Characterization of Biomarkers and the Vascular Amyloid Proteome in a Non-human Primate Model of Alzheimer’s Disease

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PROJECT SUMMARY Alzheimer’s disease (AD) is the most common cause of dementia worldwide with no highly effective disease- modifying treatment. A premature jump from studies completed in transgenic mice directly to AD patients has been cited as one of the significant reasons for failure of the vast majority of clinical trials. The potential for translatability to humans is likely enhanced by testing promising therapeutic concepts in non-human primates (NHPs), which more closely recapitulate neuropathological features of AD. Our recent study supports the use of squirrel monkeys (SQMs), neotropical primates which unlike other NHPs develops extensive cerebral amyloid angiopathy (CAA) in all aged animals, for validating the therapeutic potential of our immunomodulatory intervention planned for human use. CAA, for which there is no treatment, is present in nearly all AD cases and promotes more rapid cognitive decline. The major complications in current immunotherapeutic trials for AD are amyloid-related imaging abnormalities (ARIA), which are linked to the presence of CAA; hence the prominence of CAA in SQMs underlines the importance of advancing this model for use in AD and dementia research. The collective studies proposed here are designed to provide a comprehensive assessment of the processes driving progression of AD and CAA by integrating biofluid biomarker trajectories with imaging markers and cognitive measures, in addition to postmortem brain pathology features in SQMs. We intend to longitudinally evaluate age- related changes in cognition using an innovative Automated Cognitive Testing System (ACTS) implemented in two different-aged cohorts of socially-living SQMs. Moreover, disease progression will be monitored by a combination of MRI techniques enabling morphometric characterization, screening for microhemorrhages, and white matter hyperintensities. Brain microstructural integrity, especially white matter (WM) integrity changes, will be examined by utilizing a biophysical model of multi-shell diffusion MRI in this unique model vulnerable to cerebrovascular pathology. Further understanding of the association between microstructural WM alterations, cognitive function, and pathological correlates will provide essential insights for clinical practice. SQMs also present a valuable opportunity to identify the protein signature that defines CAA deposits. Therefore, we propose the first complete characterization of the CAA proteome across different groups of SQMs exhibiting mild and severe CAA pathology, utilizing our well-established localized proteomic approach. The power of our proteomic strategy is the combination of an unbiased mass spectrometry examination with laser capture microdissection to precisely excise and characterize defined neuropathological lesions. Overall, we believe the in-depth portrayal of this NHP model will provide a critical foundation for future translational research on the pathogenesis of CAA, in order to improve diagnostic capability and advance innovative therapies.