Notice Number: NOT-AG-18-051
Release Date: November 29, 2018
National Institute on Aging (NIA)
This Notice of Information specifies a high-priority topic of interest for PAR-19-070 "Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)".
Understanding Alzheimer's Disease in the Context of the Aging Brain
Alzheimer’s disease (AD) is the leading cause of dementia in those over the age of 65, and as many as 5 million Americans age 65 and older have AD. As the population ages, the number of people age 65 and older with AD is projected to increase between two and three fold by 2050 without a cure or prevention of the disease. AD is one of the most persistent and devastating dementing disorders of old age because it eventually leads to a complete loss of memory and of the ability to function independently. Currently there are only a few interventions that have been approved for the treatment of AD. Those approved have demonstrated only modest effects in modifying the clinical symptoms for relatively short periods, and none has shown a clear effect on disease progression. In response to this looming public health crisis in the United States, the National Alzheimer’s Project Act (NAPA) was signed into law in 2011. The primary research goal of NAPA is to find effective interventions to treat and prevent AD and related dementias by 2025. As part of the strategic planning process for the implementation of the NAPA, two Alzheimer’s Disease Research Summits entitled “Path to Treatment and Prevention” were held in 2012 and 2015. The overarching goal of the Summits was to bring together leading experts on Alzheimer’s disease to identify research priorities and strategies needed to accelerate the development of effective therapies across the disease continuum.
Age is a major risk factor for developing dementia, with imaging and biomarker data suggesting that the pathophysiological processes of AD begin more than a decade prior to the diagnosis of dementia. AD is a heterogeneous, multifactorial disease, and a challenge in AD research is to fully understand how the multiple etiologies and age-related prodromal processes contribute to the pathophysiology of AD. Knowledge of the mechanisms underlying the shift from healthy brain aging to the neurodegeneration of AD is imperative for the design and determination of effective interventions. One of the overarching transformative concepts identified by participants at the 2015 AD Research Summit was to “understand all aspects of healthy brain aging and cognitive resilience to inform strategies for Alzheimer’s disease prevention,” with a recommendation to “integrate AD research with neurobiology of aging and biology of aging research by developing new programs on systems biology and integrative physiology to gain a deeper understanding of the complex biology of disease.” A Geroscience Summit held at NIH in 2013 highlighted "how common mechanisms governing aging might underlie the pathology associated with diverse chronic diseases." How aging mechanisms impact AD neuropathological processes needs to be explored further.
Changes in brain structure and function may continue throughout life, and studies at multiple levels of analysis in model organisms and humans are helping to define the normal trajectory of changes in the brain over the adult lifespan. Structural neuroimaging and anatomical studies of brain have shown declines in total gray and white matter, along with shrinkage or atrophy and synaptic changes in certain regions of the brain in aging. Functional imaging studies are defining the workings of large-scale neural and cognitive networks in the aging human brain, and have shown, for example, disruption of the resting-state default mode network, as well as putative compensatory recruitment of brain areas to sustain cognitive function. Human and animal studies suggest that adaptive or resilient processes (i.e. brain plasticity) may be needed for maintenance of brain structure and function during normal aging. At the molecular and cellular level of analysis in animal models, brain aging is associated with changes in gene and epigenetic expression, mitochondrial and energy metabolism, calcium regulation, protein homeostasis, glia, and neural plasticity and synaptic function. What remains unclear is when these normal aging changes transition to pathological aging and disease phenotypes. Complicating the understanding of the role of aging in AD is the fact that most studies employ adult, not aged, genetic animal models of disease. Integration of research at various levels of analysis, from cells to neural networks, in older adults and in appropriate animal models is needed to reach a global understanding of brain aging and its contribution to and promotion of pathological processes underlying AD.
The goal of this high-priority topic is to establish the role and underlying mechanisms by which brain aging impacts the development and progression of AD. A comprehensive and integrative characterization of brain aging, including its crosstalk with peripheral systems and factors, will help to define the mechanisms underlying the shift from normal aging to pathological processes in the etiology of AD. Cross-disciplinary, systems-based approaches, using newly developed tools and technology, to integrate findings on AD with research on the basic biology and neurobiology of aging are encouraged to gain a deeper understanding of the complex biology and physiology of healthy and pathologic brain aging. Animal and human studies are appropriate for this high-priority topic.
Areas of research interest and opportunity include, but are not limited to:
Applications proposing clinical trials would not be considered a high priority.
Submissions should indicate that they are in response to NOT-AG-18-051 in Field 4.b on the SF 424 form.
Please direct all inquiries to:
Bradley Wise, Ph.D
National Institute on Aging (NIA)