Intensive hunt for new medicines

It's 25 years since researchers identified the beta-amyloid protein as the primary component of the hallmark plaques that form in the brain of people with Alzheimer's disease. Sine then, much progress has been made, but still the only drugs available are inhibitors and blockers. Scientists are now battling to find new drugs that can cure the disease, targeting principally beta-amyloid.

Bild på Agneta NordbergThe two types of drug currently used against Alzheimer's disease have no curative effect, but simply impede the development of the disease (see factbox). Their efficacy also varies, possibly owing to the way that doses are not adjusted to how far advanced the disease is in individual patients. This according to Agneta Nordberg, professor at the Department of Neurobiology, Care Sciences and Society.

"PET scans have shown us that the same dose of drug affects the brain in different ways in different individuals, which means that it has a varied effect," she says. "I think that, in future, we should adjust the treatment more to individual circumstances."

Many sufferers and their relatives testify to the importance of knowing the cause of the memory changes. By the time the symptoms appear, the physical effects on the brain have been long established. Recently, a major study carried out by a number of scientists from Karolinska Institutet, the Sahlgren Academy and elsewhere showed that these early changes can be measured using biomarkers in the cerebrospinal fluid. Being thus able to identify not only patients with advanced Alzheimer's but also nascent forms of the disease was a breakthrough, as it is of immense significance to the ability to find and diagnose patients at an early stage of the disease. Researchers at Karolinska Institutet have also developed a technique that uses a PET scanner to visualise and diagnose the disease.

"When it comes to discovering changes and making an Alzheimer's diagnosis, we've made great progress," says Professor Nordberg. "The problem is that we have no curative treatment to offer those who receive the diagnosis."

So far, the drugs used for Alzheimer's disease have been shown to have no effect on early forms of memory loss, or mild cognitive impairment (MCI). This, according to Professor Norberg, might be because studies have not taken into account that MCI is not an obvious prodrome of Alzheimer's disease.

"Only around half the number of people with MCI will go on to develop Alzheimer's disease," she says. "With today's knowledge, we can distinguish these patients by studying amounts of beta-amyloid in the brain. Doing this, we could make a better study in which we sort out the patients who risk developing the disease. We might then be able to show that the drug actually has an inhibiting effect even on these early forms of the disease."

Bild på Bengt WinbladThere are now great hopes of finding drugs that can cure Alzheimer's. Professor Nordberg adds that we must not forget that current attempts to find cures, which in most cases are based on the amyloid cascade hypothesis (i.e. that accumulations of beta-amyloid account for the disintegration of cerebral neurons) has only been going on for the past ten or twenty years. Bengt Winblad, professor at the Department of Neurobiology, Care Sciences and Society at Karolinska Institutet, agrees.

"The drugs in use today are 'first generation drugs' against Alzheimer's disease," he says. "Patients don't get better with the treatment, they just stop getting worse."

Professor Winblad is head of Swedish Brain Power, a national interdisciplinary initiative on neurodegenerative diseases that has as one of its aims to improve treatments for Alzheimer's disease. Linked to the Swedish Brain Power consortium is the KI-Alzheimer disease research centre, where Lars Tjernberg is one of the scientists diligently trying to find new drugs. He is currently running two projects designed to find substances that prevent either the formation or the accumulation of beta-amyloid. In one project, he is looking into the possibilities of inhibiting gamma secretase, one of the two enzymes involved in the production of the protein.

"The problem is that the same enzyme is needed for the production of many other important proteins too, so we're now trying to find a way of inhibiting the formation of beta-amyloid without disturbing the production of other proteins," he says.

Dr Tjernberg and his colleagues at Karolinska Institutet were also the first to find different substances that bind to beta-amyloid and prevent them from accumulating. He is now looking for additional suitable molecules with this property. One of the candidates is curcumin, a colourant found in curry and turmeric. Its potential as a treatment for Alzheimer's disease is currently being tested in the USA.

Bild på Lars Tjernberg"Perhaps the best effect can be achieved by combining these two strategies, and administering one drug that reduces the formation of beta-amyloid and another that prevents the accumulation of any beta-amyloid that still forms," says Dr Tjernberg.

He is also working with the Royal Institute of Technology on a project designed to find ways of visualising and studying intermediate forms of accumulated beta-amyloid, something that is currently difficult to do. In recent years, scientists have actually started to suspect that it is these forms rather than the plaque that is most toxic.

A third conceivable method of treatment is a vaccine, which would either stimulate the body's own defence mechanism to form antibodies to the beta-amyloid, or cause antibodies to be produced outside the body for subsequent injection into the patient. Both variants of the vaccine are being tested in early-phase studies by Professor Winblad and colleagues.

"We're currently examining whether the vaccine is safe and what doses should be administered," he says. "Earlier attempts to produce a vaccine were stopped owing to some serious adverse reactions, but these new vaccines have so far only produced mild side effects. We're therefore now hoping that they'll also stop the development of the disease in patients."

It is still unclear why certain people are affected by Alzheimer's disease, and detailed knowledge about how the disease damages brain cells is lacking.

"Whoever finds the missing piece of the puzzle that can explain how it all works is looking at a possible Nobel Prize," guesses Dr Nordberg.

And maybe one day it would enable scientists to develop entirely new treatment strategies.

Important breakthroughs in the history of Alzheimer's research

Bengt Winblad lists important breakthroughs in the history of Alzheimer's research:

1906 German neuropathologist and psychiatrist Alois Alzheimer presents the first ever images of plaque and neurofibrillary tangles in the brain of a former dementia patient.

1910 The disease is first named after its discoverer by Emil Kraepelin in a textbook.

1976 The lack of acetylcholine (ACH), an essential component of neurotransmission, is revealed, paving the way for the drugs in use today.

1984 Glenner and Wong identify the presence of the beta-amyloid protein in plaque.

1986 The tau protein is described in the neurofibrillary tangles.

1992 Mutations of the gene that codes for the protein deposited in plaque are identified in a British and Swedish family.

1993 A mutation of the apolipoprotein E gene is linked to Alzheimer's. The first Alzheimer's drug, an ACH inhibitor, is registered in the USA.

2002 A new form of drug, the NMDA receptor blocker, is registered.

Text: Cecilia Odlind. Published in the magazine Medicinsk Vetenskap, no. 3, 2009.