Alzheimer’s Gets a New Definition

Alzheimer’s disease has a biologically based definition, according to criteria developed by an Alzheimer’s Association workgroup.

The new criteria include biomarker classifications and a revised disease staging system, reported Clifford Jack Jr., MD, of the Mayo Clinic in Rochester, Minnesota, and co-authors in Alzheimer’s & Dementia.

They define Alzheimer’s disease as a process detectable by abnormal biomarkers when patients do not have cognitive symptoms — a point of contention among some in the Alzheimer’s community.

“Alzheimer’s pathology, which we consider represents Alzheimer’s disease, begins to appear in the brain at least 15 to 20 years prior to the onset of symptoms,” Jack told MedPage Today. “To be scientifically accurate, we therefore define high-quality biomarker evidence of Alzheimer’s pathology to represent Alzheimer’s disease, including in people who are presently asymptomatic.”

Defining diseases biologically is standard in cancer, heart disease, and diabetes, Jack pointed out. “Symptoms from Alzheimer’s disease occur because affected individuals have already undergone substantial and irreversible death of brain cells,” he said. “Ultimately, the most effective treatment for Alzheimer’s disease must begin while affected individuals are still asymptomatic. This is axiomatic for every disease in medicine for which biomarkers exist.”

The field is still awaiting clinical trial evidence about whether treating asymptomatic patients will prevent cognitive decline, Jack added.

Not Clinical Practice Guidelines

The new criteria do not constitute clinical practice guidelines. They are intended to help evaluate symptomatic adults, not those who are cognitively unimpaired, the workgroup committee emphasized. Testing cognitively unimpaired individuals outside of research studies is not recommended at this time.

“Our criteria are intended to serve as a bridge between clinical practice and research, not as a step-by-step manual for general clinical practice today,” Jack said. “Formal clinical practice guidelines around treatment and testing will be forthcoming from the Alzheimer’s Association.”

In the revised criteria, the committee outlined three broad categories of biomarkers: those specific to Alzheimer’s changes like amyloid and tau, referred to as “core” biomarkers; those important to Alzheimer’s but not specific to the disease, like neurodegeneration and inflammation; and those that reflect conditions that commonly co-exist with Alzheimer’s, like vascular pathology and alpha-synuclein.

Core 1 Alzheimer’s biomarkers become abnormal early in the disease course and include amyloid PET, approved cerebrospinal fluid biomarkers, and certain plasma biomarkers like phosphorylated tau 217 (p-tau217) that map into either the amyloid-beta or Alzheimer’s tauopathy pathway. Core 2 biomarkers reflect aggregated tau deposits and include biofluid and tau PET.

“An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of Alzheimer’s disease and to inform clinical decision-making throughout the disease continuum,” the committee wrote. Later-changing Core 2 biomarkers can provide prognostic information and increase confidence that Alzheimer’s is contributing to symptoms, they added.

The same Alzheimer’s biology may result in different phenotypic presentations, the committee noted, depending on co-pathologies, cognitive reserve, resistance, and other factors that may influence relationships between clinical and biological Alzheimer’s stages.

Criteria Critiques

The revised criteria updates the 2018 Alzheimer’s research framework. Early versions of the new criteria were presented at meetings last year and posted for public comment, and groups like the American Geriatrics Society (AGS) reacted quickly to draft versions.

“The AGS position is that the framework proposes a clinical diagnosis of Alzheimer’s disease in biomarker-positive asymptomatic individuals with insufficient attention to the potential impact on their personal identity or social and fiscal consequences,” the organization wrote in a comment last November. “While AGS understands that defining Alzheimer’s disease as a biological construct has advantages for research, the current evidence base is underdeveloped to support clinical utility.”

Some criticisms contradicted fundamental positions of the committee, Jack and colleagues noted in a Nature Medicine commentary. One was whether the term “Alzheimer’s disease” should be used to describe all-cause dementia and whether distinctions between etiology and symptoms should be ignored to avoid confusion among the general public — which the committee said was not only inaccurate, but harmful. “The etiology or etiologies underlying clinical symptoms must be understood and accurately diagnosed to enable effective treatments,” they wrote.

Another was whether a diagnosis of Alzheimer’s disease should require the presence of both abnormal biomarkers and clinical symptoms, as some people with amyloid deposits may not experience cognitive decline. “Over half of individuals newly diagnosed in their mid-70s may not experience symptoms in their lifetime, but nearly half will,” the committee pointed out. “The position of the committee is that asymptomatic individuals who may experience symptoms deserve treatment once these are approved for the preclinical population.”

Critics also zeroed in on references to blood-based biomarkers, saying they are too new to be used. Recognizing that “plasma biomarkers are a recent development, we also outline rigorous criteria that plasma biomarkers need to meet to be considered fit for the purpose of diagnosis,” the committee noted.

The revised criteria are intended to reflect current scientific knowledge, Jack observed. “Some of the biomarker tests described in the diagnosis and staging criteria are not available at this time in general medical settings, but will be in the future as the infrastructure for testing is built out,” he said.

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