Summary: A recent study questions the accuracy of proposed biomarkers for diagnosing Alzheimer’s.
Doctors currently make a diagnosis of Alzheimer’s based on symptoms and by ruling out other medical causes for those symptoms. Two groups of researchers have proposed new diagnostic criteria that add certain "biomarkers" -- physical or biochemical characteristics that are signs of disease. One set of criteria was developed by panels convened by the Alzheimer’s Association and the U.S. National Institute on Aging. A similar set, the "Dubois Criteria," was developed by the International Working Group for New Research Criteria for the Diagnosis of AD.
The goal of these new criteria is more accurate diagnosis, which hopefully will lead to earlier and better treatment. More accurate diagnosis would have been enormously valuable for my family, eliminating the long diagnostic roller coaster that my father endured.
But at least initially, these new criteria may cause more confusion than clarity. Researchers at the Karolinska Institute in Stockholm recently compared the diagnoses of memory clinic patients via the current methods with diagnoses of the same patients using the Dubois criteria. Use of the new criteria drastically decreased the number of people diagnosed with Alzheimer’s.
Why did so few memory clinic patients in this study meet the Dubois criteria for Alzheimer’s? Because symptoms and pathologies in Alzheimer’s vary widely, says Dr. Anne Rita Øksengård, lead author of the article describing this study. “We have reasons to believe that there is a large heterogeneity in general in terms of clinical patterns and neuroanatomic correlates in conditions that possibly are developing into what we call fullblown Alzheimer's dementia,” says Dr. Øksengård.
Part of the problem is how we use the term “Alzheimer’s,” she says. “The term ‘Alzheimer's dementia,’ as we use it today, contains a cluster and possibly several subgroups of disorders other than what is said to be ‘pure Alzheimer's disease’ where we find positive biomarkers. In this way, one can consider Alzheimer's more like a syndrome than a single disorder. This is often a reason for confusion in the literature where the term AD stands for both ‘Alzheimer's dementia’ and ‘Alzheimer's disease.’”
A second reason the Swedish study’s results do not confirm that the biomarkers used are reliable is that previous studies suffered from what Dr. Øksengård calls “workup bias and circular diagnostic procedures.” In the study she and her colleagues conducted, physicians making the diagnosis via the current methods were blinded to the results of any imaging or spinal fluid tests so as not to be influenced by these biomarkers that are part of the Dubois criteria. This has not been the case with previous studies, she says. “Doing this without blinding, the accuracy of the screening tools will be much higher, as there is what we call a ‘circular bias in the diagnostic procedures.’ Therefore, I am not surprised that we do not confirm the findings of others.”
I’ve written before about how public expectations for these still evolving diagnostic methods may be too high. For those who hoped that the proposed criteria would lead to an early and accurate diagnosis of Alzheimer’s for themselves or family members, finding only seven percent of people with mild memory problems would be diagnosed with Alzheimer’s is disappointing.
If these criteria are used as is, a large number of people will still be in diagnostic limbo. They may be less likely to be treated or qualify for disability programs. This is not the case in Dr. Øksengård’s practice. “Our patients having signs and symptoms and a clinical picture of possible and probable AD using the clinical diagnostic criteria, but NO confirmed AD diagnosis according to the Dubois criteria, still have the same problems and worries as those who fulfill the Dubois criteria. These patients are followed up clinically and they get the same focus as those who fulfill the criteria,” she notes.
“Personally, I welcome the Dubois criteria,” says Dr. Øksengård, “but I do think that we have to be alert in order to not restrain the academic research and be content with this, as many of the patients struggling with subjective symptoms of AD not fulfilling the Dubois criteria might be put on hold." Further research is necessary she says, “…to look for other biomarkers and clinical correlates that help us to classify and diagnose the different subgroups correctly at an early stage in order to design individual treatment packages. Another issue is that the biomarkers have to be validated in normative datasets in order to be reliable and trustworthy. Our contribution to this debate might therefore be a "wake-up call" to motivate further research."