As we wrote in our last post, the ability to accurately diagnose Alzheimer’s disease before a person’s death has been problematic. Experts estimate that a third or more of patients’ cognitive impairment or dementia may be inaccurately diagnosed. As a result, such patients may not benefit from the treatments they do receive or may have other reasons for their symptoms that could potentially benefit from other therapies (the revelation last year that actor/musician Kris Kristofferson had, in fact, been suffering from the effects of Lyme disease and not Alzheimer’s as originally diagnosed being one example. Proper therapy was happily able to reverse most of his original symptoms).
Moreover, improper diagnosis — as well as the difficulty of determining before dementia sets in who is truly at risk — has a profound effect on the study of potential new treatments. We have seen this in the number of clinical trial failures of potential treatments for Alzheimer’s disease, where intervention at earlier stages in the disease course could possibly result in greater success.
And so, a significant amount of research today is focused on developing better methods for diagnosing Alzheimer’s disease and identifying at an early stage those at great risk. Such efforts fall primarily into four areas:
1.) Imaging of Protein Biomarkers in the Brain
The aim of imaging is to look specifically at key physical hallmarks of Alzheimer’s in the brain with the goal of identifying affected patients before symptoms emerge or at a stage when their development may still be halted or significantly slowed. Two main imaging technologies are under study: PET (positron emission tomography) and MRI (magnetic resonance imaging).
In our last post, we discussed the ongoing IDEAS study of PET scanning to specifically image amyloid deposition in the brain and its ability to more accurately diagnose Alzheimer’s disease or even identify people at risk up to 15 years before symptoms begin. Similar research is ongoing with respect to the other key Alzheimer’s associated protein, tau. A PET scan uses a small amount of a radioactive tracer to show the differences between healthy and diseased tissues. Such tracers may be specific for amyloid-beta or tau, or may use a glucose analog (fluorodeoxyglucose) as a less specific measurement of cellular metabolism to distinguish between healthy and diseased tissues.
While the protein-specific PET tracers have been shown to be quite accurate, PET scans have some significant disadvantages: they are very costly (multiple $1000s per scan), there are relatively few medical centers worldwide that have access to such technology, and they expose patients to relatively high doses of radiation (equivalent to as many as 70 chest x-rays).
MRI, an imaging technology more widely available and without the need for radioactive tracers, is currently being used to look at brain atrophy as a marker of Alzheimer’s disease versus normal aging. However, new amyloid-beta MRI contrast agents are currently under development which, if successful, could make the imaging of amyloid deposition a more widely available diagnostic — and potentially disease monitoring — tool.
2.) Fluid markers of Alzheimer’s disease
The second area of interest focuses on looking for particular Alzheimer’s disease biomarkers — amyloid-beta, tau or neurofilament light chain, a component of dying neurons, in blood or cerebrospinal fluid (CSF). While efforts here are earlier, research suggests a promising correlation between PET scans and CSF (about 82-90%) and CSF/blood (about 75-80%). The advantages of a blood test for Alzheimer’s disease markers would be significant, as it would enable the development of a cost-effective screening test where positive results could be confirmed by the more costly imaging modalities.
3.) Neuropsychological tests
Neuropsychological tests are commonly used today to assess cognitive impairment in patients who have been diagnosed with mild-to-moderate Alzheimer’s disease. These include questionnaires to help test the patient’s mental abilities with respect to memory as well as other cognitive functions. Recent efforts have pushed to make these tests more interactive and to enable testing to be moved from the proctored environment of the physician’s office to the patient’s own home environment. One such test, the COGNIGRAM™ system from Australian company, Cogstate, was approved for commercialization in July 2017 by the U.S. Food and Drug Administration. The COGNIGRAM™ system is a self-administered, digital cognitive assessment tool, which can be used in the doctor’s office or at home, that is designed to provide health professionals with an objective measurement of cognition. It can be employed to obtain a single reading or to measure cognitive change over a series of periodic assessments.
4.) Functional Diagnostics
Functional diagnostics focus on tasks and abilities that change as Alzheimer’s disease progresses — characteristics such as a person’s gait, hand grip, speech patterns, keyboard usage or handwriting, for example. Such measurement tools could be developed as smart devices and wearables, and hold the prospect for generating big data that can be mined for important diagnostic insights. Such technology also raises a number of questions however with respect to collection and use of such data in meaningful ways without raising issues of privacy.
The need for better biomarker tools in Alzheimer’s disease is clear – not only to diagnose patients earlier in the course of the disease, but also to select patients for the appropriate therapy and to monitor their progression over time. Drug developers will need to determine how best to incorporate and validate these tools within their clinical development strategy, and if successful, develop a robust Go to Market strategy that can support unique diagnostic and biomarker technologies such as imaging or big data approaches.