A new nonhuman primate Alzheimer’s disease model developed by researchers from University of California, Davis and elsewhere could open the door to getting better therapies into human testing.
In the study, published this week in Alzheimer’s & Dementia, the authors altered rhesus macaque monkeys using a gene therapy-like approach to accelerate tau pathology and neuroinflammation, hallmarks of human disease not seen in existing nonhuman primate models.
While Alzheimer’s disease pathology is still not fully understood, tau misfolding and amyloid beta (Aβ) accumulation are hallmarks of disease and therapeutic targets for multiple companies.
Commonly used mouse models have failed to capture the complexity of human disease, particularly since mice have only one species of tau and lack a prefrontal cortex, a vulnerable area to Alzheimer’s disease.
In some nonhuman primates, Aβ plaques have been observed, and other researchers previously developed a vervet model of Aβ-driven Alzheimer’s disease. But tau tangles and hyperphosphorylation–typical of human disease–only occur naturally in the oldest animals, which make poor disease models.
In the current study, a team led by John Morrison delivered mutant human genes P301L and S320F into the macaque entorhinal cortex using a recombinant adeno‐associated virus capsid 1 (AAV1) vector. The genes promote Alzheimer’s-related tau pathology, and the vector has been used in humans to deliver approved gene therapies.
Morrison is director of University of California, Davis’ California National Primate Research Center.
Within three months, the researchers saw hyperphosphorylated and misfolded tau, along with neurofibrillary tangles and neuroinflammation, spread to the macaques’ hippocampus and neocortex, comparable to mid-stage human Alzheimer’s disease pathology. The spreading tau included both human and macaque species of tau proteins.
One key hurdle for the new nonhuman primate model is demonstrating that the rhesus macaques have comparable behavioral changes to humans with Alzheimer’s disease, which may be challenging due to the complexity of diagnosing disease development in people. The researchers are planning longitudinal cognitive assessments to confirm the observed tau pathology corresponds to human disease characteristics.
Accelerating drug development would be key for a space riddled with challenges. Alzheimer’s disease-modifying therapies are in high demand, but decades of research have not produced a therapy that has passed regulatory muster.
A high-profile example is the case of Biogen and Eisai’s aducanumab, the only potential therapy to even make it to U.S. Food and Drug Administration (FDA) review in years. Since 2019, the drug has been shelved, revived, then contentiously submitted for regulatory approval. But approval seems unlikely following a very negative FDA advisory committee meeting last year.