SUMMARY Bone fragility and joint disease present major challenges to the skeletal and dental health of the aging population. However, therapies for bone fragility treat low bone mass, but overlook approximately 50% of fractures that result from impaired bone quality. Furthermore, individuals with bone fragility and osteoarthritis (OA), diseases that are the focus of the parent R01, are at increased risk of cognitive decline, Alzheimer’s (AD), and other related dementias (ADRD). Vice versa – there is documented, but greatly understudied evidence that AD/ADRD patients exhibit higher risk for osteoarthritis, falls, and fractures. Here, the addition of collaborators to the parent R01, along with their established AD outcomes and models, enables us to leverage our ongoing studies of age-related skeletal degeneration to uncover mechanisms responsible for the coincident decline in skeletal and neurological health in aging. These studies are motivated by parent grant preliminary data of bone from aged mice and from TbRIIocy-/- and MMP13ocy-/- mouse bone, all of which exhibit suppression of osteocyte perilacunar canalicular remodeling (PLR), bone quality, and joint homeostasis. RNAseq and functional studies revealed evidence of mitochondrial dysfunction in each model, a common mechanism in AD. Even more surprising, pathways of AD and neurodegeneration where highly enriched in bones from both models of osteocyte-intrinsic PLR suppression and during aging. However, the mechanisms underlying these observations remain unknown. Therefore, we propose two specific aims to test the hypothesis that the coincident onset of AD, OA, and skeletal fragility arises from age-related deregulation of shared cellular mechanisms in neurons and osteocytes, which in turn disrupts bone/brain crosstalk. Aim 1 will determine the extent to which osteocyte-intrinsic defects compromise bone/brain crosstalk and cognition; whereas Aim 2 will determine the extent to which ADRD compromises osteocyte and skeletal function. We continue to take advantage of the TbRIIocy-/- mouse model in the parent grant, which will be tested for cognitive decline, behavioral changes, and other markers of early and late AD. In parallel, we introduce new AD mouse models to our studies, applying the skeletal outcomes from the parent grant to the 3xTg AD and APOE4 AD models to investigate effects of AD on osteocytes, PLR, bone quality, and OA. Throughout, we will leverage unparalleled bone and brain proteomic profiling to detect evidence of bone/brain crosstalk and to evaluate pathways common to bone and brain degenerative diseases. Obtained results will prioritize mechanistic gain and loss of function studies to test the hypothesis that TGFb-dependent PLR suppression and osteocyte mitochondrial dysfunction play a causal role in the age-related decline in bone quality and joint health, and how the latter mechanism affects bones in AD models. These studies will reveal if PLR suppression in aging and OA represe...