Alzheimer’s Disease Biomarkers, Not Cognition, Will Now Define Disorder

The Three-Part Key: AT(N)

The NIA-AA Research Framework yields eight biomarker profiles with different combinations of amyloid (A), tau (T), and neurodegeneration or neuronal injury (N).

“Different measures have different roles,” Dr. Jack and his colleagues said. “Amyloid beta biomarkers determine whether or not an individual is in the Alzheimer’s continuum. Pathologic tau biomarkers determine if someone who is in the Alzheimer’s continuum has Alzheimer’s disease, because both amyloid beta and tau are required for a neuropathologic diagnosis of the disease. Neurodegenerative/neuronal injury biomarkers and cognitive symptoms, neither of which is specific for Alzheimer’s disease, are used only to stage severity, not to define the presence of the Alzheimer’s continuum.”

The “N” category is not as cut and dried at the other biomarkers, the paper noted. “Biomarkers in the (N) group are indicators of neurodegeneration or neuronal injury resulting from many causes; they are not specific for neurodegeneration due to Alzheimer’s disease. In any individual, the proportion of observed neurodegeneration/injury that can be attributed to Alzheimer’s disease versus other possible comorbid conditions (most of which have no extant biomarker) is unknown.”

The biomarker profiles are:

• A−T−(N)−: Normal Alzheimer’s disease biomarkers
• A+T−(N)−: Alzheimer’s pathologic change; Alzheimer’s continuum
• A+T+(N)−: Alzheimer’s disease; Alzheimer’s continuum
• A+T+(N)+: Alzheimer’s disease; Alzheimer’s continuum
• A+T−(N)+: Alzheimer’s with suspected non-Alzheimer’s pathologic change; Alzheimer’s continuum
• A−T+(N)−: Non-Alzheimer’s disease pathologic change
• A−T−(N)+: Non-Alzheimer’s disease pathologic change
• A−T+(N)+: Non-Alzheimer’s disease pathologic change.

A normal amyloid biomarker with abnormal tau or neurodegeneration “implies evidence of one or more neuropathologic processes other than Alzheimer’s disease and has been labeled ‘suspected non-Alzheimer’s pathophysiology’ (or SNAP),” according to the paper.

Cognitive staging further refines each person’s status. There are two clinical staging schemes in the framework. One is the familiar syndromal staging system of cognitively unimpaired, MCI, and dementia, which can be subdivided into mild, moderate, and severe. This staging scheme can be applied to anyone with a biomarker profile.

Biomarker Grouping and Cognitive Status Interactions

“This three-category division serves as the basis for cognitive categorization in many large, ongoing studies,” Dr. Jack and his colleagues wrote. “Numerous researchers feel that it has been and continues to be effective for clinical research and that abandoning it would unnecessarily disrupt ongoing studies.”

The second staging scheme, a six-stage numeric clinical staging scheme, will apply only to those who are amyloid-positive and on the Alzheimer’s continuum. Stages run from 1 (unimpaired) to 6 (severe dementia). The numeric staging does not concentrate solely on cognition, but also takes into account neurobehavioral and functional symptoms. It includes a transitional stage during which measures may be within population norms, but have declined relative to the individual’s past performance.

The numeric staging scheme is intended to mesh with FDA guidance for clinical trials outcomes, the committee noted.

“A useful application envisioned for this numeric cognitive staging scheme is interventional trials. Indeed, the NIA-AA numeric staging scheme is intentionally similar to the categorical system for staging Alzheimer’s disease outlined in recent FDA guidance for industry pertaining to developing drugs for treatment of early Alzheimer’s disease…. It was our belief that harmonizing this aspect of the framework with FDA guidance would enhance cross-fertilization between observational and interventional studies, which in turn would facilitate conduct of interventional clinical trials early in the disease process.”

The entire system yields a shorthand biomarker profile for each subject. For example, an A+T−(N)+ MCI profile suggests that Alzheimer’s and non-Alzheimer’s pathologic change may be contributing to the cognitive impairment. A cognitive staging number could also be added.

This biomarker profile introduces the option of completely avoiding traditional Alzheimer’s disease nomenclature, the committee noted.

“Some investigators may prefer to not use the biomarker category terminology … but instead simply report biomarker profile (ie, A+T+(N)+ instead of Alzheimer’s disease),” the authors said. An alternative is to combine the biomarker profile with a descriptive term—for example, “A+T+(N)+ with dementia” instead of “Alzheimer’s disease with dementia.”

Dr. Jack cautioned that the paradigm is not currently intended for clinical use. It relies on biomarkers obtained by methods that are either invasive (lumbar puncture), unavailable outside research settings (tau scans), or expensive when privately obtained (amyloid scans). Until this situation changes, the biomarker profile paradigm has little clinical impact.

IDEAS on the Horizon

Change may be coming, however. The Alzheimer’s Association-sponsored Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study is assessing the clinical usefulness of amyloid PET scans and their impact on patient outcomes. The goal is to accumulate enough data to prove whether amyloid scans are a cost-effective addition to the management of dementia patients. If federal payers decide to cover amyloid scans, advocates hope that private insurers might follow suit.