Amyloid-β oligomers drive amyloid deposit and cascaded tau pathology of Alzheimer's disease in aged brains of non-human primates.

Alzheimer's disease (AD), the most prevalent form of dementia, disproportionately affects the elderly population. While aging is widely recognized as a major risk factor for AD, the precise mechanisms by which aging contributes to the pathogenesis of AD remain poorly understood. In our previous work, the neuropathological changes in the brains of aged cynomolgus monkeys (≥18 years old) following parenchymal cerebral injection of amyloid-β oligomers (AβOs) have been characterized. Here, we extend our investigation to middle-aged cynomolgus monkeys (≤15 years old) to establish an AD model. Surprisingly, immunohistochemical analysis reveals no detectable AD-related pathology in the brains of middle-aged monkeys, even after AβOs injection. In a comprehensive pathological analysis of 38 monkeys, we observe that the amyloid-β (Aβ) burden increases significantly with advancing age. Notably, the density of Aβ plaques is markedly higher in the ventral regions compared to the dorsal regions of aged monkey brains. Furthermore, we demonstrate that tau phosphorylation coincides with the accumulation of extensive Aβ plaques and exhibits a positive correlation with Aβ burden in aged monkeys. Collectively, these findings underscore the critical role of the aged brain in providing the necessary conditions for AβO-induced AD pathologies in cynomolgus monkeys.