Developing New Diagnostic Approaches for Alzheimer’s Disease
Reflecting their leadership role in Alzheimer’s disease research, Elan scientists are developing and implementing new tools in clinical trials – including tests that measure protein levels in cerebrospinal fluid and advanced imaging techniques – for diagnosing Alzheimer’s disease.
The cerebrospinal fluid assay and imaging techniques are used to select patients for clinical trials and to determine if investigational therapies are having the desired impact on Alzheimer’s disease pathology and markers of disease.
“We believe that improved therapeutics go hand in hand with improved diagnostics,” said Dale Schenk, Elan’s 
chief scientific officer and a leading authority on Alzheimer’s disease. “Moving beyond the current diagnostic paradigms is essential for creating new Alzheimer’s disease therapies. Elan is committed to advancing the diagnostic field.”
Current diagnostic standards are only 90% accurate and are based on already significant loss of cognition due to disease-induced neurodegeneration, Schenk noted, so improved tools are critical in avoiding delays and providing appropriate care and treatment as quickly as possible
Diagnostic Challenges
Alzheimer’s disease is a progressive and fatal brain disease, and is the most common form of dementia. The first consensus definition for the clinical diagnosis of Alzheimer’s disease was published in Neurology in 1984, and currently, a diagnosis is based on assessment scores of a variety of clinical symptoms, including memory, cognition and the ability to perform basic functions and activities. A definitive diagnosis of Alzheimer’s disease can only be made based on evaluation of brain tissue at an autopsy.
There are a range of limitations in using clinical symptoms and assessment scores to diagnose Alzheimer’s disease, rather than biochemical or pathologic markers of disease.
- Many symptoms overlap with those of other diseases, including other types of dementia and Parkinson’s
disease. - Symptoms appear late in the disease process, and by the time a patient begins having memory or cognitive
losses, there’s already been significant damage to brain cells. - Inaccurate diagnoses can distort clinical trial results. If current methods are 90% accurate, then 10% of
patients in trials are not likely to respond to the treatment being tested. Including 10% patients without
Alzheimer’s disease can make the difference between showing a statistically significant benefit and having
the trial not meet its endpoints.
Improved diagnostic tools, along with therapeutic treatments, will give Alzheimer’s disease patients more hope than they have now, and encourage them to seek treatment earlier.
“Patients who are diagnosed with Alzheimer’s disease now face a grim outlook,” said Peter Seubert, from Elan’s Neurodegeneration Research group. “As disease modifying therapy becomes available, people will actively seek diagnosis early to retain or improve cognition. Improved diagnostic tools will be critically important to detect and manage the disease early before it progresses.”
Improving Alzheimer’s Disease Diagnostics
Elan scientists are focused on developing and identifying a combination of tests that will enable definitive diagnosis of Alzheimer’s disease long before the need for autopsy.
More than a decade ago in the Annals of Neurology (October 1995) and the Archives of Neurology (October 1998), Elan researchers and clinical collaborators demonstrated that levels of certain proteins found in cerebrospinal fluid could be used to identify Alzheimer’s disease patients. Subsequently, scores of other peer-reviewed publications have confirmed that levels of the 42 amino acid form of the beta-amyloid protein (Aβ-42) are decreased in the cerebrospinal fluid of Alzheimer’s disease patients and that the protein tau, which also plays an important role in the disease pathology, is increased.
Elan is working with members of the Alzheimer’s disease community – drug developers, regulators and advocacy groups – to validate and implement the cerebrospinal fluid assay as a standard diagnostic tool that will measure proteins that contribute to the underlying molecular cause of Alzheimer’s disease. In addition, Elan also has pioneered the clinical use of imaging techniques for monitoring the progression of Alzheimer’s disease.
These tools are being used in Phase 3 bapineuzumab clinical trials. While clinical criteria and magnetic resonance imaging rule out other conditions such as brain tumors, CSF assays of Aβ-42 and tau, and PET analysis of beta-amyloid will be evaluated in subsets of patients. The MRIs measure brain volume, because reductions in volume are a sign of Alzheimer’s disease progression.
“We believe that using these diagnostics in the clinical trial will inform the understanding of how bapineuzumab impacts Alzheimer’s disease pathology and clinical symptoms, while also providing additional information on how to use these tools in trials and in the clinic,” said Dora Games, Experimental Neuropathology. “In addition, this information will further aid the development of preclinical models”
Going forward, Elan will continue to evaluate how a variety of Alzheimer’s disease diagnostics could be used to diagnose the disease earlier, assess its severity, and measure how patients respond to therapy. Ultimately, these enhanced diagnostics are expected to make a significant contribution to improving the care and outcomes of Alzheimer’s disease patients.