Amyloid-associated cognitive trajectories in aging dogs mirror early changes in humans.

Amyloid-β (Aβ) accumulation begins many years before the onset of clinical symptoms in Alzheimer's disease (AD). Studies in humans suggest that unimpaired individuals with elevated Aβ exhibit subtle changes in cognitive trajectories over time, particularly in memory. Identifying animal models that recapitulate these early changes is critical for translational research on preclinical AD. Here, we hypothesized that aging dogs, which naturally accumulate Aβ, show similar patterns to those observed in humans. Forty-three beagles underwent longitudinal cognitive testing on tasks assessing spatial memory, landmark discrimination, and reversal learning, while Aβ burden was measured using cerebrospinal fluid Aβ42/40. Parallel analyses were conducted in cognitively unimpaired older adults from the Harvard Aging Brain Study (n = 287) using Aβ PET imaging and neuropsychological assessments. Despite no baseline differences, dogs with lower CSF Aβ42/40 showed worse longitudinal trajectories on a spatial memory task. No comparable effects were observed for landmark discrimination or reversal learning. Using a data-driven approach, Low CSF Aβ42/40 dogs were more likely to be classified in the Lower trajectory group than High CSF Aβ42/40 dogs. A similar pattern emerged in humans: Aβ+ individuals showed lower memory trajectories compared to Aβ- individuals. Across species, memory deficits were characterized by reduced benefits of practice effects rather than abrupt decline. Together, these findings suggest that aging dogs show Aβ-associated memory trajectories that parallel patterns observed in cognitively unimpaired older adults and support the canine model as a valuable translational platform for studying the earliest stages of AD.