Project Summary / Abstract Alzheimer’s disease and related dementias (ADRD) pose major personal and public health burdens, with few interventions currently available to delay or prevent progression. The neuropathogenesis of ADRD is dependent on both genetic and non-genetic risk factors; the latter appearing to accelerate AD development via inflammatory pathways. Chronic inflammatory diseases compromise brain health and increase dementia risk, yet anti-inflammatory drug trials have been largely unsuccessful. Thus, a major gap exists in our understanding of the mechanisms that connect systemic inflammation to the pathogenesis of ADRD, preventing our ability to effectively reduce risk of dementia by targeting inflammatory pathways. Current models portray a long prodromal phase preceding onset of cognitive decline. Identifying the mechanistic inflammatory pathways active during this phase would provide more precise intervention targets. The systemic inflammation that occurs in asthma represents a highly novel target for study of mechanistic pathways operational in the preclinical phase. Asthma is a chronic inflammatory airway disease that typically begins in childhood, affects ~10% of the US population and is associated with greater risk for dementia. Primary neuropathological features of AD are amyloid-ß plaques and neurofibrillary tangles. However, neuroinflammation has emerged as an important component of AD pathology. Animal models of asthma show that neuroinflammation and neurodegeneration can result from airway inflammation and in humans, we show brain imaging evidence that asthma compromises brain health and relates to biomarkers of neuroinflammation, amyloid, tau, and cognitive decline. Here, we propose to use [18F]-FEPPA PET imaging to assess neuroinflammation as a mechanism by which asthma impacts brain health and confers greater risk for AD. We will combine longitudinal human PET imaging in mild asthma to model effects of an acute asthma episode on microglial activation, and cross-sectional PET imaging to compare glial activation in unprovoked asthma at varying severity levels. This will be complemented by a mouse model of asthma AD comorbidity to address the following aims: (1) identify mechanistic links between systemic and neuroinflammation by measuring changes in glial activation and key signaling pathways involved in response to airway inflammation in asthma (2) determine how patterns of biomarker expression in the Amyloid, Tau, Neurodegeneration classification system relate to asthma severity and asthma-related glial alterations and the extent to which asthma accelerates development of AD pathology and (3) explore the relationship between neuroinflammation and cognitive performance. The resulting knowledge will delineate the signaling pathways active in chronic inflammatory diseases that confer ADRD risk, with the ultimate goal to spur novel treatments that precisely target these pathways.

Project Narrative Asthma and other chronic inflammatory diseases increase risk for Alzheimer’s disease (AD). The proposed project seeks to benefit public health by determining how asthma contributes to development of AD other types of dementia using a combination of brain imaging, biomarkers measured in blood, and a mouse model of AD and asthma. Ultimately, this line of research is aimed at identifying pathways to prevention of dementia and developing new treatments and intervention strategies for Alzheimer’s disease.