A proposed Alzheimer’s disease classification system eschews neurocognitive testing and relies instead on the presence or absence of known biomarkers.
These markers of Alzheimer’s pathophysiology fall into three distinct categories: amyloid, tau, and neuronal injury (A/T/N). By rating patients as positive or negative for each category, the criteria aim to allow researchers to differentiate true Alzheimer’s patients from those with suspected non-Alzheimer’s pathology (SNAP), a diverse group that experiences neurocognitive decline in the absence of amyloid ( Neurology. 2016 Aug 2;87:539-47 ).
The A/T/N system could be employed in three clinical groups: clinically normal patients, those who meet the clinical criteria for mild cognitive impairment (MCI), and patients with a probable Alzheimer’s disease diagnosis based on the 2011 criteria established by the National Institute on Aging–Alzheimer’s Association (NIA-AA) staging system ( Alzheimers Dement. 2011 May;7:257-62 ).
The proposed research criteria represent the next logical step from the NIA-AA system, according to Clifford Jack, MD, a member of the 14-person committee that has spent the last year working on this project. It also allows for more specific classification than does the 2014 International Working Group (IWG) criteria (Lancet Neurol. 2014 Jun;13:614-29).
Both the NIA-AA and IWG systems comprise five biomarkers (low cerebrospinal fluid [CSF] amyloid-beta42; positive PET amyloid imaging; elevated CSF tau; hypometabolism in the temporoparietal cortex on 18F-fluorodeoxyglucose PET imaging; and atrophy in specific brain regions) plus cognitive testing.
The NIA-AA system defines three clinical stages of Alzheimer’s, each with separate classification criteria: stage 1, preclinical; stage 2, MCI; and stage 3, Alzheimer’s disease (AD) dementia. The IWG system is more complex than the NIA-AA system and takes into account biomarkers, cognition, and other clinical manifestations.
The A/T/N system doesn’t require cognitive testing, and includes additional biomarkers that should allow for a much more nuanced classification of patients. It also reflects the field’s growing confidence in objective markers that measure the pathophysiology of the disease, rather than the way it manifests symptomatically, said Dr. Jack, professor of radiology at the Mayo Clinic, Rochester, Minn.
He was the lead author on the August 2016 paper that provided a first look at the proposal. He presented a more mature version of the system at the Clinical Trials on Alzheimer’s Disease meeting in San Diego last fall. The committee is refining the document now, and intends to present a final draft at the Alzheimer’s Association International Conference in London this summer.
Would the A/T/N system benefit clinical research?
Researchers desperately need a better classification system, Dr. Jack said in an interview. The vast majority of AD drug trials have enrolled clinical cohorts that, by most estimates, are only 70% amyloid positive. The other 30% are patients whose neurocognitive deficits are due to other disorders. Many in the field believe this cohort impurity is directly tied to the consistently negative findings on anti-amyloid drugs: Simply put, anti-amyloid drugs won’t work in patients who don’t have amyloid brain plaques to begin with.
With the A/T/N system, “We take the position that cognitive impairment is a late occurrence,” in the Alzheimer’s disease trajectory, Dr. Jack said. “Clinical symptoms are not a good way to diagnose AD. This system does not require clinical symptoms for a diagnosis. In fact, the term ‘Alzheimer’s disease’ should refer only to the pathology in the brain, as it can exist in the absence of clinical symptoms or in the presence of atypical symptoms [such as language dysfunction], as well as in patients with the classic phenotype.”
The classification system comprises seven CSF and imaging biomarkers:
• A (amyloid) may be measured by an amyloid PET scan or by cerebrospinal fluid level of amyloid-beta42.
• T (tau) may be measured by CSF level of phosphorylated or total tau, or by tau PET imaging. Although tau imaging is still in the early phase, with no approved imaging agents, research is moving quickly and the committee wanted to be well positioned to incorporate it into the model as soon as an agent is approved.
• N (neurodegeneration/neuronal injury) may be measured by CSF level of total tau, hypometabolism on 18F-fluorodeoxyglucose PET imaging, or MRI that shows brain atrophy in regions characteristic of AD.
Since each component can be measured with CSF or imaging, the A/T/N system can be globally adopted despite different preferences for how biomarkers are acquired, Dr. Jack said.
“In the U.S., it’s much more common to use imaging, while in the E.U., it’s more common to use CSF for biomarkers. This is the beauty of the A/T/N system. With a single lumbar puncture or a series of imaging tests you can classify every research participant.”
In any of the patient groups, amyloid positivity is a key finding that an individual is probably on the path to Alzheimer’s disease. The biomarker permutations can be compared to the NIA-AA and IWG classifications as follows.
For clinically normal patients:
• A+/T-/N- is analogous to NIA-AA preclinical AD stage 1 and IWG asymptomatic at risk for AD (if A+ is established by amyloid PET).
• A+/T+/N- and A+/T+/N+ are analogous to NIA-AA preclinical AD stage 2/3 and IWG asymptomatic at risk for AD.
For MCI patients:
• A+/T-/N-, A+/T+/N-, and A+/T-/N+ are all analogous to the NIA-AA MCI core clinical criteria and IWG typical AD.
• A+/T+/N+ is analogous to NIA-AA MCI probably due to AD and IWG typical AD.
The A/T/N system offers the most useful details for patients who meet clinical criteria for probable AD dementia. Here, clinical criteria can be considered to help clarify the diagnostic picture:
• A-/T-/N-, analogous to NIA-AA dementia unlikely due to AD and is undefined by IWG.
• A+/T-/N-, analogous to NIA-AA intermediate likelihood of probable AD dementia, based on clinical criteria, and IWG typical AD (if A+ is established by amyloid PET).
• A+/T+/N-, analogous to NIA-AA high likelihood of probable AD dementia, based on clinical criteria, and IWG typical AD.
• A+/T-/N+, analogous to NIA-AA high likelihood of probable AD dementia, based on clinical criteria, and IWG typical AD (if A+ is established by amyloid PET).
• A+/T+/N+, analogous to NIA-AA high likelihood of AD pathophysiology and IWG typical AD.
• A-/T+/N+, analogous to NIA-AA probable AD dementia, based on clinical criteria and is undefined by IWG.
• A-/T-/N+, analogous to NIA-AA intermediate likelihood of probable AD dementia, based on clinical criteria, and is undefined by IWG.
• A-/T+/N+, analogous to NIA-AA intermediate likelihood of probable AD dementia, based on clinical criteria, and is undefined by IWG.
Would the A/T/N system benefit diagnostic accuracy?
The August paper sheds some additional light on how the system could hone diagnostic accuracy.
“For example, an A-/T-/N+ profile would be expected with pathologies such as ischemic cerebrovascular disease or hippocampal sclerosis, whereas an A-/T+/N+ profile would be expected with primary age-related tauopathy. An A+/T-/N+ profile might indicate an individual in the earliest stage of preclinical AD (accounting for the A+/T- status), who also has a non-AD pathology such as hippocampal sclerosis (accounting for the N+ status).”
Other typical profiles will certainly emerge as the A/T/N system is applied in large cohorts, the paper noted.
While the system is now aimed at building stronger research cohorts, it may eventually be adopted – and adapted – by clinicians.
“Right now, the reality is that most clinical practices don’t have access to getting these biomarkers,” Dr. Jack said. “Having said that, we also know that clinicians will vote with their feet. If they think this is useful they’ll end up adopting it, at least in the highly specialized centers that have access to these tests. The ultimate outcome someday will be a clinical practice guideline where people don’t get the label of AD unless they really have positive biomarkers.”
Dr. Jack has been a consultant for Eli Lilly.
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