New Alzheimer's Diagnostic Techniques: Not Ready for Widespread Use?

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.

In this study, of the 23 patients diagnosed with Alzheimer’s via the current method, only 12 met the proposed Dubois criteria.  And for a group of 96 patients who complained about their memory or had been diagnosed with Mild Cognitive Impairment, only 7 (a little over 7 percent) fit the Dubois criteria for pre-dementia Alzheimer’s disease. 

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."

Comments

[richard taylor]

Hello, why is it that every press release concerning another breakthrough with some issue related to Alzheimer's disease ends with words like "of course this needs more study, more research is required, if proven true these results will...) and ends with similar caveat emptor like warnings?

Unlike most of the questions I ask, I know the answer to this. Its because most folks aren't really confident about the assumptions upon which their studies are based. Therefore even when their natural tendency is to crow accompanies their press release, they feel compelled to peep at the end of their announcements.

Begging the question is a common fallacy in logic. We assume beliefs that aren't facts, and then based upon those beliefs we conduct research, draw conclusions and issue press releases based on the research results, begging so many questions our conscious' force us to end with a "buyer beware" (caveat emptor) statement.

Those of us living directly and indirectly with dementia have a difficult time not begging questions we want others to be sure of. Do you know what causes Alzheimer's disease? Do you know if there is more than one form of Alzheimer's disease? How did you distinguish between those with pure Alzheimer's disease, and those with mixed forms of dementia? Do different responses to my symptoms occur when my symptoms are in different stages of development? What variables did you control for in your study, other than someone told someones they did or did not have Alzheimer's disease? Do you know all the variables that determine who, what, and when someone shows the symptoms of dementia? How did you adjust for these variables? What are your own biases /assumptions vs. widely accepted facts and growing consensus concerning Alzheimer's disease? Do external variables ever affect your research assumptions?

We all need to stop begging and stand up and speak out!

Richard

[Danny]

Richard got right to the heart of it above, as usual.

Besides the issue of false positives/false negatives that you touched on Mona, we also should be mindful of the cost of these procedures if adopted by our healthcare system (one rep from Athena, a biotech company that does biomarker screen, charges over $2,000 for an amyloid/tau test...not to say anything about cost for nurses/doctors who perform the test), and the intrusiveness of these procedures (do we want to give everyone w/ a subjective complaint a spinal tap and multiple scans?).

Just so many outstanding questions for these researchers to answer before we can even faintly consider the adoption of these guidelines.

Great article, Mona

[Marty]

Thanks for your thorough analysis, Mona. This adds to my doubts about stats in less wealthy countries. Could they be way off simply because they can't afford diagnoses? Then we go and base our assumptions about Alzheimer's on comparative statistics when the process of obtaining figures itself is wrought with barriers and is in so much flux.
Nevertheless, we have to keep trying to figure things out even if it's two steps forward, one step back. Eventually we'll inch toward the truth.