Thais Rafael Guimarães¹, Jung Eun Park¹, Catrina Spruce², Stephanie Hachem¹, Swati Banerjee¹, Lauren K Hayrynen Schaeffer¹, Gregg E Homanics¹, Stacey J Sukoff Rizzo¹, Gregory W Carter,², Afonso C Silva¹, and Amantha Thathiah¹

Progress in preclinical Alzheimer’s disease (AD) research has been constrained by models that fail to faithfully recapitulate human aging and overt AD neuropathology. The common marmoset (Callithrix jacchus), a New World non-human primate, exhibits aging trajectories, genetic heterogeneity, and complex social behaviors closely resembling those of humans, providing a highly translational platform for age-related neurodegenerative research. Importantly, marmoset studies uniquely enable longitudinal correlation of in vitro cellular models with in vivo assessments across the marmoset lifespan. We performed an integrated ex vivo and in vitro characterization of marmoset AD and tauopathy models. Immunohistochemical analyses of postmortem brains revealed robust amyloid-β (Aβ) and tau pathology, along with the associated cellular pathology. To establish an in vitro cellular system, we adapted a well-established human direct reprogramming protocol to generate age-conserved induced neurons (iNs) from marmoset fibroblasts. Comparative, unbiased RNA-seq analyses of marmoset and human iN conversion trajectories revealed significant species-specific differences, guiding targeted optimization of the reprogramming strategy. The refined protocol achieved high-efficiency neuronal conversion, improved cell survival and maturation, and preserved AD-relevant protein expression, including amyloid precursor protein (APP)/Aβ and tau. Together, this integrated framework establishes the marmoset as a powerful translational model for AD research. This platform enables minimally invasive mechanistic studies, longitudinal analyses, high-throughput drug screening, and therapeutic discovery aimed at accelerating disease-modifying strategies for AD.

¹University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

²The Jackson Laboratory, Bar Harbor, ME, USA