Specialists concerned it will complicate discussions with patients Can the Alzheimer's disease biomarker genie be kept in the bottle? The National Institute on Aging and the Alzheimer's Association yesterday came out with a new definition of Alzheimer's disease based on biomarkers. It's intended solely for research purposes, potentially including recruitment for clinical trials -- but is not meant for clinical diagnosis. Still, once the door is opened to a biomarker definition, it may be difficult to keep it out of the clinic, as patients and their families may ask questions to which their physicians must respond. We invited top Alzheimer's specialists to discuss the new definition and the issues it raises. John C. Morris, MD, Director, Knight Alzheimer Disease Research Center, Washington University School of Medicine: I've advocated for years that the diagnosis of dementia be made on the basis of the underlying etiology, whether determined by clinical assessment or by biomarkers (or both). Hence, I support the concept of biomarker-based diagnoses, although in current practice the obtaining and interpretation of Alzheimer biomarkers will be restricted primarily to physicians who specialize in memory disorders (largely neurologists). Steven T. DeKosky, MD,Deputy Director, McKnight Brain Institute, University of Florida: Neuroradiologists outside of research institutions do not do volumetric determinations in the hippocampus (they can't bill for it and they would need large numbers of control images to compare it to); amyloid imaging is approved by the FDA but no third parties pay for it so it is not done unless the patient/family want to pay for it, and it is several thousand dollars; and tau imaging is not yet FDA approved, or validated, so physicians can't order it outside of a research protocol. Kostas Lyketsos, MD, MHS,Professor of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine: A key open question is whether payers will reimburse for the biomarker tests proposed since they are costly and not very well standardized -- at present only some of these tests are covered (e.g., FDG-PET, MRI, but not other PET, CSF, blood tests). The CMS is finishing up a study that will test the utility of biomarker testing. The results will be key. We might find ourselves with this very elegant definition of AD and no way to pay to use it clinically. I doubt that will happen but it could given the huge costs. James Mastrianni, MD PhD, Director, Center for Comprehensive Care & Research on Memory Disorders, University of Chicago: One aspect that may trickle down to the clinician is the demand for a more accurate diagnosis from the patient and family members, knowing of the availability of these tests. Unfortunately, the cost of these has been prohibitive. Insurance companies do not pay for these tests, presumably because they are "experimental" and very expensive. Medicare participated in a large scale study of amyloid PET imaging, to assess the benefits in clinical practice, but there has yet been no change in policy. Unintended Consequences Sam Gandy, MD, PhD, Professor of Neurology, Mount Sinai Hospital: Application of this definition will cause the estimates of the prevalence of AD to skyrocket. I think that the lay public penetration of the notion that there is a "silver tsunami" that will bankrupt and cause enormous misery to millions of families. I do not see any up side to driving up the "scare factor." Mary Sano, PhD, Director of the Alzheimer's Disease Research at Mount Sinai School of Medicine: To date we have no evidence that early intervention is beneficial. In fact many drugs have failed in the presence of pathology with only the mildest symptomatology. Further at a certain age, pathology may never lead to symptomatology so the value is again unknown. It is an important question but that is not the same as an answer and there are many conditions in which pathology does not correspond to symptomatology. George T. Grossberg MD, Director, Geriatric Psychiatry, Department of Psychiatry & Behavioral Neuroscience, St. Louis University School of Medicine: At present, it is primarily a research construct, to make sure that subjects in Alzheimer's clinical trials do indeed, at least, all meet biomarker criteria for Alzheimer's Disease. in the office, whether for primary care physicians or even neurologists and geriatric psychiatrists, clinical diagnosis remains most important. Clinical diagnosis can be supported by biomarkers but biomarkers are not yet ready to be used exclusively in absence of clinical symptoms. Reisa Sperling, MD, Director, Center for Alzheimer Research and Treatment ,Brigham and Women's Hospital: This framework is explicitly for research only at this point -- will require a lot more testing in large cohorts before it is ready to port to clinical practice. Susan Besser MD, family practitioner, Mercy Medical Center, Baltimore: I know it said repeatedly that it's for research purposes (at this time), but if the general media gets hold of it, people will be flocking to the doors of their PCP to be tested for the biomarker. And then they will want treatment. Practically speaking, we aren't ready for that. We are a while before we determine if a) the biomarkers are predictable and b) if with the positive biomarkers there actually is a treatment. Ron Petersen, MD, Director, Mayo Clinic Alzheimer's Disease Research Center: I think that ... is actually insightful because she is quite right. Even though you put in here 15 times it's research, it's research, it's research, and Cliff Jack noted that well, and you really inserted it in the document in prominent places multiple times, it just trickles into clinical practice. It just happens. All of a sudden biomarkers now function as if they are validated and the whole point of the exercise is to validate these biomarkers and see if, in fact, they do what they're supposed to do. Costantino Iadecola, MD, Chair, Feil Family Brain and Mind Research Institute,Weill Cornell Medicine: I agree, it needs to be communicated to the general public carefully, pointing out that this definition does not provide diagnostic insights that can be used in the doctor's office at this time. In addition, it will be difficult to communicate to the public the the fallacies and complexities of the currently available AD biomarkers. Morris: This PCP's comments are both appropriate and in keeping with my prediction that, at present, the obtaining and interpretation of AD biomarkers in clinical practice will be limited primarily to specialists in memory disorders clinics. Given the limitations of biomarkers ... I think that it makes sense to have them obtained and interpreted by specialists at the current time. Zaven Khachaturian, PhD, Editor-in-Chief, Alzheimer's & Dementia: The comment / predictions from your primary care colleague is a bit harsh/extreme. The simple answer a care provider is to educate the patient about the uncertainties in accurate diagnosis and that the current NIA-AA criteria is a step (an experimental one) towards more provision/accuracy. Petersen: The general public will interpret this probably differently and will say, "Oh, there's a test out there. I can find out if I've got Alzheimer's disease." Well, yeah, but what do you do about it. The Challenge Gandy: Yes, disclosure of a positive amyloid scan is a bell that cannot be un-rung, but the evidence in favor of early intervention is overwhelming; the main question is how early is early enough? The only way to answer this question will involve clinical trials of younger and younger populations and that will involve more and more amyloid scans on asymptomatic subjects. If we walk away from this challenging situation because we cannot accustom the public to the uncertain implications of amyloid scans, we will have squandered a century's worth of dementia science. Petersen: I still think there's a million-dollar question out there. Like you have a 72-year-old woman who is cognitively normal, functionally normal, but has a positive amyloid PET scan. What does that mean? What do you tell her? Right now, according to this, you're going to say, "Well, you're on the Alzheimer's continuum. You have Alzheimer's pathology changes. What does that mean? Well, the bottom line is we don't know." Source
