A Biomarker for Alzheimer’s Disease

by Guy McKhann, M.D.

February 10, 2011

In 1984 I chaired a group to determine the criteria for the diagnosis of Alzheimer’s disease. It was apparent at that time that Alzheimer’s was getting increasing attention as a major cause of dementia in older people. One could envision that there would be increasing numbers of studies about this disease process in terms of its clinical course, prediction of outcome, familial patterns and genetics, and hopefully, attempts at treatment. In establishing these criteria, it was the intent to get everyone on the same page, to be talking about the same disease process. These criteria have stood the test of time very well, and have been the linchpin for studies of Alzheimer’s disease in the intervening 26+ years.

However, our concepts about Alzheimer’s disease have changed over this time period. The most important change is that the disease process starts long before it becomes clinically evident. That is, the pathological hallmarks of the disease—the accumulation of a protein, amyloid, in so-called “plaques,” and the presence of a different protein, tau, in so-called “tangles”—are present in the brain in people whose cognitive functioning may be normal, or only minimally impaired. An obvious question for researchers was whether demonstrating the accumulation of these proteins in the brain would be a biomarker of the disease. Attempts to identify tau have been unsuccessful, so far. Demonstration of evidence of accumulation of amyloid is a different story.

There have been two approaches to determining whether amyloid is present in the brain. One is measuring the level of an amyloid breakdown product in the cerebrospinal fluid (CSF). This has been done for some time and is valuable. The other is to identify the presence of amyloid in a scan of the brain. This latter method is non-invasive—the subject simply lies there while the machine does its work.

The initial credit for imaging amyloid should go to two investigators at the University of Pittsburgh: geriatric psychiatrist Bill Klunk and radiochemist Chet Mathis. In investigations which took years to accomplish, they devised a compound, labeled with an isotope, which would get into the brain and selectively bind to amyloid. They could then visualize the complex of their compound and amyloid on brain images. The images of subjects with Alzheimer’s lit up like a Christmas tree.

The investigators’ compound, known as “Pittsburgh Compound  B” or “PiB,” has been available for about 8 years, but only applied in examining people over time in the last few years. For those with dementia, a negative PiB scan (one without evidence of accumulation of amyloid) strongly suggests that the cause of the cognitive problem is not Alzheimer’s.

PiB as a measure for demonstrating Alzheimer’s disease is still a research tool and not available for general use. The major reason for this is that its use is quite limited—limited by the need for specialized equipment, a cyclotron to make the isotope, and a Positron Emission Scanner (PET) to detect the compound in the brain. Further, the PiB compound uses the isotope C-11, a compound that loses its radioactivity quickly. Thus it has to be made on site and used promptly.

The recent advance in this field is the introduction of a new compound, containing a different isotope, F-18, as outlined in the article “FDA Sees Promise in Alzheimer’s Imaging Drug.” The big advantage of this new compound is that it contains the isotope F-18 instead of C-11. F-18 maintains its radioactivity much longer than C-11, and can be made at a central site and then shipped to where it will be used. Several companies are making such a compound, but the first to get one on the market and approved by the FDA is Avid Pharmaceuticals, now owned by Eli Lilly. This opens the door for use of amyloid imaging outside of research studies. The FDA approved the compound to rule out the presence of amyloid. As more experience is gained, these scanning studies may become useful in determining if a treatment is having the desired effect of reducing amyloid in the brain.

Don’t rush out to get your amyloid scan just yet. The field is not ready for that. But if the goal is to treat Alzheimer’s disease early in its course, before the ravages of dementia have occurred, a valuable tool has been added to our armamentarium.