Investigating the Alzheimer’s disease puzzle
Alzheimer’s disease is an irreversible, neurodegenerative brain disease that is associated with a progressive decline in memory, thinking, language and learning capacity. It is the most common cause of dementia in people aged 60 years and over, and accounts for approximately 75% of the total dementia cases worldwide.
The global prevalence of Alzheimer’s disease is approximately 3.9% in people over the age of 60, but close to 45% in people over the age of 85. And despite a major new study showing that rates of dementia in at least one industrial country are falling because of healthier lifestyles,(1) the disease will remain a major burden to families and healthcare systems for some time to come. Given the spectre of ever-rising costs, and the impact of the disease on patients and families, governments and industry are allocating more resource towards finding new treatments. Unlike in the past, the focus is on treatments that will tackle the disease early, thereby stopping a patient’s decline into dementia.
Like detectives investigating a major crime, however, the medical world has many clues to the Alzheimer’s puzzle but as yet, no real solutions. In this article we summarise the leading theories about the disease, and some of the efforts that are underway to develop novel therapies.
Current treatments for Alzheimer’s disease treat the symptoms only, and their effect is limited or absent in many patients. No drug has yet been approved that can slow the progression of the disease. In fact, efforts to develop ‘disease modifier’ medicines received a setback in 2012. Last year alone, two promising late-stage monoclonal antibodies targeting beta-amyloid in patients with mild-to-moderate Alzheimer’s disease failed to meet their primary efficacy endpoints. They were Eli Lilly and Company’s solanezumab, and an antibody jointly developed by Johnson & Johnson Inc and Pfizer Inc called bapineuzumab (2). More recently, in 2013, two products with different mechanisms of action failed in human studies, while a third investigation into a new indication for a marketed drug came to a sudden halt. The failures were for Baxter International’s intravenous immunoglobulin and Lilly’s beta secretase (BACE) inhibitor, LY2886721. A Phase 3 study of the Baxter drug failed to confirm the results of an earlier Phase 2 study in which the drug had halted disease progression for a small number of patients for three years. The trial of the Lilly drug was stopped because of abnormal liver test results in patients.
Finally, the development of an Alzheimer’s indication for bexarotene, a marketed skin cancer agent, stopped after three teams of researchers were unable to replicate the findings of mouse studies using the drug. The mouse studies had shown that bexarotene achieved an astonishing reduction in amyloid plaque production, but this could not be confirmed.
Alzheimer’s disease is a progressive disorder that affects nerve cells, or neurons, which are essential for memory, thinking and language skills. According to conventional theory, these nerve cells can be destroyed by two types of abnormal lesions that have been found in the post-mortem brains of Alzheimer’s patients. They are sticky clumps of protein fragments called beta-amyloid plaques that form outside and around neurons, and neurofibrillary tangles, or fibers which are largely composed of the Tau protein and accumulate inside nerve cells. These deposits interfere with the normal functioning of neurons which lose their ability to communicate with one another and eventually die. As the damage spreads, it affects the hippocampus which is essential for memory. As more neurons die, regions of the brain shrink and in the final stage of the disease, the damage is widespread.
Although it is still unclear how the Alzheimer’s disease process begins, scientists believe damage can be incurred to the brain a decade or more before people start showing symptoms (3). And while the beta-amyloid plaques and tau are hallmarks of the disease, it is still unclear whether they cause it, or are a byproduct of it.
This uncertainty, coupled with the urgent need to find better therapies, has stimulated new research, some of which challenges the conventional hypotheses.
One novel approach has come out of the University of Southampton in the UK where a team led by Roxana Carare have shown the importance of perivascular drainage of soluble beta-amyloid from the brain. Professor Carare and colleagues have noted that, as people age, the arteries in the brain stiffen, reducing the elimination of soluble beta-amyloid. The team describes this pathology as cerebral amyloid angiopathy (CAA) (4).
In a similar vein, researchers from the Weill Cornell Medical College in New York City, US have reported that the innate immunity receptor CD36 plays a role in damaging cerebral blood vessels and promoting the accumulation of amyloid deposits – or CAA. They argue that CD36 might be a rational target for a future Alzheimer’s therapy (5).
Further to the ‘cleansing’ hypothesis, a team from the University of Rochester Medical Center, also in the US, has identified a network of conduits around the outsides of arteries and veins that help clear waste products from the brain. Using imaging technology to study mice, the researchers report that the system pushes large volumes of cerebrospinal fluid through the brain each day as well as amyloid protein. They say Alzheimer’s disease arises when the system, which they call the glymphatic system, fails to clear the protein.
In a recent article in Science, the research group argues that magnetic resonance imaging might be used to monitor this system and identify patients at risk for Alzheimer’s disease – before neurodegeneration begins. Such tools could also be used to monitor drug treatments or identify genetic markers that could predict susceptibility to the disease (6).
Still another approach has come from the Department of Chemistry at the University of Cambridge in the UK where Professor Christopher Dobson and colleagues have described the existence and the role of ‘aberrant’ forms of protein molecules called ‘toxic oligomers’. These molecules are said to be a cause of Alzheimer’s disease. In May, the researchers reported a new finding – the molecular pathway controlling the formation of these ‘toxic oligomers’. This discovery could lead to the development of new diagnostics and/or a new generation of targeted drugs, they said (7).
FOCUS ON EARLY-ONSET DISEASE
Alzheimer’s disease can be the result of genetic inheritance, environmental factors, general health and of course, old age. Most people who develop Alzheimer’s are over the age of 60 years and have what is called ‘late-onset’ disease. By contrast, ‘early-onset disease’ can occur in people from the age of 30 upward. Early-onset Alzheimer’s is rare and represents fewer than 5% of all cases. Most early-onset cases are familial and caused by variants in one of three known genes inherited from a parent. Monogenetic diseases are the target of drug research everywhere because scientists now believe that these diseases might be prevented, or even cured.
It is no surprise therefore that early-onset Alzheimer’s disease is the focus of a unique drug trial in Colombia involving funding from the US National Institutes of Health. This is a trial of 2,500 family members in Medellin who have the gene for early-onset Alzheimer’s disease. Medellin contains the largest known population in the world with early-onset autosomal-dominant disease. Besides the US government, the trial is being run by Banner Alzheimer’s Institute in Phoenix, Arizonia, the University of Antioquia in Medellin and Genentech (Roche). Genentech’s experimental antibody drug crenezumab, which targets beta amyloid being used in the trial. The goal is to see if crenezumab can sustain memory and cognitive skills in people who are genetically disposed to the disease.
Meanwhile, another prevention trial for patients with early-onset disease is taking place in the US under the auspices of Washington University School of Medicine in St Louis, Missouri. This trial is testing the investigational antibody gantenerumab from Roche and solanezumab from Lilly. Both antibodies bind to amyloid-beta. [Editors note: Although solanezumab did not meet its primary endpoint in a Phase 3 AD trial in 2012, pooled data did show a slowing of cognitive decline].
These innovative trials will both test novel therapies for the disease and validate biomarkers and diagnostics including the recently licensed Amyvid. Amyvid is a radiopharmaceutical used in positron emission tomography imaging to highlight amyloid protein plaques.
THE REGULATORY ANGLE
In both the US and Europe, the regulatory authorities now accept that clinical trials of prospective Alzheimer’s disease treatments will have to be different than those for other diseases where one first targets late-stage patients, and if successful, moves on to patients at risk of early-stage disease. There is now a consensus that Alzheimer’s disease must be tackled at a much earlier stage – as illustrated by recent draft guidance from the Food and Drug Administration. In this guidance, the US agency says it supports the concept of enriching trial populations in early-disease trials with patients who are most likely to progress to more over dementia using clinical and biomarker-based criteria. The agency says that it is “open to considering the argument” that a positive biomarker result in combination with a positive finding on a primary clinical outcome measure may support a claim of disease modification (8).
Meanwhile, Europe’s biggest public-private partnership, the Innovative Medicines Initiative, is funding projects to improve clinical trial outcomes in Alzheimer’s disease.One project, Pharma-Cog, is assembling data from previously conducted trials, together with the results of blood tests, brain scans, and behavioural tests to simulate Alzheimer’s disease symptoms in healthy volunteers and then test the effect of candidate medicines. The goal is to develop new drugs faster and treat patients earlier.
One thing is clear: public and private authorities are investing in Alzheimer’s research like never before. And new companies are springing up to develop innovative therapies. These include, most recently, Rodin Therapeutics in Cambridge Massachusetts, US which was launched in June by Atlas Venture LP and Proteros Biostructures GmbH of Germany. The company aims to apply insights from epigenetics to the discovery of candidate Alzheimer’s therapies.
Many countries have launched local or regional initiatives to tackle the Alzheimer’s problem and such initiatives should be pursued. Nevertheless, breakthrough results may not occur without the strong determination of a vast international collaboration where all stakeholders involved in the field share information through a large, common and open framework.
1. Matthews, Fiona E, ‘A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England’, The Lancet, 16 July 2013.
2. Bapineuzumab AD programme discontinued, 6 August 2012, and Lilly to discuss solanezumab results with regulators, 25 August 2012, MedNous, www.mednous.com.
3. Alzheimer’s Foundation of America, ‘About Alzheimer’s’, www.alzfdn.org and Alzheimer’s Disease Fact Sheet, US National Institute on Aging, www.nia.nih.gov.
4. Perivascular Drainage of Amyloid-beta Peptides from the Brain and its Failure in Cerebral Amyloid Angiopathy and Alzheimer’s disease, Brain Pathology 18 (2008) 253-266.
5. Innate immunity receptor CD36 promotes cerebral amyloid angiopathy, Proc Natl Acad Sci USA, 2013 Feb 19;110(8):3089-94.
6. Nedergaard, Maiken, ‘Garbage Truck of the Brain’, Science Vol 340 28 June 2013. 7. Knowles, Tuomas, ‘Scientists identify molecular trigger for Alzheimer’s disease’, University of Cambridge, 21 May 2013, www.cam.ac.uk/research/news.
7. February 2013, www.fda.gov.
8. FDA offers new guidance on developing drugs for Alzheimer’s disease,
Author : Jean-Claude MULLER, Special Advisor,Innovation & International Relationship (I&IR)
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