New Alzheimer’s Diagnostic Criteria Remain ‘Research Only’

Series - Clinical Trials on Alzheimer's Disease (CTAD) 2023 - 16th:

The latest effort to rewrite the diagnostic criteria for Alzheimer’s disease has stirred more than a little controversy. While the proposed revisions have garnered praise from researchers for more accurately reflecting the underlying biology of the disease, they also have sparked criticism for advancing toward clinical use what were previously research criteria. In particular, the American Geriatrics Society called the move to the clinic premature, noting that many uncertainties remain about how well biomarkers predict symptom onset. The AGS also questioned the extent of the National Institute on Aging’s involvement in the working group. The NIA has now removed its name from the criteria, though its representatives continue to advise the group.

  • Updated AD diagnostic criteria no longer carry the NIA name.
  • The criteria now split tau biomarkers into two categories, T1 and T2.
  • The former represents soluble tau and is for diagnosis, the latter, fibrillar tau for staging.

At last month’s Clinical Trials on Alzheimer’s Disease conference in Boston, representatives of the Alzheimer’s Association Workgroup discussed how they have revised the draft criteria to incorporate community input. The group’s leader, Clifford Jack of the Mayo Clinic in Rochester, Minnesota, emphasized that the new criteria should not be considered guidelines for clinical practice at this time; rather, they represent a bridge between research and practice. Jack also noted that tau biomarkers have been split into two categories, to better distinguish between soluble and fibrillar forms, and to distinguish the different roles of each of these forms in diagnosis. This change was suggested by biomarker scientists.

The Concept of Preclinical AD Draws Flak
The working group first presented the draft criteria at last summer’s AAIC in Amsterdam, and solicited feedback from the field (Aug 2023 conference news). This generated 64 public comments from practicing neurologists, pathologists, and organizations such as the Gerontological Society of America. There were also comments from advocacy groups, including the National Down Syndrome Society and the National Task Group on Intellectual Disabilities and Dementia Practices, and from industry, such as Biogen and C2N Diagnostics.

Among the commentators was the AGS, a nationwide organization that represents more than 6,000 healthcare professionals who care for the elderly. Their comment was influential. The geriatricians noted that the NIA had been a co-equal convener in the 2018 NIA-AA criteria but was taking merely an advisory role for the 2023 update. The 2018 criteria were articulated as a research framework, in keeping with NIA’s mission as a research agency. It would be unusual for the NIA to take part in developing clinical criteria, the AGS argued.

The National Institutes of Health has now directed NIA to remove its name (see Forbes article). Jack told Alzforum that this was done to conform to NIH guidelines regarding the use of institute names. He noted that NIA involvement in the project has not changed, including neuroscience division director Eliezer Masliah holding a position on the four-member steering committee.

The AGS also criticized the extent of industry ties of the working group, in which 16 of the 22 members either work for companies or have received consulting fees from pharma or the Alzheimer’s Association. The panel includes highly regarded biomarker scientists, but few clinicians who regularly see patients.

Some Alzheimer’s researchers remain troubled by the idea of defining people with plaque buildup in their brain, but no symptoms, as having AD. Many others have been moving in this direction for years. Writing for the group Methods for Longitudinal Studies in Dementia (Melodem), Deborah Blacker of Massachusetts General Hospital, Boston, noted that a diagnosis of AD can still induce dread, and might confuse patients and family members. “Many of us would prefer a term like brain amyloidosis or the neuropathologists’ ‘Alzheimer disease neuropathologic changes’ to stress the difference,” she wrote (see comment under Working Group Meetings on Melodem page).

Two Types. Updated biomarker scheme distinguishes between markers of soluble and fibrillar tau. The former are more closely tied to amyloidosis than tangles, and are diagnostic of the disease, whereas the latter are more useful in staging.

In Biomarkers, Tau Doesn’t Equal Tau
Many updates to the draft criteria were technical, part of a continuing refinement of diagnostic and staging biomarkers as new pathophysiology data roll in. The biggest change is that tau biomarkers have now been split into two categories, T1 and T2 (see table above). The former comprise markers of soluble phosphorylated tau, such as p-tau217, p-tau181, and p-tau231; the latter mark fibrillar tau, such as cerebrospinal fluid MTBR-tau243 and tau PET.

T1 biomarkers are considered “core 1” markers, capable of diagnosing disease on their own. The updated criteria specify that such biomarkers should have a demonstrated accuracy of 90 percent or better; at the moment, this would include only amyloid PET, CSF markers, and some plasma p-tau217 assays. Jack emphasized the crucial role of clinicians’ judgment in interpreting biomarker results for the patient before them, particularly when the person has other medical conditions or co-pathologies that may affect the assays.

T2 biomarkers are “core 2,” not intended to be used as stand-alone tests. Instead, they should be combined with core 1 markers to stage disease, Jack said. The updated criteria now suggest staging be done only with amyloid and tau PET, as fluid biomarkers are not yet well enough established for this. This change is also a response to comments from the field.—Madolyn Bowman Rogers

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References

News Citations

  1. Revised Again: Alzheimer's Diagnostic Criteria Get Another Makeover

External Citations

  1. draft criteria
  2. public comments
  3. comment
  4. Forbes article
  5. comment under Working Group Meetings

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