New Framework for Future Alzheimer’s Research Proposed
Owing to a 15-year record of clinical failures and pulled by an FDA searching for a practical new path forward for Alzheimer’s drug research, a joint committee organized by the NIH’s National Institute of Aging and the Alzheimer’s Association is suggesting a biomarker-based approach to defining the illness that can guide new development efforts.
This proposed “biological construct” is based on measurable changes in the brain and is expected to facilitate better understanding of the disease process and the sequence of events that lead to cognitive impairment and dementia.
The identification of Alzheimer’s disease (AD) biomarkers and their ability to measure pathology antemortem has led to a fundamental reconsideration of the pathogenesis of AD. The importance of biomarkers was already reflected in revised diagnostic criteria proposed by the National Institute on Aging and the Alzheimer’s Association in 2011.
Beginning in 2016, the NIA and AA convened a new workgroup to develop a research framework for AD that embodied the paradigm shift occurring in the field. Rather than conceptualizing AD primarily as a clinicopathological entity, biomarkers have demonstrated that AD pathology exists over the continuum of the
disease–from a stage preceding overt symptomatology (the “preclinical state”) to the progressively more impaired symptomatic states of mild cognitive impairment (MCI) and dementia. The same biomarkers have also shown in greater resolution how dementia may occur in people with both AD and non-AD pathology.With this construct, researchers can study Alzheimer’s, from its earliest biological underpinnings to outward signs of memory loss and other clinical symptoms, which could result in a more precise and faster approach to testing drug and other interventions.
“With the aging of the global population, and the ever-escalating cost of care for people with dementia, new methods are desperately needed to improve the process of therapy development and increase the likelihood of success,” said Maria Carrillo, Ph.D., Alzheimer’s Association chief science officer and a co-author of the new article. “This new Research Framework is an enormous step in the right direction for Alzheimer’s research.”
According to the authors, “This evolution of the previous diagnostic criteria is in line with most chronic diseases that are defined biologically, with clinical symptoms being a … consequence.” They say, “the goal of much of medicine is to identify and treat diseases prior to overt symptoms. The [NIA-AA Research] Framework is intended to provide a path forward to … prevention trials of Alzheimer’s disease among persons who are clinically asymptomatic.”
The biomarker-based definition relies on three neuropathological measures of beta-amyloid deposition, abnormal microtubule-associated protein tau (tau; MAPT; FTDP-17) and neurodegeneration, collectively called the “ATN system” that can be measured with imaging technology and analysis of cerebral fluid samples.
The authors suggest the ATN framework can help in the design and execution of observational studies and clinical trials, and can enable trials to use biologically defined target populations in addition to clinically defined populations. Innovative trial approaches that have been tested in other disease areas such as oncology- platform trials, umbrella and basket designs- could be used with stratification of patients by ATN profiling.
In an accompanying editorial, members of the NIH who worked on the report emphasized that the framework is still a work in progress. As science advances, even more biomarkers might need to be considered, they admit.
And though the NIH expects and hopes scientists use the framework in designing their studies when submitting for grants, they won’t shut out those who don’t use these specific biomarkers in their research.
“The NIH will consider research applications using the Framework as well as proposals using alternative schemes when designing experimental approaches,” they wrote. “The NIH continues to welcome applications where biomarkers may not be appropriate.”
