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Biological definition of Alzheimer’s disease not suitable for clinical diagnosis

Journal
The Lancet Neurology
Reuters Health - 21/05/2021 - The current biological definition of Alzheimer's disease (AD), developed for use in research settings, is not appropriate for use in clinical settings, especially to evaluate individuals without symptoms, according to members of the International Working Group (IWG).

The biological definition, which relies on biomarkers, was put forth by the 2018 US National Institute on Aging and Alzheimer's Association Research Framework.

"In clinical settings, we would diverge from the research criteria and not recommend biomarkers in those who are asymptomatic and cognitively normal," Dr. Howard Feldman of the University of California, San Diego, principal author of the IWG paper, told Reuters Health by email.

"The presence of positive biomarkers of Alzheimer in cognitively unimpaired is insufficient to predict a further progression of clinical disease," he said. "We consider such individuals as being at-risk only, highlighting the need to be able to reliably define their level of future risk of progression."

"We offer the view that a formal AD diagnosis be applied only when persons have symptoms and clinical phenotypes that suggest the expression of disease," he said. "The presence of a specific clinical phenotype is recommended because Alzheimer lesions can also be found in people who have other neurodegenerative diseases, as co-pathology.

"Therefore, in both preclinical and clinical stages of the disease, a purely biological definition of Alzheimer's disease can lead to serious diagnostic errors in the clinical setting," he noted.

In addition, he said, "In real world clinical practice, there is often limited or no financial coverage for biomarkers and these tests are both expensive and difficult to use on an individual basis to predict subsequent course."

"Furthermore," he added, "the reality is that the requisite biomarkers in the 2018 Framework have limited availability in real-world settings outside of a select few academic health centers where the research on them has been pioneered."

As reported in The Lancet Neurology, limitations of the current definition from a clinical perspective include:

- Risk of confusion between the presence of Alzheimer's brain lesions and Alzheimer's disease. A definition based on ATN (amyloid beta, tau, neurodegeneration) status risks considering AD as a purely biological condition, dissociated from the clinical components.

- Low predictive accuracy, as shown in previous studies.

- Presence of other pathologies, such as dementia with Lewy bodies, which may result in positive biomarkers, thereby creating confusion - i.e., does the patient have AD, dementia with Lewy bodies, or both?

- Uncertainty about the pathogenesis model of Alzheimer's disease. The biological definition is based on the ATN classification. However, follow up of cognitively impaired biomarker-positive individuals suggests most do not progress over time.

- Difficulty in classifying cognitively unimpaired biomarker-positive individuals. As Dr. Feldman noted, IWG recommends considering these individuals as "at risk."

"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)," the APACE investigators conclude. "We recommend that the diagnosis of Alzheimer's disease in the clinical setting remains tied to the clinical phenotypic presentation."

The paper includes highly specific IWG recommendations for a clinical definition of AD and a proposed stratification of risk of asymptomatic people, according to biomarker results.

Dr. Feldman added, "The importance of this diagnosis and its impact in a person's life cannot be overstated. This is even more amplified in those who are asymptomatic and who may not during their lifetime experience disease symptoms."

Dr. William Jagust of the University of California, Berkeley, author of a related editorial told Reuters Health by email that the current framework " can put clinicians into a difficult situation because we cannot accurately predict what is going to happen to people based simply on biomarkers, so telling someone without symptoms that they have AD is fraught with ethical and clinical problems."

"In addition," he said, "biomarkers are complicated, frequently unavailable, and the expertise to interpret them is not always available. The IWG makes the wise comment that, in a clinical setting, careful clinical evaluation is necessary to interpret biomarkers."

Dr. Maria Carrillo, Alzheimer's Association chief science officer, told Reuters Health by email, "In our view, the updated IWG proposal is largely consistent with the ideas in the 2018 National Institute on Aging-Alzheimer's Association Research Framework, and the workgroup's recommendations do not invalidate the AT(N)+ system for research use."

"They are built in part on the idea that biological changes are the cause of the clinical symptoms," she said. "Disease, even preclinical disease, is different from 'at risk.' We want to detect and treat at the earliest biological stages in order to change the trajectory of the disease, as we do now with high blood pressure and high cholesterol."

SOURCE: https://bit.ly/3wpLVj3 and https://bit.ly/3wrCHTA The Lancet Neurology, online April 29, 2021.

By Marilynn Larkin



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