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DonateThe McCusker Foundation for Alzheimers Disease Research
a world free of
Alzheimer’s disease
184 Hampden Rd,
Nedlands, WA 6009.
Telephone: (08) 9347 4200
Facsimile: (08) 9347 4299
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Current Research
Current Research of the Sir James McCusker Alzheimer's Disease Research Unit.
Professor Ralph Martins is the Director of Research of both the Sir James McCusker Alzheimer’s Disease Research Unit, which is administered by Edith Cowan University, and the Centre of Excellence for Alzheimer’s Disease Research and Care. His research is conducted under the auspices of both organisations.
The following is an overview of the major research projects and related activities the Sir James McCusker Alzheimer’s Disease Research Laboratory is undertaking.
Multidisciplinary approach to enhanced diagnosis in Alzheimer’s disease. Molecular and Neuropsychological Predictive Markers of Cognitive Decline
The major aim of the project is to investigate the association between genetic, biochemical, brain imaging and neuropsychological factors that may contribute to cognitive decline and the development of Alzheimer’s disease. The study recruits individuals with or without subjective memory complaints. A variety of neuropsychological, imaging, biochemical, genetic and clinical analysis are being performed to generate a “high risk” profile for Alzheimer’s disease (AD). Positron emission tomography (PET) is also being used to image the brain to identify hallmarks of the disease (ie beta amyloid deposition). The major outcome of this project will be to determine whether a ‘high risk’ biochemical and genetic profile exists in individuals that have a higher frequency of cognitive decline as determined by neuropsychological testing. In addition, results from the study will assess the possible predictive value of PET imaging for AD. By developing accurate early diagnostic strategies, appropriate therapeutic or preventative interventions for AD can be implemented prior to disease onset.
In 2006, 129 new participants were recruited to the study group which now totals 486. There are now 8 years of cognitive data on some of our participants. A manuscript is being prepared on the relationship of subjective memory complaint to measures of quality of life and cognition, using these longitudinal data (abstract to be presented at the 20th Anniversary Cognitive Aging Conference, 2007).
PET scans have been performed on individuals to examine the effect of an AD-related genetic risk factor on brain glucose metabolism. These results have been presented at an international conference (36th Annual Meeting of the Australian and New Zealand Society of Nuclear Medicine, 2006) and will be prepared for publication.
Also being investigated is the link between body mass index and risk of developing Alzheimer’s disease by performing body fat analysis on our participants. This enables the examination of any association between body fat, cognitive decline, genetics and Alzheimer’s related proteins in blood. An analysis of cholesterol, body composition and cognition has recently been completed. A manuscript is currently being prepared for publication (abstracts to be presented at IBRO 2007 and the Alzheimer’s Australia National Conference 2007).
This project is crucial as it will lead to the development of early diagnostic tests that in turn will result in more effective preventive and therapeutic approaches.
Understanding the Mechanism of Action of the Major Alzheimer Gene Apolipoprotein E
This project is part of a program grant funded by the Institute of Health (NIH), involving Professor Ralph Martins's team and three other US research teams investigating other aspects of beta amyloid metabolism and accumulation.
There is strong evidence that a certain type of the APOE gene (the 4 allele) is a strong risk factor for Alzheimer’s disease (AD). It is now generally accepted that individuals possessing a single 4 allele have a 3-fold increased risk for AD, and those containing two 4 alleles have 9-fold increased risk of developing AD by 80 years of age.
The type of protein (apoE4) produced by this gene has a role of increasing beta amyloid levels in the body.
In animal studies, Professor Martins demonstrated that the presence of apoE alters the rate of clearance of beta amyloid from two major organs known to clear this protein from the body, the liver and kidney. The research is being extended to investigate the metabolism and clearance of beta amyloid from peripheral tissues and brain in various animal models. The results from this project will provide considerable insight into the mechanism(s) involved in beta amyloid clearance/metabolism. This may lead to the identification of ways to enhance clearance of accumulated beta amyloid within the AD brain, which may have therapeutic potential.
The animal studies have commenced and preliminary data in a small number of mice indicate that apoE e4 delays the clearance of the beta amyloid from the blood. The animal studies are continuing to validate these results in a larger number of animals and to determine the effect of beta amyloid metabolism and clearance from the brains and peripheral tissues of these animals.
This work will enhance our understanding as to why APOE 4 carriers are at such high risk of Alzheimer’s disease and allow the development of effective preventive programs in this highly susceptible group that represents half the patients affected by Alzheimer’s disease.
This project is being undertaken in collaboration with:
Dr Jacqueline Phillips (Associate Investigator, Murdoch University).
Professor Sam Gandy (Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia.)
Investigating the Role of Gonadotropins in the Pathogenesis of Alzheimer’s Disease
Hormonal changes associated with ageing have been implicated in the increased risk of developing Alzheimer’s disease. Many studies have provided evidence to show that low levels of oestrogen or testosterone increase the risk of developing AD. This effect may be due to these hormones altering the levels of beta amyloid (A ), a molecule that is thought to be central to AD pathogenesis. Sex hormones are under the control of complex feedback loops that involve hormones called gonadotropins. High levels of the gonadotropin, luteinizing hormone (LH), have also been implicated in the increased risk of developing AD and in disease pathogenesis. The clinical significance of LH and the sex hormones and their relative contribution to the pathogenesis of AD remain to be determined. This is an ongoing project that investigates the role of LH in AD pathogenesis and assesses in animal studies the use of gonadotropin lowering agents as a therapeutic strategy for this disease.
In 2004, we published findings showing that LH can increase the production of beta amyloid in neuronal cells. In a small study of elderly men (40) we have recently shown that increases in blood levels of LH are associated with increases in blood levels of beta amyloid, providing further evidence the LH can modulate beta amyloid levels. These findings will be presented by Dr Giuseppe Verdile, at the International Brain Research Organisation (IBRO), world congress of Neuroscience in Melbourne, in July 2007 and a manuscript has been submitted for publication to the journal Molecular Psychiatry.
One of our international students, Mr Limbikani Kanyenda successfully completed his Masters thesis recently, extending our original findings to investigate the more potent analogue of LH, the pregnancy hormone, hCG. He showed that hCG can influence the metabolism of the parent molecule to beta amyloid, APP in rats. In a small pilot study PhD student, Miss Anna Barron has shown that hCG, can impair memory in a mouse model for AD.
Further work is required to determine if these changes are associated with AD-like pathology and if LH exacerbates pathology in the brains of these mice. In addition these findings require validation in a larger number of mice. Her preliminary findings will be presented at the 30th Annual Meeting of the Japan Neuroscience Society in Yokohoma, Japan in July, 2007.
We were recently awarded an NHMRC grant in conjunction with Professor Gary Hulse and Professor Tae Ji to investigate the mechanism(s) involved in LH and hCG mediated changes in beta amyloid production using cell culture and AD animal models. In addition, LH lowering agents will be assessed in an animal model for AD as a therapeutic strategy for treating this disease. Further human clinical studies to assess the therapeutic efficacy of one of the LH lowering agents is planned to be undertaken by the Clinical Trials Division in the near future.
This project is being conducted in collaboration with:
Professor Gary Hulse (Chief Investigator, School of Psychiatry and Clinical Neurosciences, UWA).
Professor Tae Ji (Chief Investigator, Department of Biological Chemistry, University of Kentucky, USA).
Investigating the Role of Testosterone in Alzheimer’s Disease.
Several studies have reported that compared to controls, men with AD and other dementias have lower serum testosterone levels. Professor Martins, together with Professors Almeida and Gandy have shown that reducing blood levels of testosterone in men is associated with an increase in blood levels of beta amyloid. In addition, supplementing neuronal cells in culture with testosterone has been shown to reduce beta amyloid levels and attenuate its toxicity. Taken together, these studies suggest that the reduction in testosterone during aging could contribute to the development and the underlying causes of AD.
This project investigates the role of testosterone in beta amyloid production and assesses testosterone replacement therapy in animal and human studies as a potential therapy for the
effective treatment of AD. The work is part of a PhD undertaken by Dr Eka Wahjoepramono, a neurosurgeon from Siloam Gleneagles Hospital, Lippo Karawaci, Tangerang, Indonesia.
Preliminary findings from the animal studies indicate that testosterone replacement as a physiological dose reduces beta amyloid levels in both the blood and the cerebrospinal fluid. This work will be presented at the Fifth International Society for the Study of Androgen Deficiency held in London in March, 2007. Further analysis of brain tissue from these animals is required to determine if testosterone can attenuate beta amyloid levels and oxidative stress in the brains of these animals.
The human study will involve men with memory complaints, mild cognitive impairment (MCI) or AD. The human study is divided into two parts, a short term (pilot) study to determine the dose of testosterone to use and the long term, randomized study to assess the efficacy of testosterone at lowering beta amyloid and improving memory.
The pilot study has been completed and the dose of testosterone to be used in the long-term study determined. There have been 63 people screened for the study of which 31 are eligible for the study. Twelve have commenced the treatment.
In addition an open labeled study has commenced in Perth with 25 men recruited to date. Preliminary work clearly demonstrates that testosterone treatment lowers beta amyloid levels in 4 months in most of the men in this study and lowers the hormone LH, a major contributor to Alzheimer’s disease, in all participants.
This approach provides a promising avenue for effective prevention and treatment of Alzheimer’s disease which has the advantage over other agents of being rapidly implemented following successful clinical trials.
This study is being conducted in collaboration with Dr Malcolm Carruthers in London, England.
Therapeutic Efficacy of a Cholesterol lowering agent in a mouse model for Alzheimer’s disease
High cholesterol levels associated with coronary artery disease and atherosclerosis has also become an important risk factor for developing AD. Studies have shown that high levels of cholesterol results in the accumulation of beta amyloid within cells in culture and within the brains of mice.
This project aims to assess the ability of the cholesterol lowering drug, avasimibe (an ACAT inhibitor that has reached phase 3 human clinical trials for atherosclerosis) at reducing levels of beta amyloid and oxidative stress within the brains of a mouse model for AD. In addition we will assess the inhibitors ability to improve memory in these mice. This project will determine whether this inhibitor has value as a therapeutic agent for AD.
Efficacy of Combined Nutritional Supplement Therapies in the Prevention of Alzheimer’s disease in a mouse model of AD.
Diet is now considered to be an important environmental factor in AD, with a recent study of 3,718 subjects aged over 65 years showing that over a 6 year period, those subjects with the highest vegetable intake were associated with a slower rate of cognitive decline. Converging epidemiological data has also suggested that a low dietary intake of omega-3 essential fatty acids is another possible risk factor for AD.
Therefore, the use of complimentary and alternative medicine (CAM) therapies offers the potential for preventative therapies. However, these therapies need to be critically evaluated for their mechanisms, efficacy and safety before human clinical trials are undertaken.
This project will evaluate, in a mouse model for AD, the efficacy of the nutritional supplements; EGCG from green tea, curcumin, omega-3 essential fatty acids and lipoic acid, to determine whether these treatments in combination offer preventative therapies for the treatment of AD.
The development of effective preventative strategies for the treatment of AD is critical if we are to reduce the number of people that are expected to develop AD over the next 50 years, due to the rapidly aging population. This is an exciting approach that builds on our long term understanding of different antioxidants and beta amyloid metabolism resulting in a combination of these compounds to provide maximal synergy. If successful in the current animal study, it has the advantage of being able to progress rapidly to clinical trials as these antioxidants are food products known to be very safe for human consumption.
This project is being undertaken in collaboration with:
Dr Gerald Munch (Chief Investigator, Department of Biochemistry and Molecular Biology, James Cook University).
Dr Markus Wenk (Chief Investigator, Department of Biochemistry and Department of Biological Sciences National University of Singapore, Singapore).
Prof Barry Halliwell (Chief Investigator, Department of Biochemistry and Department of Biological Sciences, National University of Singapore, Singapore).
Prof Migayalakshmi Ravindranath (Chief Investigator, Department of Molecular & Cellular Neuroscience National Brain Research Centre, India).
Developing agents that selectively target the enzyme responsible for beta amyloid generation
The enzymatic mediated generation of beta amyloid from its larger parent molecule (the amyloid precursor protein – APP) is a key event in the pathogenesis of Alzheimer’s disease. The enzyme responsible for this catalytic process is termed gamma secretase. Dys-regulation of APP processing leading to the overproduction and accumulation of beta amyloid leads to neuronal death/dysfunction culminating in dementia.
The current therapeutic strategies aimed at inhibiting gamma secretase to lower beta amyloid levels have failed, most likely due to the activity of this enzyme on other proteins that are important cellular pathways and functions. This additional role for the enzyme is very important to consider when developing agents that reduce beta amyloid production.
This project aims to identify the particular site within the gamma secretase that is directly responsible for the production of beta amyloid. The site will be identified using an array of molecular biological and protein analysis techniques and will utilise an insect cell culture model of gamma secretase activity that we are currently developing. The critical site will then be used to screen for peptide agents that selectively reduce beta amyloid production without affecting other enzyme products that are important in cellular function. Overall, this project will provide valuable insight into the site(s) that are directly responsible for gamma secretase activity and thus provide more specific targets for development of rational therapeutic strategies.
We are currently developing the gamma secretase insect cell model. An honours student (Kirsteen Lingoh, supervised by Professor Ralph Martins and Dr Giuseppe Verdile) contributed to this work and submitted her thesis in 2006. She passed her degree with first class honours. An international student, Mr Sudarsan Krishnaswamy has enrolled in a PhD and is currently being supervised by Professor Ralph Martins and Dr Giuseppe Verdile to undertake this work.
This project is being undertaken in collaboration with:
Associate Professor David Groth (Curtin University)
Professor Paul Fraser (Centre for Research into Neurodegenerative Diseases, University of Toronto, Canada)
Professor Sam Gandy (Professor Sam Gandy (Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia).
Gene Hunting
AD tends to run in families, but it does not necessarily mean that all family members will get the disease. Just as not having AD in your family does not mean that you won’t get it. As with most diseases, both environmental factors and genes play a role in the development of AD.
There are two basic types of AD known as familial and sporadic. Familial AD (FAD), which runs in families, is a rare form of the disease, affecting less than 10% of AD patients. It occurs more frequently in younger people (usually before age 60) than sporadic AD. It is the result of a certain inheritance pattern called autosomal dominance in which, all offspring in the same generation have a 50/50 chance of developing AD if one of their parents have the disease.
To date, mutations in three genes have been identified as causing FAD. Mutations have been identified in the amyloid precursor protein (APP) gene on chromosome 21, in the presenilin-1 (PS1) gene on chromosome 14 and in the presenilin-2 (PS2) gene on chromosome 1. Ultimately, all three genes appear to influence whether an abnormal protein, known as beta amyloid, is deposited in the brain to cause AD.
The McCusker Foundation has identified many of the mutations in these genes in Australian families, thus offering the next generation a better chance of more effective treatment due to early diagnosis in those families.
While the identification of these three genes has helped considerably in advancing our understanding of the disease, studies over the last few years suggest that other genes may play an important role in AD. Researchers in the McCusker laboratory are hunting for new genes that will provide the potential for improved diagnosis as well as better understanding of the mechanisms causing the disease.
Over the last 10 years a number of families have been interviewed and blood samples collected in order to identify the genes that lead to Alzheimer’s disease in these families. Sufficient families have now been recruited for the team to commence work to identify these genes and this research program has recently commenced in collaboration with leading scientists from the CSIRO division of Genetics based in Sydney.
Identification and Validation of peptide agents that neutralise beta amyloid toxicity.
Beta-amyloid is considered a prime target for drug development based on the overwhelming evidence in favour of this peptide being central to the pathogenesis of Alzheimer's disease (AD). One approach to developing effective treatments for AD is to design therapies that would inhibit beta amyloid toxicity. This goal can be achieved either via inhibiting beta amyloid production, enhancing its clearance, or by directly neutralising its toxicity. The neutralisation strategy focuses on inhibiting the ability for beta amyloid to produce an oxidant called hydrogen peroxide which is thought to be responsible for the oxidative stress observed in AD. Professor Martins and his team developed a novel screening method to identify peptides that selectively recognize the unique part of beta amyloid that is responsible for hydrogen peroxide production and thereby reduce/ inhibit its damaging effects on neuronal cells. Three small peptides were identified by a molecular biology technique called phage display. This work led to an international patent (PCT/AU02/01754) and the formation of a spin-off company, Alzhyme Pty Ltd. Alzhyme was awarded a Biotechnology Innovation Fund grant, which was matched dollar for dollar by a commercial group allowing further validation of these peptides.
One of three peptides identified (referred to as ANA-1) was most effective at reducing hydrogen peroxide and attenuates beta amyloid induced neuronal death in cell culture. In stage two of this project, which is currently underway, we evaluate the therapeutic potential of ANA-1 and a modified version of this peptide referred to as ANA-5, to be delivered directly to the brain, and assessing their activity in a transgenic animal model of Alzheimer’s disease (AD).
Current Research of the Centre for Excellence in Alzheimer's Disease Research and Care
(information being updated)
Current Collaborations
University of Adelaide & ECU. Truncating presenilin mutations and their effects of gamma-secretase activity, tau and beta-catenin. CIA Michael Lardelli, CIB Ralph Martins.
ECU Martins R, Verdile G, Hulse G, (UWA) Ji Tae. The role of Gonadotropins in the production of Alzheimer's beta amyloid.
Dementia Collaborative Research Centres on Prevention, Early Intervention and Risk Reduction. Grant funded by Australian Government Dept of Health & Ageing comprising Australian National University; University Melbourne; Alzheimer’s Australia, Victoria; Edith Cowan University; University of Queensland.
Edith Cowan University, together with Western Australian Dept of Health, University of Western Australia and in collaboration with University of Melbourne headed by Professor Colin Masters CSIRO Flagship Collaborative Research Program Detecting and Preventing Alzheimer's Disease: towards diet and lifestyle interventions.
“Molecular and Neuropsychological Predictive Markers of Cognitive Decline. Pr. Ralph Martins, Dr Ian Martins, A/Pr Nicola Lautenschlager. ECU & UWA
Centres of Excellence in Science and Innovation Program Award funding in support of the Alzheimer’s Disease Research Centre entitled Centre of Excellence for Alzheimer’s Disease Research and Care. Awarded by Western Australian State Government 2005. Submitted by Edith Cowan University representing partners: Australian Neuromuscular Research Institute, Anglican Homes Inc. and the Sir James McCusker Training Foundation, The Hall and Prior Aged Care Group, Hollywood Private Hospital, The McCusker Foundation for Alzheimer’s Disease Research and the University of Western Australia. State Government $1.3 million from the State Government and $2.6 million from the participating universities.
NIH (USA) Program Grant, Prof Sam Gandy Farber Institute at Thomas Jefferson University, Prof Jorge Ghiso, New York University, Prof. Joseph D Buxbaum Mt Sinai School of Medicine, and Prof. Ralph Martins, University of Western Australia and Edith Cowan University Interdisciplinary Approach to Alzheimer Drug Discovery.
Collaboration has been ongoing for the last 11 years with Professor Sam Gandy from Farber Institute for Neurosciences, Thomas Jefferson University Philadelphia into an interdisciplinary approach to Alzheimer Drug discovery. The collaboration with Professor Sam Gandy has resulted in his visit in 2000 to the University of Western Australia as the Raine Visiting Professor and several joint publications including a recent publication in JAMA and the subsequent 4 month (April-July 2003) visit to Professor Gandy's Farber Institute by Professor Ralph Martins to further progress our ongoing collaborative partnership.
Close collaboration has been established since 2004 with Dr Markus Wenk and Dr RH Yang from the National University of Singapore. Project entitled “Lipodomics of neuronal membranes – Identification of lipids involved in neurosecretion and neurodegenerative diseases".
Drs Peter Hyslop and Paul Fraser from the University of Toronto to identify genetic risk factors in Alzheimer’s disease. This collaboration has involved exchange of students and staff between the University of Western Australia and the American and Canadian institutes.
Professor Judit Miklossy from the University Institute of Pathology, University of Lausanne in Switzerland and latterly from Kinsmen Laborotory of Neurological Research, University of British Columbia, has supplied 200 brain samples from post-mortem confirmed Alzheimer’s disease cases for biochemical and genetic studies. This collaboration has resulted in several publications.
The role of oestrogen in Alzheimer's disease is being undertaken in collaboration with Professor Susan Craft from the University of Washington.
The structure and function of the amyloid precursor protein in Alzheimer’s disease is being studied in collaboration with Professor Toshihara Suzuki of Tokyo University, Japan.
A study into the role of gonadotropins in the development and progression of Alzheimer's disease is being undertaken in a joint collaboration with Ass. Professor Craig Atwood from Wisconsin University Maddison Medical School, USA.
Collaboration has been instituted with Professor D. Allan Butterfield from the Dept of Chemistry and Center of Membrane Sciences, University of Kentucky, Lexington USA. This collaboration is to study oxidative stress in Alzheimer's disease and this year one of our PhD students has spent 6 months with Professor Butterfield investigating the protective effects of apoE isoforms on Abeta induced oxidative stress in cell culture.
Collaboration is ongoing with Associate Professor Joachim Hallmayer from Stanford University Department of Psychiatry and Behavioural Science to identify genetic and molecular risk factors in neurodegenerative diseases. This collaboration has resulted in several papers.
Professor Hans Forstl from Klinik und Poliklinik fur Psychiatrie und Psychoptherapie der Technischen Universitat Munchen, Munich, Germany and Dr Nicola Lautenschlager from the School of Psychiatry & Clinical Neurosciences, UWA, Dept of Old Age Psychiatry Royal Perth Hospital.
Ongoing collaboration has been established with Dr Lautenschlager and Professor Forstl into identification of biomarkers for cognitive decline in subjective memory complainers.
Ongoing collaboration has been established with the three major research groups working on Alzheimer’s disease in Australia led by Professor Colin Masters at the University of Melbourne, Associate Professor Peter Schofield from the Garvan Institute in Sydney and Professor Tony Broe from the Prince of Wales Medical Research Institute, Sydney, New South Wales.
Dr Elizabeth Milward from the University of Newcastle New South Wales, ongoing research into "Iron-related genes and neurodegenerative disorders".
Grants
NHMRC 453622 University of Adelaide & ECU Truncating presenilin mutations and their effects of gamma-secretase activity, tau and beta-catenin. CIA Michael Lardelli, CIB Ralph Martins. Yr 1 2007 $118,050, Yr 2 2008 $193,500, Yr 3 2009 $183,500. Yr 4 62,250 08 The funding for this grant is shared between the participants with the actual distribution varying each year depending on the stage of the research.
NHMRC 426406 ECU Martins R, Verdile G, Hulse G, Ji Tae. The role of Gonadotropins in the production of Alzheimer's beta amyloid. No salary for CIA Std Project Grant. 3 years Yr 1 2007 $168,750; Yr 2 2008 $108,750; Yr 3 2009 $123,750
FIB-Lief The Nanoscale Characterisation Centre WA Focussed Ion Beam Nanofabrication and Milling Facility Arie Van Riessen, Ralph Martins et al (Curtin) (UWA) (ECU) $500k for the FIB-SEM.
Thus grant was for a major piece of equipment which is shared between a number of Universities.
Dementia Collaborative Research Centres on Prevention, Early Intervention and Risk Reduction. Grant funded by Australian Government Dept of Health & Ageing comprising Australian National University; University Melbourne; Alzheimer’s Australia, Victoria; Edith Cowan University; University of Queensland Total budgets Yr1: $625.000 Yr 2: $650.000; Yr 3: $677.000
CSIRO Flagship Collaborative Research Program Detecting and Preventing Alzheimer's Disease: towards diet and lifestyle interventions. Edith Cowan University, together with the Western Australian Dept of Health, University of Western Australia and in collaboration with University of Melbourne headed by Professor Colin Masters Total Value of Application $3,000,000. Western Australia’s share is 40%.
The Wickings Trust R Newton, RN Martins "Keeping the Aged Healthy, Happy and Independent through Physical and Cognitive Exercise" project. – 2006 $155,600, 2007 $167,500, 2008 $123,000.