A new definition of Alzheimer's disease

Alzheimer's disease has a biological definition, according to criteria developed by a working group of the Alzheimer's Association.

The new criteria include biomarker classification and a revised disease staging system, reported Clifford Jack Jr., MD, of the Mayo Clinic in Rochester, Minnesota, and coauthors. Alzheimer's and Dementia.

They define Alzheimer's disease as a process that can be detected by abnormal biomarkers when patients do not exhibit cognitive symptoms, a definition that is controversial in some parts of the Alzheimer's community.

“We believe that Alzheimer's disease pathology begins to appear in the brain at least 15 to 20 years before symptoms appear,” Jack said. Today's Medpage. “Therefore, to be scientifically accurate, we need to define high-quality biomarker evidence of Alzheimer's disease pathology as representative of Alzheimer's disease, including in people who are currently asymptomatic.”

Defining disease biologically is standard for cancer, heart disease and diabetes, Jack noted. “Alzheimer's symptoms appear because patients have already experienced significant and irreversible death of brain cells,” he said. “Ultimately, the most effective treatment for Alzheimer's must begin when patients are still asymptomatic. This is axiomatic for any disease in medicine for which biomarkers exist.”

Jack added that they are still waiting for evidence from clinical trials as to whether treating asymptomatic patients can prevent cognitive decline.

Not a clinical practice guideline

The new criteria do not constitute clinical practice guidelines. The task force emphasized that they are intended for evaluating symptomatic adults, not cognitively impaired adults. Testing cognitively unimpaired individuals outside of research studies is not currently recommended.

“Our standards are intended to be a bridge between clinical practice and research, rather than a step-by-step manual for today's common clinical practice,” Jack said. “Formal clinical practice guidelines on treatment and testing are expected to be published shortly by the Alzheimer's Association.”

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

Core 1 Alzheimer's biomarkers show abnormalities early in the disease progression and include amyloid PET, approved cerebrospinal fluid biomarkers, and specific plasma biomarkers such as phosphorylated tau 217 (p-tau217) that map to either the amyloid beta or Alzheimer's tauopathy pathways. Core 2 biomarkers reflect aggregated tau deposits and include biofluids and tau PET.

“Abnormal results for Core 1 biomarkers are sufficient to confirm a diagnosis of Alzheimer's disease and to inform clinical decision-making throughout the disease trajectory,” the committee wrote. Core 2 biomarkers, which change later, can provide prognostic information and increase confidence that Alzheimer's disease is responsible for the symptoms, the committee added.

The committee noted that the same biology of Alzheimer's disease may result in different phenotypic manifestations, depending on comorbid pathology, cognitive reserve, resistance, and other factors that may affect the relationship between clinical and biological Alzheimer's disease stages.

Review of standards

The revised criteria are: 2018 Alzheimer's Research FrameworkAn early version of the new standards was presented at a conference last year and posted for public comment, with groups such as the American Geriatrics Society (AGS) responding quickly to the draft.

“AGS's position is that the framework proposes a clinical diagnosis of Alzheimer's disease to asymptomatic individuals who are biomarker positive, but does not pay sufficient attention to the potential impact on an individual's identity or the social and financial consequences,” the organization said in the report. comment Published last November, “AGS understands that there are research benefits to defining Alzheimer's disease as a biological construct, but the current evidence base is too underdeveloped to support clinical utility.”

Some of the criticisms contradict the committee's basic position, Jack and others said. Nature Medicine The committee's comments included: “Whether the term “Alzheimer's disease” should be used to describe dementia of any cause, and whether the distinction between etiology and symptoms should be ignored to avoid confusion among the general public. The committee said that confusion is not only inaccurate but harmful. “Effective treatment is not possible without understanding and accurately diagnosing the etiology underlying the clinical symptoms,” the committee wrote.

Another was the question of whether a diagnosis of Alzheimer's disease requires the presence of both abnormal biomarkers and clinical symptoms, since some people with amyloid deposits never experience cognitive decline. “Although more than half of people newly diagnosed in their mid-70s may never experience symptoms in their lifetime, nearly half will,” the committee noted. “The committee's position is that asymptomatic individuals who may experience symptoms would be worthy of receiving the treatment if approved in the preclinical population.”

Critics also took aim at references to blood-based biomarkers, saying they are too new to be used. “Recognizing that plasma biomarkers are a more recent development, we also outline strict criteria that plasma biomarkers must meet to be considered suitable for diagnostic purposes,” the committee noted.

Jack said the revised criteria are intended to reflect current scientific knowledge. “Some of the biomarker tests listed in the diagnostic and staging criteria are not currently available in general practice but will be available in the future as the testing infrastructure is built,” he said.