January 7, 2022
PAR-22-093, Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)
National Institute on Aging (NIA)
This Notice of Special Interest (NOSI) is aimed at improving our understanding of how age-associated metabolic changes in peripheral tissues or in the brain affect the onset and/or progression of Alzheimer’s disease (AD).
Changes in metabolism and mitochondrial function have been identified as hallmarks of the aging process. Since aging is the greatest risk factor for the development of AD and other neurodegenerative conditions, it is reasonable to posit that age-associated changes in metabolism play a major role in the onset or progression of these diseases. Consistent with this notion is the fact that the brain consumes 25% of the body’s glucose, of which 80% is metabolized via oxidative phosphorylation in the mitochondria. Glucose metabolism includes uptake controlled by insulin and the insulin signaling pathways, glucose transporter (GLUT)-dependent brain glucose uptake and the glycolytic pathway, and ultimate ATP generation in the mitochondria. As the primary fuel for neurons and glial cells, glucose usage is critical for brain function, and micro-positron emission tomography (PET) scanning studies have shown a significant decline in glucose uptake in aging brains of rodent models that show neuronal loss, impaired cognition and memory, and an increased risk for neurodegenerative disorders. Normal brain aging is associated with reduced insulin signaling, while activation of the AKT pathway is thought to promote glucose metabolism, neuronal survival, and synaptic plasticity, whereas reduced AKT activity has been implicated as a possible mechanism accounting for high GSK3beta activity and tau hyperphosphorylation. Consistent with these results in animal models, clinical studies have demonstrated hyperphosphorylation of tau protein in individuals with AD and type 2 diabetes mellitus (T2DM), a known risk factor for AD.
Glucose is metabolized via oxidative phosphorylation in the mitochondria, and there is extensive literature describing changes in mitochondrial biogenesis, function, turnover, efficiency of ATP production, and release of free radicals during aging. More recently, free radicals generated in the mitochondria and other so-called mitokines have been shown to act as signaling molecules cell-autonomously or cell non-autonomously. These wide-ranging, age-related metabolic changes are likely to affect AD etiology, and require further investigation.
In addition to age-related changes in insulin signaling and glucose handling, other changes in metabolism that occur with age include a massive change in lipid metabolism. Considering the high lipid content of myelin sheaths in the brain, these changes are likely to impact connectivity and other crucial neuronal functions, thereby possibly affecting the development of neurodegenerative conditions, including AD. Thus, it is highly likely that identifying the precise molecular and cellular mechanisms involved in these processes will provide important therapeutic targets.
The goal of this NOSI is to encourage research projects focused on the impact of changes in metabolism that occur with aging and their possible role in AD onset, pathogenesis, and progression. Under this overarching goal, the following topics illustrate the areas of research that are encouraged:
NIA views this topic as highly interdisciplinary and encourages researchers who have expertise in metabolic regulation and aging to collaborate with AD researchers in order to identify critical links between metabolic modulation and AD pathogenesis and/or progression.
Application and Submission Information
This notice applies to due dates on or after March 11, 2022 and subsequent receipt dates through November 13, 2024.
Submit applications for this initiative using the following funding opportunity announcement (FOA) or any reissues of the announcement through the expiration date of this notice.
All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:
Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.
Yih-Woei Fridell, Ph.D.
National Institute on Aging (NIA)