PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD), the most common form of age-related dementia, is characterized by cognitive impairment, neurodegeneration, β-amyloid (Aβ) deposition, and neurofibrillary tangle (NFT) formation. Adult hippocampal neurogenesis (AHN), a relatively novel form of brain plasticity that refers to the birth of new neurons in the adult hippocampus, remains strong in healthy human brains but drops steeply in AD patients, even before the presence of Aβ plaques and NFTs. On the other hand, adult-born neurons are significantly more abundant in non-demented individuals with AD neuropathology (resilient). AHN levels correlate with cognitive function in AD and mild cognitive impairment patients. Using Aβ-overexpressing 5×FAD mice, we identified AHN as a primary event that mediates AD pathogenesis when impaired, and as a potential treatment strategy for AD when enhanced in combination with elevating brain-derived neurotrophic factor (BDNF). Increasing either AHN or BDNF alone was not sufficient to ameliorate cognitive dysfunction. We hypothesize that stimulating both AHN and BDNF could serve as a brain resilience enhancing strategy to slow AD. Further study on how AHN and BDNF cooperate and on how AHN is preserved in resilient brains is required to assess their role as therapeutic agents to treat cognitive decline in AD. The objective of this proposal is to rigorously test our hypothesis using mechanistic molecular and cellular techniques, bioinformatics integration, morphological and functional studies, and behavioral testing. We will achieve our objective by exploring the mechanism(s) by which AHN cooperates with BDNF and by testing whether our strategy to improve cognition by increasing both AHN and BDNF can be generalized in tauopathy (Aim 1); by performing integrative single-cell transcriptomic analysis of AHN in AD and resilient human brains, mouse models, and iPSC-derived neuronal cell models (Aim 2); and by testing the therapeutic potential of newly-identified pharmacological/natural compounds that trigger AHN and BDNF in AD (Aim 3). A successful therapy would ideally both remove those pathological hallmarks of AD (e.g., Aβ and tau pathologies, neuroinflammation, and cell loss) and provide a level of functional recovery. Thus, we will test whether increasing AHN, in part, could be a potentially powerful adjunct therapeutic for AD that provides functional recovery.