# Inflammatory mechanisms underlying early Alzheimer’s disease pathology: evidence from the aging rhesus macaque brain

## TL;DR

Aging rhesus macaques show early Alzheimer’s disease pathology linked to inflammation and calcium dysregulation, offering a model for studying and treating the disease.

## Contribution

The study identifies rhesus macaques as a translational model for early sporadic Alzheimer’s pathology involving inflammation and calcium signaling.

## Key findings

- Soluble pT217Tau is neurotoxic and spreads pathology across cortical networks.
- Age-related inflammation drives calcium dysregulation, leading to tau hyperphosphorylation and amyloid accumulation.
- Pharmacological targeting of inflammation reduces pTau pathology in aged macaques with minimal side effects.

## Abstract

Inflammation plays a large role in the etiology of the late onset, sporadic form of Alzheimer’s disease (AD), yet these critical factors are not adequately modeled in mice where inflammatory mechanisms often differ widely from primates. In contrast, aging rhesus macaques offer a powerful translational model for investigating how advancing age and inflammation initiate early-stage pathology in sporadic AD, and for evaluating preventive therapeutic strategies. Unlike rodents, macaques possess highly developed association cortices with magnified calcium signaling, human-like inflammatory responses, and are naturally homozygous for ApoE-ε4—factors that together contribute to the spontaneous emergence of tau and amyloid pathology alongside cognitive decline. Critically, macaques allow the detection of early, soluble forms of hyperphosphorylated tau (pTau), including pT217Tau, which rapidly dephosphorylates postmortem and is rarely observable in human brain tissue outside of biopsies. New findings reveal that soluble pTau is neurotoxic and capable of propagating pathology across cortical networks, with elevated pT217Tau in plasma. Growing evidence points to age-related inflammatory signaling as a key driver of calcium dysregulation, which in turn promotes tau hyperphosphorylation, amyloid-β (Aβ) accumulation, synapse loss and autophagic degeneration. Both GCPII (glutamate carboxypeptidase II) and kynurenic acid inflammatory signaling have expanded roles in the primate association cortices that contribute to cognitive deficits. Pharmacological interventions in aged macaques demonstrate that targeting inflammation and restoring calcium homeostasis can significantly reduce pTau pathology with minimal side effects—highlighting a promising path for early intervention in AD.