benzodiazepines, statins and nonsteroidal anti-inflammatory drugs are often prescribed to patients.

The future
New treatments focus on discovering the genes that cause Alzheimer's and blocking or slowing them before symptoms begin. Currently nine genes have been linked to Alzheimer's definitely, three of which affect only the relatively rare forms of the disease, one affects the risk of the late-onset form and five genes discovered earlier in 2011 affect the more common one.

Drugs in development aim to modify the disease process by impacting one or more of many brain changes that Alzheimer's causes. These changes offer a potential target for new drugs to stop or slow the progress of the disease. Many researchers believe that successful treatment will eventually involve a cocktail of medications aimed at several targets, in a similar way to the latest cancer and AIDS treatments.

A breakthrough drug would treat the underlying disease and stop or delay the cell damage that leads to worsening symptoms. There are several promising drugs in development and testing, but the industry needs more volunteers to complete clinical trials.

The Author
Liz Wells is deputy editor of PME.
She compiled this article from her own research.

1st August 2011

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