The Journal of Quality Research in Dementia, Issue 4 (lay summary)

The amyloid hypothesis and potential treatments for Alzheimer's disease

Ayesha Khan

Scientific Liaison Officer, Alzheimer's Society, Gordon House, 10 Greencoat Place, London, SW1P 1PH, UK Telephone 0207 423 3607; Email

Amyloid seems to be the most likely cause of the damage that underpins Alzheimer's disease. Improving understanding the role of amyloid will help to identify ways to prevent or stop the damage that causes the disease.

Current treatments for Alzheimer's disease merely address symptoms. A deeper understanding of the brain pathology of dementia, with a focus upon the so-called amyloid hypothesis, is leading to the development of a number of new treatments which may be able to hold off the progress of the disease, offering new hope to those who receive them soon after diagnosis.

The current limited numbers of drug treatments for Alzheimer's disease actually treat the symptoms of the disease rather than the root cause. Better treatments would tackle the death of cells in the brain that is the underlying cause of the condition.

Researchers into Alzheimer's disease are hopeful that they can find a way of stopping the destruction of brain cells altogether or at least to slow it down considerably. Developing a treatment that can do this will need researchers to identify, understand and then prevent the causes of Alzheimer's disease. The exact causes of the disease are not yet understood, although one theory - known as the amyloid hypothesis - has come to dominate explanations for the damage that occurs to the brain. This article is a review of how research into the amyloid hypothesis is enabling researchers to identify ways to develop early and effective treatments for Alzheimer's disease.

The amyloid hypothesis

Amyloid precursor protein (APP) is a protein found widely throughout the body. The amyloid hypothesis is that a fault with the processing of amyloid precursor protein (APP) in the brain leads to the production of a short fragment of APP known as beta-amyloid. The theory rests on the idea that it is the accumulation of this sticky protein fragment in the brain that triggers the disruption and destruction of nerve cells that causes Alzheimer's disease. The accumulated clumps of beta amyloid are known as amyloid plaques. The hypothesis is thus that there is a fault with the over production of beta amyloid or with the mechanism that usually clears it from the brain, or possibly both.

The nature of beta-amyloid

APP is a long protein made up of up to 771 amino acids and beta-amyloid is produced when two different enzymes chop down this long chain. Betasecretase makes the first cut and then gammasecretase gets to work to produce beta-amyloid, which can be 38, 40 or 42 amino acids long. When beta amyloid is 42 amino acids long it is chemically stickier than the other lengths and is therefore more likely to clump into plaques. The three genetic faults that lead to early-onset Alzheimer's disease all alter the role of gamma secretase, leading to an increased production of beta amyloid 42.

The accumulation of beta-amyloid in the brain is thought to lead to damage to neurons which in turn triggers inflammatory responses as the brain attempts to repair itself. It is also thought to cause the formation of tangles made up of a protein called tau. The tangles also contribute to the damage to brain cells which causes the symptoms of dementia.

As well as the link with the genetic faults that lead to early-onset Alzheimer's disease, there is a range of other evidence for the amyloid hypothesis For example, beta amyloid has been found to kill neurons that have been cultured in the laboratory; mice with human Alzheimer genes inserted in their DNA have both developed plaques and shown decreases in their learning and memory skills and animals with induced Alzheimer's disease developed the condition more slowly when they were given an anti-amyloid vaccine. Despite all of this evidence that the accumulation of beta-amyloid is key to the damage that causes Alzheimer's disease, the missing link in the hypothesis remains the question of how exactly the damage is done. There is increasing evidence that it's in the early stages that most of the damage is done. It seems that the toxic ingredients are present from the moment that the first few strands of protein stick together, making the deposits literally poisonous to nerve cells. It may also be significant that early on the clumps are smaller, more mobile and thus able to affect more nerve cells in the brain.

The route to potential treatments

A number of treatments that either target the removal of beta-amyloid or aim to disrupt its production from APP in the first place are currently being developed and tested.

Preventing production

Researchers are trying to establish whether it is possible to prevent beta-amyloid from being produced by interfering with the two enzymes that create it from APP. There has been some success in preventing the action of beta- secretase in animal models by hindering the work of an enzyme that works with it. Attempts to interfere with the action of gamma-secretase have been even more successful with several drugs reaching the Phase III stage of trials; however none have yet gone beyond this stage.

Another route is to prevent beta-amyloid from clumping together to form the harmful deposits that eventually become plaques. Tests in the laboratory have identified drugs that can prevent the protein from accumulating. The next step will be to see if these compounds work in animal models of the disease.

Containing copper

Metals such as copper and zinc are present in the brain and are thought to be involved in the processing of APP. There is evidence that an antimicrobial drug called clioquinol, which interacts with copper, can help to prevent the formation of very small early clumps of beta-amyloid in the brain. However the interactions associated with copper are very complex and not all scientists agree that copper contributes negatively towards the development of Alzheimer's disease, with some people arguing that it should be given as a supplement to try and prevent the disease.


After positive results in animal models, where an active vaccine had repeatedly shown that it was possible to trigger a process that used the immune system to clear away the deposits or plaques of amyloid in the brain, a human form of this treatment was developed.

After good results from initial safety tests the clinical trial started in 2000. The vaccine was delivered by injection, but the trial was halted two years later when 12 out of the 360 participants developed serious inflammation in the brain following their second injection of the vaccine. The inflammation was caused by their immune system over-reacting to the treatment. This disappointing end to the trial did not mean that the idea of a vaccine to clear deposits had failed, rather that this particular vaccine or method of delivery had been unsuccessful. In fact post mortem investigations have revealed that participants that both did and did not experience side effects all had fewer amyloid plaques than would have been expected.

Nicotine and current Alzheimer's drugs

Research at Lancaster University has developed two new techniques to measure the size and rate of development of the clusters of beta-amyloid in the very early stages. This has enabled researchers to test a number of substances to see if any of them could slow down or prevent the development of the plaques.

Two of the substances tested threw up intriguing results. The first was nicotine, which was observed to hinder plaque formation, the second was galantamine, which is the chemical name for the cholinesterase inhibitor currently marketed as Reminyl.

The researchers tested all three of the current Alzheimer's drugs and found that Reminyl appears to block beta-amyloid from sticking together. More research is needed, but this evidence suggests that Reminyl might turn out to have more beneficial effects for people with Alzheimer's disease than is currently thought. Preventing beta-amyloid from accumulating will mean that it could be used to treat the root cause of the damage to brain cells as well as fulfilling its other role as a cholinesterase inhibitor of boosting communication between cells.

Overall there is positive evidence from work in the laboratory and using animal models that there are ways that we can prevent the formation of amyloid plaques or to boost the brain's ability to clear away the deposits once they form. The challenge for research is to turn this promising early evidence into treatments that can be used safely in humans. Results from trials in the next five years will provide evidence of whether or not the routes to treatments that are currently being investigated are going to bear fruit.

Further Reading

Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002;297:353-6. [Erratum, Science 2002;297:2209.]

Shoji M, Golde TE, Ghiso J, et al. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 1992; 258 (5079): 126-9

Pollack SJ, Lewis H. Secretase inhibitors for Alzheimer's dis-ease: challenges of a promiscuous protease. Curr Opin Investig Drugs 2005; 6 (1): 35-47

Caughey B, Lansbury PT. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 2003; 26: 267-98

Rogers JT, Lahiri DK. Metal and inflammatory targets for betaAlzheimer's disease. Curr Drug Targets 2004; 5 (6): 535-51

Moore SA, Huckerby TN, Gibson GL, Fullwood NJ, Turnbull S, Tabner BJ, El-Agnaf OMA & Allsop D. (2004) Both the D-(+) and L-(-) enantiomers of nicotine inhibit Aβ aggregation and cytotoxicity, Biochemistry 43, 819-826

CG, Ballard, K. A. Chalmers, C. Todd et al. Cholinesterase inhibitors reduce cortical Aß in dementia with Lewy bodies Neurology 2007;68:1726- 1729

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