This Notice of Funding Opportunity (NOFO) invites applications proposing innovative strategies to target and manipulate brain cell subtypes that are altered in aging, Alzheimer Disease (AD), and AD-Related Dementias (ADRDs). ADRDs include frontotemporal disorders (FTD), Lewy body dementia (LBD), vascular contributions to cognitive impairment and dementia (VCID), and multiple etiology dementias (MED). Specifically, the goal of the NOFO is to encourage the development and utilization of sophisticated tools that pair breakthroughs in adeno-associated virus (AAV) capsid engineering with enhancer element identification to (1) optimize precise targeting of disease-relevant cell subtypes in aged and degenerating mammalian brains and (2) monitor and/or manipulate these cells in vivo to address mechanistic hypotheses related to brain aging and AD/ADRD in animals models. To achieve this goal, the NOFO utilizes the R61/R33 Exploratory/Developmental Phased Award activity code. The R61 phase provides up to 2 years of support for pilot activities to demonstrate proof-of-principle. The R33 phase provides up to 3 years of support for implementation activities including hypothesis testing. AD is a progressive neurodegenerative disease of the brain and the most common form of dementia in older adults. It is estimated that AD starts 15–20 years before the appearance of the onset of clinical symptoms and ultimately leads to a loss of memory, cognitive skills, and the decline in quality of life in older adults. An estimated 6.5 million Americans aged 65 and older were living with AD in 2022. In response to this public health crisis, the National Alzheimer’s Project Act (NAPA) was signed into law in 2011. As part of the strategic planning process to implement NAPA, NIH AD Research Summits identified research priorities and strategies needed to accelerate basic research.

The progression of AD often follows a predictable temporal and spatial pattern where specific brain regions are affected at different stages of the disease. However, it is unclear why the disease affects certain regions of the brain or why specific cell subpopulations within these brain regions are selectively vulnerable. Several large-scale efforts funded by the National Institute on Aging (NIA) are identifying cell types that are altered in the AD brain by generating high quality single cell transcriptomic and epigenetic datasets in human tissue and model organisms during normal aging and AD progression. These NIA-supported projects have uncovered disease-associated gene signatures across all major brain cell types and have identified subtype-specific alterations in neurons, astrocytes, microglia, oligodendrocytes, and vascular cells in AD. Despite a rapidly growing catalog of brain cell subtype changes in AD progression, it is not clear how these changes contribute to deficits in cell, circuit, or brain function.

Innovative approaches to target and manipulate selectively vulnerable brain cell subtypes could promote breakthroughs in understanding the mechanisms underlying aging and AD/ADRD. Recent advances in technology, supported in-part by the Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, have generated sophisticated tools that enable unprecedented access to specific cell subtypes in the vertebrate animal brain. There have been two major developments in technology that drove this leap in capabilities: 1) adeno-associated viruses (AAV) capsid engineering and 2) cell subclass-specific enhancer element identification. First, the newly engineered AAV capsids can cross the blood-brain barrier in mouse and nonhuman primate and several capsids are biased toward specific brain cell types, such as neurons, astrocytes, oligodendrocytes, or vascular cells. The second major advance arises from high resolution single-cell epigenetics technology, which allows the identification of cell subtype specific enhancer elements that enable refined access to cell subclasses when coupled with AAV transduction. To promote further development of this AAV-enhancer technology, the BRAIN Initiative Armamentarium for Precision Brain Cell Access supports the validation and dissemination of these tools to encourage broad use by the scientific community.