Radical New Definition of Alzheimer's Relies on Biomarkers

Batya Swift Yasgur, MA, LSW

April 11, 2018

Alzheimer's disease (AD) should be defined by biomarker pathology rather than clinical symptoms, according to a new research framework.

Scientists at the National Institute on Aging (NIA) and the Alzheimer's Association (AA) have proposed that a radical change in the definition of AD be used in the research setting. The current one is based on clinical cognitive and behavioral symptoms, with biomarkers used to confirm the diagnosis. The new definition is based on biomarkers alone.

"The biggest change we are proposing — for research purposes only — is that AD no longer be defined by the presence of clinical symptoms and a stereotypical clinical presentation, which has historically been the definition used for clinical and research purposes," lead author Clifford R. Jack Jr, MD, of the Mayo Clinic, Rochester, Minnesota, told Medscape Medical News.

"We are proposing that the disease be defined in living people by evidence of brain pathology using biomarker studies, either brain imaging or body fluid examination, and that clinical symptoms should be regarded for what they are — a product or result of the disease, as opposed to the definition of the disease," he said.

The proposal was made in an article published online April 10 in Alzheimer ' s and Dementia.

Syndrome vs Disease

In 2011, the NIA and the AA published three articles containing diagnostic recommendations for the preclinical stage, the mild cognitive impairment (MCI) stage, and the dementia stage of AD.

"There were inconsistencies between the three documents, and some aspects of the contents were not correct, in light of current science," Jack said.

"Our intention in developing the current document was to create a research framework that harmonized and updated the 2011 guidelines to reflect current thinking in the field," he said.

Another intention was to "create a common language for researchers in the AD field all over the world to categorize patients, define the disease, and categorize disease severity, which we think will facilitate understanding of the natural history of the disease and also facilitate international clinical trials," Jack added.

The authors state that dementia is not a disease but rather "a syndrome composed of signs and symptoms that can be caused by multiple diseases, one of which is AD."

Approximately 10% to 30% of individuals who are clinically diagnosed with AD dementia do not display neuropathologic changes associated with AD at autopsy or have normal findings on amyloid positron-emission tomography (PET) or cerebrospinal fluid (CSF) Aβ42 studies.

Conversely, neuropathologic changes associated with AD can be present without signs or symptoms. Thirty percent to 40% of cognitively unimpaired individuals are found to have neuropathologic changes at autopsy or abnormal amyloid biomarkers.

"The fact that an amnestic multidomain dementia is neither sensitive nor specific for AD neuropathological changes suggests that cognitive symptoms are not an ideal way to define AD," the authors observe.

The traditional approach incorporates biomarkers into AD diagnosis after patients develop clinical symptoms, which is relatively late in the disease process. The research framework suggests using the biomarkers themselves to define AD.

Definition and Staging

The researchers identify three general groups of biomarkers, determined on the basis of the nature of the pathologic process that each one measures. They call their scheme "AT(N)(C)."

"A" refers to Aβ, as measured either by amyloid PET imaging of amyloid plaques or in the CSF as Aβ42, or by the Aβ42-to-Aβ40 ratio.

"T" refers to tau pathology, as measured by CSF phosphorylated tau (p-tau) or tau PET imaging of parenchymal neurofibrillary tangles.

"(N)" refers to neurodegeneration or neuronal injury and dysfunction, as measured by anatomic MRI, fluorodeoxyglucose PET, or CSF total tau.

The neurodegeneration or neuronal injury in the "(N)" category can be attributed to many causes and are not specific to neurodegeneration caused by AD.

The authors use "(C)" to indicate cognitive symptoms.

Complete AT(N) biomarker characterization "is possible using either imaging or CSF biomarkers alone, although some research groups may prefer a mixture of both for AT(N) characterization," the authors note.

Pathologic changes and AD are not "regarded as separate entities but earlier and later stages of the 'Alzheimer's continuum' (an umbrella term that includes both)."

Staging of AD severity in research participants can be assessed using two independent sources of information: biomarkers, and severity of cognitive impairment.

"Measures used to define AD must be specific for the disease, whereas measures used to stage severity need not be," the authors note.

The authors indicate that they prefer the term "biomarker profile" rather than "stage," because "stage" implies a sequence; by contrast, the AT(N) biomarker system "does not imply a specific order of events."

The AT(N)(C) measures have different roles for definition and staging.

"A" biomarkers determine whether the individual is in the AD continuum, while "T" biomarkers determine whether someone on the continuum actually has AD.

Neurodegenerative and neuronal injury markers and cognitive symptoms are used in staging.

"A and T indicate specific neuropathologic changes that define AD, whereas (N) and (C) are not specific to AD," the authors state.

The authors note that the AT(N) system can be expanded in the future to include other (eg, inflammatory or vascular) biomarkers and that other MRI measures can provide important information about cerebrovascular disease.

Cognitive Continuum

The researchers reframe cognitive changes from their original conceptualization of preclinical AD, MCI, and dementia to a "cognitive continuum."

Syndromal cognitive staging "divides the cognitive continuum into three traditional categories — CU, MCI, and dementia, with dementia further subdivided into mild, moderate, and severe stages."

Clinical trials in this category can include patients with all biomarker profiles.

The second scheme is numeric clinical staging, which is applicable only to those on the AD continuum.

Each research participant in a clinical trial can receive a descriptive nomenclature that combines syndromal cognitive staging with biomarkers.

Numeric clinical staging, on the other hand, "reflects the sequential evolution of AD," with biomarker changes accompanied by progressive worsening of cognitive symptoms.

The new research framework proposes changes in the traditional terminology used to describe and stage AD.

A person with biomarker of Aβ alone and normal tau would be assigned the label "Alzheimer's pathologic change." The term "Alzheimer's disease" would be applied only if biomarker evidence of both Aβ and pathologic tau was present.

"We hope that two categories of research — natural history studies and interventional clinical trials — will emerge from this," Jack said.

"In the area of interventional studies, our hope is that people will adopt this framework for classification and definition, which will enable the field to identify risk factors and prognostic factors for AD specifically," he said.

"We also hope this will serve as a template for designing clinical trials, since about 30% of people enrolled in clinical trials with a diagnosis of AD actually don't have AD and are being treated for a disease they don't have."

For Research Purposes Only

Commenting on the article for Medscape Medical News,Ara Khachaturian,PhD, executive editor Alzheimer's and Dementia, who was not a member of the group that developed the research framework, noted that the biological construct "will enable the classification of individuals with greater precision."

Additionally, "there is a tendency to not fully appreciate the great variety of forms and expressions of dementing diseases, and the NIA-AA research framework provides a nomenclature so that we may better classify/sort out individuals to provide the best opportunities for care, treatment, and participation in research studies," said Khachaturian, who is the lead author of an accompanying editorial.

Also commenting on the article for Medscape Medical News, Nina Silverberg, PhD, program director, Alzheimers Disease Center, National Institute on Aging, and lead author of an accompanying editorial, noted, "For the research community, there are so many different types of research we do that this will apply to ― many, but not all research."

She added that at the NIA, "we have a very broad research agenda, and this is definitely a piece of it. Having a biological definition will help with addressing biological aspects of the disease."

A companion article summarized a roundtable consisting of experts in the field from industry, academia, and government.

The authors discussed barriers for the adoption of the new research framework in clinical trials.

For example, obtaining biomarkers by either CSF or imaging "adds expense and burden to any study and involves invasive procedures and/or exposure to radiation."

Nevertheless, the framework "could enable more precise staging of individuals along the AD continuum of pathologic progression," which could "allow future proof-of-concept trials to be conducted in biologically defined (in additional to clinically defined) target populations and to more directly investigate whether modulation of a specific target interferes with a specific component of disease pathologic change," they write.

Although the impact on research is profound, the impact on individual patients still lies in the future, Jack pointed out.

"Since there is currently no treatment for AD, there is no call to incorporate this framework into general clinical practice now, because it won't do the average patient any good," he said.

Dr Jack serves as a consultant for Eli Lilly, Eisai, and Elan, is an investigator in clinical trials sponsored by Baxter and Pfizer Inc, and owns stock in Johnson & Johnson. Marilyn Albert serves as a consultant to Genentech and Eli Lilly and receives grants to her institution from GE Healthcare. The other authors relevant financial relatiomnships are listed on the original article. Dr Knopman serves on a Data Safety Monitoring Board for Lilly Pharmaceuticals, is an investigator for clinical trials sponsored by Elan Pharmaceuticals, Forest Pharmaceuticals, and Baxter Healthcare, is deputy editor of Neurology, and receives compensation for editorial activities. The other authors' disclosures are listed on the original article. Dr Khachaturian is executive editor of Alzheimer's and Dementia: The Journal of the Alzheimer's Association. The other authors' affiliations are listed on the original article. Dr Silverberg and coauthors are affiliated with the National Institute on Aging.

J Alzheimers Dis. Published online March 16, 2018. Full text

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