Zeiss_2025_Toxicol.Pathol__1926233251388069

Non-invasive predictive biomarkers for preclinical Alzheimer's disease (AD) may inform future dementia risk and support early intervention for AD. In this review, we describe clinical, biomarker and neuropathologic characteristics in spontaneously aged Old World monkeys (OWMs) in the context of preclinical AD. Reliable age-related amyloid-beta (Abeta) plaque deposition occurs in OWMs. Plaque composition is complex, signifying significant disruption of synaptic connectivity. Pretangle pTau pathology in brainstem nuclei and limbic system prevails, consistent with Braak Stage 1b in macaques. Soluble pTau distribution approximates Braak Stage III-IV stage in perfused frozen macaque tissue, and colocalizes with Abeta and acetylcholinesterase labeling in AD-vulnerable circuits. Tau and Abeta pathology in OWMs is accompanied by fluid biomarker changes consistent with Core 1 AD diagnosis in humans but cannot be visualized using amyloid or tau tracers. Despite age-related cognitive decline, aging OWMs do not experience significant hippocampal atrophy or neuropathologic co-morbidities. Minimal expression of senescence markers implicates differences in rates of biological brain aging between OWMs and humans. OWMs support mechanistic studies and biomarker discovery in the areas of Abeta plaque and pTau evolution and resolution following anti-amyloid or Tau-directed therapeutics, as well as effects of senotherapeutics, lifestyle intervention or co-morbidities on biological brain aging.