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New paper estimates AT(N) framework impact on effectiveness of Alzheimer’s research

Using data from the NIA-funded Adult Changes of Thought (ACT) study, researchers found that among participants who had Alzheimer’s biomarkers but who did not have dementia five years before death, nearly one in three remained dementia-free at death. A paper published April 26 in Alzheimer's & Dementia: Journal of the Alzheimer's Association highlights the continuing need for better ways to identify those people most likely to develop dementia.

The paper is the latest of many exploring and applying the 2018 NIA-Alzheimer’s Association Research Framework. This biological construct is based on three general groups of biomarkers: beta-amyloid (A), tau (T), and neurodegeneration or neuronal injury (N). Also referred to as the AT(N) research framework, it is designed to facilitate better understanding of the disease process and the sequence of events that lead to cognitive impairment and dementia.

While this paper illustrates important considerations surrounding current biomarkers, the AT(N) framework remains an effective approach for the scientific community to continue the tremendous progress made in Alzheimer’s and related dementias research over the past few years and to validate these biomarkers in various populations. Part of the original goal in developing and releasing the framework was to evaluate it in different contexts; for example, it must be extensively tested in diverse populations and with more sensitive biomarkers. In addition, it is well-established that better measurable definitions of Alzheimer's are needed to help better understand the disease’s natural history and heterogeneity, including prevalence of mimicking conditions.

Before biomarker tests were developed in the early 2000s, the only sure way to know whether a person had Alzheimer’s disease was via autopsy. Now researchers can use a biomarker-based definition of Alzheimer’s disease using cerebrospinal fluid (CSF) tests or positron emission tomography (PET) scanning to detect amyloid or tau; and magnetic resonance imaging (MRI) to measure neurodegeneration. Blood-based tests are already emerging as easier, faster, cheaper, and less invasive options. As the paper authors note, there is a need for improved tools to predict beyond current AT(N) biomarkers.

The paper also suggests a substantial proportion of older individuals without cognitive problems could have high levels of amyloid, tau, and neurodegeneration yet not develop dementia during life. This clearly comes with familiar concerns: Are the right people being enrolled in clinical trials; are invasive and expensive tests given to appropriate research participants; and are there enough sensitive, specific, and accurate biomarkers?

With recent major funding increases for research in Alzheimer’s and related dementias, there continues to be a clear need for a unified, measurable approach, which the AT(N) framework establishes. Researchers also welcome other approaches and indicators, for example, the framework could be expanded to include other factors that contribute to dementia, such as inflammation, the immune system, genetic changes, and viruses and bacteria.

Our understanding of Alzheimer’s and related dementias will continue to grow dramatically, leading to better and minimally invasive diagnostic tests. That paired with a widening pipeline of potential treatments, precision medicines — the right treatments for the right person at the right time — seem closer than ever.

This study was funded by NIA grants U01AG006781, P50AG005136, and 1K08AG065426-01.

Reference: Burke, BT et al. Theoretical impact of the AT(N) framework on dementia using a community autopsy sample. Alzheimer’s & Dementia. 2021 April 26. doi:10.1002/alz.12348.

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