“A new way to think about Alzheimer’s Disease” (AD),  [online Jan 3] is a thoughtful Op-Ed by Dr. Gayatri Devi, the noted cognitive disorders neurologist and clinical professor.  She describes a lawyer who came to her, worried about his memory.  She included spinal fluid testing in his workup. Using tests some call “biomarkers,” she was able to consider his condition “biological Alzheimer’s,” a concept based on theories of the role of amyloid beta and tau proteins.

She initially did call his problem “cognitive impairment,” probably Mild Cognitive Impairment (MCI), a diagnostic label. She describes this person operating at such a high level that even as his neurologist, she couldn’t detect memory issues during conversation. Sadly, he continued to have measurable worsening on sophisticated cognitive tests, despite therapy. In the end, she does call the lawyer’s problem “his own private Alzheimer’s disease.” She highlights how the availability of certain tests may be changing the diagnostic process, but evidently uses existing functional tests for her patient.

AD biomarkers include brain scans for amyloid and tau. Devi mentions a Mayo Clinic study last year correlating these scans with diagnoses listed in medical records. The authors call abnormal scans evidence for “biological AD.”  They show that at age 70,  ~10% of women in their cohort had biological AD, but only 1% had “clinically defined probable AD”.  At age 85, biological AD had increased to 33%, and the clinical AD rate was 10%. One might say that there was a high “false positive rate” at both ages (men were slightly different). “Potential confusion” is listed as a Key Point in the paper.

As with any test, one may ask about specificity and sensitivity, or positive predictive value numbers.  Of course, one obvious comment is that there might be a time lag in biomarker predictive value.  The JAMA Neurology commentary, by Gomez-Isla and Frosch states:

“…while it is widely assumed that plaques and tangles are causally related to the cognitive symptoms in AD, observations from multiple studies suggest that associations between plaques, tangles, and cognition are not particularly strong and do not suffice to reliably predict clinical outcome at an individual level….” [note: they refer to a brain autopsy study]

The Devi Op-Ed also mentions that there is some controversy about the concept that amyloid beta is the primary problem in clinical AD problems. That might make tests like amyloid neuroimaging and spinal fluid amyloid findings even harder to interpret.

So how useful is the biological definition of AD? Some sticklers feel that the diagnosis of AD is only made with post-mortem brain tissue pathology, so for the living, they prefer the old school clinical term “Dementia, Alzheimer Type” or the more recent “Major Neurocognitive Disorder” (DSM-5).  I won’t mention ICD billing diagnoses.

Devi feels that the definition of AD might be too broad, with a need for subtype definition and a more “precise” diagnosis.  But what has the ton of AD “precision” genetic literature yielded that helps patients today?

In a JAMA Viewpoint last year, “Preclinical AD–Early diagnosis or overdiagnosis?” Langa and Burke address the issue of biomarker defined AD, and discuss the clinical problems one might see if using imaging and other biomarkers to label folks with asymptomatic preclinical AD. They also do a quick economic analysis of the huge costs that might follow. Current AD imaging may not be very predictive, given the Mayo Clinic study cited above, yet the FDA might use the concept for accelerated approval  of new agents.

Medicine, especially in the US, might have a problem with overdiagnosis.  We live in a land where an unspoken rule is that doing something is better than doing nothing, that it’s heroic to be the smartest doctor who finally figures out a diagnosis when all the previous dummies failed. And with a diagnosis, one can initiate therapy, if there is such a therapy. But in AD, there are no disease-modifying drugs. Still, one could implement lifestyle changes or use drugs off-label.

Her call for defining AD with precision invokes the opposite idea:  why not broaden the definition, be more inclusive, and officially call Alzheimer’s a “spectrum” disorder? Devi uses the word in her Op-Ed, and in her book title, The Spectrum of Hope (AlzGadfly liked it, and discloses there is no affiliation). In a published Letter to the Editor in Alzheimer’s & Dementia, this writer proposed “dementia spectrum disorder” or “progressive cognitive impairment disorder.”

We now use the term “Autism Spectrum Disorder;” that change happened in DSM-5 only seven years ago. Baker has fascinating comments on the controversy, and the worry families had with the change in nomenclature.  He concludes: “Rather than argue over the true definition of autism, it may be more helpful to ask what definition is appropriate for the task at hand.”

Using the spectrum concept acknowledges that folks might have variations, or might be at different stages of worsening, can emphasize clinical criteria instead of autopsy material, perhaps using handy screening tools or even extensive neuropsychological testing; it does not imply any certain pathophysiology, like the Amyloid-Tau (Neurodegeneration) Research Framework, ideas about the ACh system, or the APOE proteins [dramatic recent case report from Harvard discussed here].

All diagnostic labels are a bit of a short-hand for problems that beset individual patients.  It’s a common language to be used for communication between the persons and families affected, the caregivers and the caring professions, and researchers. Perhaps considering AD a spectrum will help patients and families understand what might be useful and predictable, and what might be individualistic, in coping and hoping for the best.

A broader definition may be more inclusive, allow for more nuance and variation, perhaps carry less stigma, perhaps allow for more services.  Most importantly, it may also allow more participation and enrollment of subjects, especially for therapy screening, broad based non-amyloid therapies (for neuroinflammation, cognitive enhancers, non-drug therapies, etc) and for pragmatic clinical trials.

Even if diagnostic terminology changes, which happens in oncology all the time, how does the change help patients like the lawyer?  Devi is terrific in championing the individual patient.  She alludes to important aspects of care, like privacy issues, but is more explicit about stigma and a humanistic approach in her own NEJM Perspective.

Did knowing he had biological AD help the lawyer? She mentions that he now has quite a bit of self-doubt, and presumably, some anxiety about his condition and his future.  Current biomarkers don’t seem to help in prognosis, either. Changing diagnostic nosology and precision diagnosis won’t help anybody without effective therapy. Labelling questions aside, AlzGadfly wants to know: how will defining “biological AD” get us to disease-modifying therapy for those already afflicted?