Aβ42 Induces Selective Degeneration in Hippocampal Cells of Aged Monkeys

The hippocampus is one of the earliest and most severely affected brain regions in Alzheimer’s disease (AD) and is critical for memory formation. However, the precise mechanisms through which AD disrupts hippocampal neurons remain poorly understood. To investigate the effects of Aβ42 in a model closer to humans, we performed stereotaxic injections of an AAV9 vector encoding human Aβ42 into the hippocampus of young (7-year-old) and aged (>20-year-old) cynomolgus monkeys. We found that AAV9-mediated Aβ42 expression induced more severe neuropathology, reduced daytime activity, and increased sleep disturbances in aged monkeys compared to young controls. snRNA-seq revealed an age-dependent reduction in disease-associated microglia (DAM II) in the aged hippocampus. Furthermore, we identified a specific subtype of hippocampal pyramidal neuron (TRPS1+RELN+) that is selectively vulnerable to Aβ42 toxicity in aged monkeys. Our findings indicate that Aβ42 toxicity is exacerbated in the aged primate hippocampus due to a combination of microglial decline and the selective vulnerability of a distinct neuronal subtype (TRPS1⁺RELN⁺ PCs). This identified subtype represents a new potential therapeutic target for treating hippocampal dysfunction in AD.