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.
