Alzheimer’s disease (AD), the most common form of dementia, affects one in 14 people over the age of 65, according to data published by the UK’s Alzheimer’s Society. This debilitating illness occurs following the premature death of billions of cholinergic neurons in the brain. But current treatments – mainly acetyl cholinesterase inhibitors, such as Aricept, Reminyl and Exelon, and more recent N-methyl D-aspartate receptor antagonists, such as Ebixa – come with side effects, treat only symptoms, and don’t stop progress of the condition (C&I, 2011, 20, 5).
And although the post-mortem brains of Alzheimer’s patients show a plethora of β-amyloid plaques and neurofibrillary tau tangles, there has been some debate as to whether the plaques and tangles are a symptom or cause of the disease.
‘Current thinking is that plaque is a consequence of AD but it may contribute to toxicity,’ says Samantha Burnham, who is working for the Commonwealth Scientific Industrial Research Organisation (CSIRO) on the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study. ‘It is believed that the major toxicity lies in the soluble oligomers of amyloid protein before it is deposited into the plaque. Plaque may be a means for the brain to cope with amyloid toxicity – a rubbish dump for the more toxic soluble amyloid protein, if you like.’
‘The evidence pointing to β-amyloid as a cause of Alzheimer’s disease seems overwhelming,’ says K. Srinivas Sashidhar, research analyst at Frost & Sullivan. ‘Genetic studies reveal abnormal β-amyloid production in familial Alzheimer’s disease, and cell-culture and animal studies, implicate the misfolded protein in everything from neuronal death to behavioural and memory problems.’
Indeed, for nearly two decades, most of the therapeutic research by companies like Pfizer, Elan and BMS, has focused on stopping the formation of β-amyloid before plaques are formed, inhibiting the β- or γ-secretase enzyme involved in β-amyloid production, or trying to prevent the inappropriate aggregation of β-amyloid at a later stage. However, it is still unclear at which point the β-amyloid becomes toxic and which other processes in the body are affected by secretases.
As a result, the sector has been riddled with failures. ‘One of the greatest disappointments in Alzheimer’s therapeutics so far came last year [August 2010] when Eli Lilly abruptly halted a Phase 3 trial of its γ-secretase inhibitor, Semagacestat,’ says Sashidar. Preliminary results from two Phase 3 trials showed that patients treated with the drug showed worse cognition than placebo and showed an increased rate of skin cancer. As well as a blow for Lilly, the news cast some doubt on β-amyloid as a target for effective drug development (C&I, 2010,17,6).
‘The failure of Lilly’s Semagacestat fits the general pattern – so far, no drug designed to modulate the amyloid pathway has proven to be efficacious,’ says Allan B. Haberman, head of Haberman Associates, lifescience consultants in Wayland, Maryland, US. ‘This is making other companies developing γ-secretase inhibitors and modulators nervous.’
Despite some early setbacks, however, many companies like Eli Lilly are continuing development of candidates targeting β-secretase and γ-secretase. ‘Other γ-secretase inhibitors/ modulators are moving forward in their testing, so companies have not given up on the whole class,’ says William Thies, chief medical and scientific officer at the US Alzheimer’s Association.
With current drugs not meeting patients’ needs and the number of AD patients apparently increasing rapidly, the potential market may be the biggest in medicine, certainly in CNS. The current global Alzheimer’s disease market, which was estimated to be around $8bn in 2010, is expected to grow at a CAGR close to 4% from 2010 to 2017, according to Frost & Sullivan. ‘Despite [Lilly’s] failure, research is being continued in this sector due to the attraction of Alzheimer’s disease market – the ultimate high-risk and, if successful, high-reward market is too great for drug manufacturers to resist,’ says Sashidhar.
With the β-amyloid issue unresolved, some researchers have been concentrating on the pathological features of tau, the protein that stabilises microtubules in healthy neurons but if it acquires too many phosphate groups it forms tangles that block neuronal signalling. Although there is a better correlation between dementia and phosphorylated tau, there has been less focus on this area by companies because it is technically more difficult to target and there is some evidence that aggregation of β-amyloid led to toxic forms of tau at a later stage. Nevertheless, at least four companies – Allon Therapeutics, Prana Biotechnology, TauRx Pharmaceuticals, and Noscira – currently have tau inhibitors in Phase 2 trials, according to Frost & Sullivan.
Others are taking different approaches. Pfizer and Medivation’s candidate latrepirdine (Dimebon), for example, has been used as a hayfever treatment and is thought to prevent neurons from malfunctioning by acting on mitochondria. Dimebon is currently in Phase 3 trials.
Meanwhile, writing in Nature Medicine, Dennis Selkoe from Harvard Medical School says previous candidate drugs aimed at β-amyloid may have failed because they were flawed, the mouse models were inadequate or they were not tested on people with only mild or presymptomatic Alzheimer’s (doi: 10.1038/ nm2460).
‘It is widely believed that amyloid deposition and plaque builds up in the brain up to 15 years prior to disease detection by cognitive testing, when there is already significant brain damage,’ say Burnham and her AIBL colleagues. ‘It is likely that, due to the late detection of the disease, drug candidates for AD have been largely ineffective. Drug candidates need to be tested at the early stages of disease before irreversible damage occurs. There is thus a real need for early detection as well as a means to measure the rate of progression of AD.’
Early detection of AD
Some of the questions surrounding β-amyloid and tau may be answered thanks to recent, early stage research. For example, Burnham and her AIBL colleagues have correlated blood measurements with the amount of amyloid plaque seen in the brain – a step towards a screen for Alzheimer’s that could also be used as a research tool to monitor drug candidates. The work was presented at the recent Alzheimer’s Association International Conference in Paris, France.
Before it can be turned into a population-based screening test for Alzheimer’s, however, the efficacy of the test must be validated and its efficacy improved, say Burnham and AIBL colleagues.
Biomarkers and screens are a key development trend at the moment. ‘The Alzheimer’s research field is very actively exploring biomarkers for a number of reasons,’ says Thies. ‘Certainly, the opportunity and attractiveness of early detection and treatment is one of the main reasons. The need to track the clinical effectiveness of treatments is also very important.”
Recent research at the European Neuroscience Institute suggests that a microRNA, called miR- 34c, may be a diagnostic marker for the onset of cognitive decline linked to Alzheimer’s, as well as a possible target for therapeutic approaches. The researchers found that miR-34c is elevated in the hippocampus of aged mice, a mouse model for Alzheimer’s, as well as in Alzheimer’s patients and that inhibiting miR-34c restores memory performance (EMBO DOI: 10.1038/ emboj.2011.327).
Meanwhile, researchers in the US have shown that antidepressants cut levels of amyloid in the brains of mice, and that the brain scans of healthy people show less amyloid in those with a history of antidepressant use (J. Cirrito et al, PNAS,in press).
‘Amyloid plaques are one of the hallmarks of Alzheimer’s disease. The plaques precede AD by many years, perhaps decades so there is a potential window to intervene,’ says one of the researchers, Yvette Sheline, associate professor of psychiatry, radiology and neurology at Washington University, US.
Sheline says her team is now examining the effect of antidepressants in reducing β-amyloid production in the cerebrospinal fluid in normal volunteers, and is also exploring how to conduct a prophylactic trial of antidepressants in cognitively normal volunteers who have increased amyloid in the brain.
Making brain cells
More recently, scientists in the US have made basal forebrain cholinergic neurons (BCFN) – among the earliest cells that die from Alzheimer’s disease – from human embryonic stem cells (doi: 10.1002/ stem.626 - hESCs).
The researchers have also made BFCN from induced pluripotent stem cells by using cells from patients with Alzheimer’s disease, according to one of the researchers John Kessler, director of the Northwestern University Stem Cell Institute. The BFCN generated this way could be used for a variety of uses, for: high throughput screening to identify drugs that support their survival; studying the differences between BFCN from patients with Alzheimer’s disease and controls; and potentially for transplanting to help ameliorate memory deficits, says Kessler.
But it is Eli Lilly’s candidate Solazenumab and Pfizer’s/Johnson & Johnson’s Bapineuzumab that everyone currently has their eye on, says Sashidhar. Both are monoclonal antibodies that work with the immune system, binding to β-amyloid and helping to clear accumulated β-amyloid peptides in the brain. Both are being tested in Phase 3 trials on thousands of participants with mild-to-moderate Alzheimer’s disease.
‘If the drugs being tested work, there will be an explosion of new anti-amyloid therapies being tested; if they don’t work, I expect that there will be diminished interest in anti-amyloid therapy,’ says Thies. ‘Most people either in or observing the field realise that until the current trials are done the debate will remain roughly where it is now: There are believers, non-believers and agnostics – and it will stay that way until more human data are available.’
Emma Dorey is a freelance science writer based in Brighton, UK.