Defining Alzheimer’s: Should Cognitively Unimpaired People Be Included?

How do you define Alzheimer’s disease?

The International Working Group (IWG) argued that for everyday clinical use, a biological definition alone — the basis of the National Institute on Aging and the Alzheimer’s Association (NIA-AA) framework — is not enough.

Cognitively unimpaired individuals can have biomarker evidence of both amyloid beta and tau pathology but may not develop clinical signs of Alzheimer’s disease in their lifetime, said Bruno Dubois, MD, of Assistance Publique-Hôpitaux de Paris in France, and a group of 19 other IWG physicians.

“Furthermore, a positive Alzheimer’s disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer’s disease pathology is present as a comorbidity,” the team wrote in the Lancet Neurology.

“We recommend that Alzheimer’s disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer’s disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer’s disease,” the IWG proposed.

While the 2018 NIA-AA framework was intended for research purposes, “it has engendered debate and challenges regarding its use in everyday clinical practice,” the group noted.

In 2011, NIA-AA criteria defined three preclinical stages of Alzheimer’s: amyloid lesions came first, then tau pathology and neurodegeneration, and then subtle cognitive changes.

In 2016, an IWG and NIA-AA consensus document included Alzheimer’s diagnosed at a preclinical stage based on both in vivo amyloid beta and tau positivity “when the risk [of progression to clinical Alzheimer’s disease] is high.”

In the 2018 NIA-AA research framework, Alzheimer’s diagnosis centered exclusively around a biomarker definition based on amyloid, tau, and neurodegeneration (ATN).

“The development of in ­vivo biomarkers has moved the diagnosis of Alzheimer’s disease from the dementia stage towards the prodromal stage, and has introduced the potential for preclinical diagnosis (i.e., before symptom onset),” Dubois and co-authors observed.

“Based on ATN status, Alzheimer’s disease could be considered as a purely biological condition, dissociated from a clinical component or individual status,” the team wrote. “As a consequence, the term Alzheimer’s disease includes a continuum that ranges from cognitively unimpaired individuals to people with severe dementia.”

Challenges center mostly around preclinical stages of Alzheimer’s, the IWG authors said, noting that a major limitation of a biological Alzheimer’s definition is its low predictive accuracy. “Several studies indicate that the presence of both tau and amyloid beta positivity is insufficient to definitively predict the occurrence of symptoms (mild cognitive impairment or dementia) in individuals without clinical impairment,” the team wrote.

A clinical diagnosis of Alzheimer’s disease needs clinician expertise to assess both clinical and biomarker data, the IWG authors stressed. “The diagnosis of Alzheimer’s disease is clinical-biological. It requires the presence of both a specific clinical phenotype of Alzheimer’s disease (phenotype positive) and biomarker evidence of Alzheimer’s disease pathology (amyloid­ positive and tau positive).”

Removing clinical criteria in the NIA-AA definition “eliminated the syndromic aspect of Alzheimer’s disease and its inherent non­specificity,” noted William Jagust, MD, of the University of California, Berkeley, in an accompanying commentary. But it offered distinct advantages for Alzheimer’s research, he said.

Waiting until clinical symptoms appear is likely too late for therapeutic trials; at that point, amyloid and tau pathology is widespread, Jagust pointed out.”This approach is analogous to hypertension or hyperlipidemia, in which asymptomatic people are targeted by biomarkers for treatment, regardless of symptoms, with the intention of reducing cerebrovascular disease,” he wrote.

And while expert evaluation is crucial to a clinical diagnosis of Alzheimer’s disease, “as more biomarkers for different pathological processes become available, the nature and importance of clinical evaluation might also evolve,” Jagust added.

“Ultimately, the question of how best to diagnose Alzheimer’s disease will revolve around therapy: at what point, and in whom do we start it?” he asked. “The relative importance of clinical examination and biomarkers will depend on the answer.”