In search of Alzheimer’s Disease Holy Grail
In late March this year (2018) I attended the Advances in Alzheimer’s and Parkinson’s Therapies An AAT-AD/PD Focus Meeting in Torino (Turin), Italy.
This meeting provides the most up-to-date information on scientific developments and treatment approaches for Alzheimer’s disease in particular. It is held every two years in a European city and on alternate years an affiliated meeting – the Alzheimer’s and Parkinson’s Diseases Congress – is held in Europe. Next year this congress is being held in March in Lisbon, Portugal. I travelled to Milan from Brisbane via Dubai with Emirates Airlines. I then got to Turin on one of the impressive fast trains in Italy (speed up to 300 kph).
The meeting runs for three and a half days. It covers basic pre-clinical and clinical science as well as progress in clinical trials of drug and other treatments for Alzheimer’s disease and related dementia conditions. I have been keen to keep informed of these developments because I treat many patients with these conditions in my Gold Coast Memory and Cognitive Disorders Clinic in Southport. The social program is rather Spartan but his is made up for by the high quality of keynote plenary sessions, oral presentations, and poster displays.
New treatments for Alzheimer’s disease have been few and far between over the past 20 years. Following the introduction of the cholinesterase inhibitor drug donepezil in the USA in 1996, only two other drugs in this class have appeared (rivastigmine and glantamine). A glutaminergic drug memantine was brought to market about 10 years ago. All these drugs are symptomatic treatments rather than disease modifying agents. They have an important but limited role. Since then there have been no new effective medications despite hundreds of clinical trials. Very disappointing and very disheartening for patients.
However, data provided at the Turin Focus Meeting may finally offer some light at the end of the tunnel. The monoclonal antibody – aducanumab – targets aggregated forms of β-amyloid – the main component of amyloid plaques found in the brains of Alzheimer patients. Since 2015 trials with this agent have shown clinical benefit on patient cognitive performance along with clearance of CNS β-amyloid in a dose dependent fashion. Using a very slow dose titration of the drug has now controlled the main serious adverse effect of aducanumab – amyloid-related imaging abnormalities (ARIA) on MRI brain scans (reflecting edema from inflammation arising from removal of β-amyloid).
This development means that aducanumab may become the first disease-modifying drug for Alzheimer’s disease. Other monoclonal antibodies against β-amyloid show similar properties in clearing amyloid plaques in a dose dependent way. Monoclonal antibodies directed against hyperphosphorylated misfolded tau protein (the pathogenic element of Alzheimer neurofibrillary tangles) are also being tested. I am participating as the principal investigator of one of these clinical trials conducted out of Griffith University Clinical Trials Unit in Southport.
Introduction of monoclonal antibody drugs will change the face of treatment of dementia in Australia. These drugs are probably going to be very expensive and government is only likely to subsidize treatment for patients showing the relevant underlying brain pathology. This will mean demonstration of β-amyloid or phosphorylated tau accumulation in brain by Positron Emission Tomography (PET) scans or estimations of β-amyloid 42 and phosphorylated tau in cerebrospinal fluid. It is likely that these drugs will be most effective when given very early in the course of the illness – perhaps before cognitive or memory symptoms have developed.
Diagnosis of pre-clinical or prodromal Alzheimer’s disease will depend on demonstration of biomarkers for the disease – presence of β-amyloid and phosphorylated tau, as well as neurodegeneration marked by cerebral atrophy or cortical hypometabolism.
As antibodies can only be given now by injection (subcutaneous, intramuscular or infusion) and the trials suggest a repeated regular injection schedule is required (with the duration not yet known), there will be huge implications for the infrastructure required to treat large numbers of patients. I am looking forward to hearing more news of these developments at the 2019 Lisbon meeting!
This article was written by Professor Philip Morris, President of the Australian & New Zealand Mental Health Association
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