Biomarkers for Alzheimer’s disease: A new frontier
David Cribbs, Ph.D.
The National Institutes of Health defines a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” For purposes of this article, an Alzheimer’s disease biomarker is simply defined as an indicator of disease progression that may be altered by drug treatment, thereby demonstrating that the drug is hitting its disease target. Importantly, all clinical trials for Alzheimer’s disease utilize biomarkers of some form to access whether the drug is actually affecting the disease pathway in the brain.
There is an enormous effort underway to identify and verify novel Alzheimer’s disease biomarkers, particularly early stage markers that reflect disease in the brain before there are any clinical symptoms. This is likely to be essential for effective drug development because so much damage has been done to the brain by the time clinical symptoms become evident. Over the past 15 years, cerebrospinal fluid biomarkers have been helpful diagnostically as well as for predicting who will eventually develop Alzheimer’s disease. For example, cerebrospinal fluid levels of amyloid-β42 are a very good marker for the presence of amyloid deposition in the brain, regardless of clinical status. Likewise, total tau and phosphorylated forms of tau are useful in detection of neurodegeneration. When combined together, these cerebrospinal fluid markers are useful not only in identifying people with Alzheimer’s disease, but also for predicting conversion from cognitive normalcy to very mild dementia, as well as monitoring progression from Mild Cognitive Impairment or very mild dementia to more severe impairment.
Recently, the National Institute on Aging and Alzheimer’s Association included biomarkers in new diagnostic criteria for Alzheimer’s disease because they are believed to result from specific pathological changes in the brain. For convenience, Alzheimer’s disease biomarkers can be divided into two general classes: 1) imaging methods that can detect amyloid deposits in the brain, metabolic activity, or brain atrophy or shrinkage, and 2) biological samples, such as cerebrospinal fluid, where various forms of amyloid and tau can be measured. However, the order and magnitude of pathologic and biomarker processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Many diagnostic and therapeutic approaches to Alzheimer’s disease are currently changing due to the hypothesis that the underlying pathology starts 10 to 20 years before clinical signs of dementia appear (see figure below).
Evidence for very early changes in brain pathology come from investigating individuals with autosomal dominant Alzheimer’s disease mutations as these individuals have a predictable age of onset and thus provide an opportunity to determine the sequence and magnitude of pathologic changes that occur before clinical symptoms can be detected. The Dominantly Inherited Alzheimer Network (DIAN) is a collaborative effort of international Alzheimer’s disease centers that are conducting a multifaceted prospective biomarker study in individuals who are at risk for Autosomal Dominant Alzheimer’s Disease (ADAD). These researchers found that ADAD was associated with a series of pathophysiological changes over decades in cerebrospinal fluid biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Concentrations of amyloid-β42 in the cerebrospinal fluid appeared to decline 25 years before expected symptom onset. Amyloid-β deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the cerebrospinal fluid and an increase in brain atrophy were detected 15 years before expected symptom onset. Studies in Down syndrome present similar opportunities, and UCI is home to unique studies investigating biomarkers in this population.
Rapid advances in the identification of Alzheimer’s disease biomarkers now make it possible to detect Alzheimer’s disease biology in the preclinical stage of the disease, in cognitively normal individuals. There currently is great optimism that improvements in Alzheimer’s disease biomarkers will make it possible to select high-risk populations for clinical trials. In vivo visualization of Alzheimer’s disease neuropathology and biological, biochemical or physiological confirmation of the effects of treatment likely will substantially improve development of new more effective drugs.
Dynamic biomarkers of the Alzheimer’s pathological cascade
Aβ is identified by CSF Aβ42 or PET amyloid imaging. Tau-mediated neuronal injury and dysfunction is identified by CSF tau or fluorodeoxyglucose-PET. Brain structure is measured by use of structural MRI. Aβ=β-amyloid. MCI = Mild Cognitive Impairment. (With permission: Clifford R Jack Jr., et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurology Vol 9 January 2010)