Lauren Bailey, PhD¹, Takeshi Murai, PhD¹, Lauren Mongeau¹, Abbey Setlik¹, Tingting Zhang, PhD¹, Seung-Kwon Ha, PhD, DVM¹, Gregory W. Carter², Afonso C Silva, PhD¹ and Stacey J Sukoff Rizzo, PhD¹,

Fundamental questions remain regarding the mechanisms that initiate Alzheimer’s disease (AD), drive its progression, and link pathology to cognitive impairment. As part of our MARMO-AD consortium, we established a comprehensive testing battery sensitive to detecting age-dependent cognitive decline across the lifespan in our colony of aging marmosets, and marmosets genetically engineered with mutations in the PSEN1 gene which confers early onset AD in humans. Beginning in adolescence, marmosets are trained using touchscreens through a battery of tests that captures a spectrum of cognitive domains including spatial working memory (delayed match to position), behavioral flexibility and reversal learning (delayed non-match to position), recognition memory (trial unique delayed match to sample), attention (serial reaction time task), and episodic-like memory (paired associative learning task). Behavioral and cognitive function are aligned with longitudinal PET neuroimaging and blood-based biomarkers to track AD progression. Similar to human PSEN1 mutation carriers, plasma Aβ42:40 is significantly elevated relative to non-carrier controls Despite robust biomarker and pathological changes, PSEN1 marmosets show no significant deficits in task acquisition or performance across cognitive domains up to 4 years of age. These data are not surprising and recapitulate the disease trajectory of increased amyloid in plasma and brain years before cognitive decline. These ongoing longitudinal studies are enabling the identification of the molecular and cellular mechanisms other than amyloid that contribute to and precede cognitive decline associated with Alzheimer’s disease progression.

(1)University of Pittsburgh School of Medicine, Pittsburgh, PA, USA (2) The Jackson Laboratory, Bar Harbor, Maine, USA

This work is supported by U19AG074866 and 5T32AG021885-19.