By Prof. Alan Trounson AO, Dr Jing Yang Tee, Dr Andrew French, Dr Richard Boyd

There is increasing recognition that bidirectional communication between the peripheral immune system and the central nervous system (CNS) is fundamental to maintaining neurological health. Contrary to widely held belief, immune cells interact directly with CNS-resident cells, and disturbances in this communication – particularly shifts toward a pro‑inflammatory immune state – may act as early triggers of neurodegenerative processes underlying Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).

Most of the current clinical therapeutics have largely focused on using therapeutic antibodies to prevent and clear protein aggregates such as β‑amyloid, tau, and α‑synuclein, but the clinical returns have been modest. Instead, recent research trends suggest there may be an emerging immune-centric target that could unlock the neurodegenerative disorder puzzle.

The review by Bennett et.al. in the scientific journal Cell (August 2026) is a very comprehensive compilation of the evidence in support of the dysregulation of the immune communications underlying the cascades of pathology that arise when the immune and neural systems become misaligned. Peripheral immune cells can be identified in the CNS and do clearly communicate at specific boundaries in the brain. Notably, there is a well-recognised gut-brain neuroimmune axis that transmits in both directions and is likely driven by extracellular vesicles (EVs) trafficking in neurones and immune cells. These communications involve activated T cells, macrophages, dendritic cells and natural killer (NK) cells of the peripheral immune system that are known to access the CNS under specific conditions and communicate at defined neuroimmune interfaces. These interactions can be protective, supporting microglial and astrocytic homeostasis, or destructive, promoting inflammation and neuronal loss when dysregulated.

Two landmark studies published by Zemke et.al. in Science (July 2026) and by Belk et.al. in Nature (July 2026) recently demonstrated that human microglia, which originate from yolk sac-derived progenitor cells exclusively during embryogenesis, undergo age‑related replacement by peripheral blood monocytes. Because microglia are of fetal origin and do not persist for the full human lifespan, by approximately 70 years of age substantial regions of the brain – especially the hippocampus that is responsible for memory and cognition – may be repopulated predominantly by monocyte‑derived macrophages. These replacement cells frequently exhibit pro‑inflammatory phenotypes, providing a plausible initiating mechanism for the early pathological changes observed in AD, PD, and ALS.

This large‑scale turnover of microglia may represent an attempted repair mechanism to maintain immune surveillance, yet it may inadvertently exacerbate neuroinflammation and disrupt glial regulatory networks. These findings reinforce that neurodegenerative diseases cannot be fully addressed by targeting protein aggregates alone; effective therapies must also correct the underlying immune imbalance within the ageing brain. The CNS should now be understood as an integral immune organ, not an isolated neural structure.

The studies showed that the aged hippocampus is made up of microglia with origins tracing back to adult peripheral blood-derived monocytes; their pro-inflammatory phenotype is hypothesised to be one of the key initiators of the pathologies seen in AD, PD and ALS. The large-scale replacement of brain microglia by blood immune cells may be a repair mechanism triggered by the body to maintain homeostasis but may lead to an opposing adverse effect that worsens neuroinflammation and further imbalances to brain immunity. It is then understandable why the antibody centric therapeutic approaches that have dominated research in neurodegeneration have been ineffective. The new therapeutic horizons must now address the fundamental underlying causes centred around brain immunity and appreciation of the human brain as a key node of the immune system.

Evinco’s Neuro‑Immunotherapy Approach

Evinco has been established to bring neuro-immunotherapy to AD and related conditions. Our core technology focuses on the use of Natural Killer (NK) cells of the immune system that appear to stabilise or alleviate symptoms and biomarker pathologies in AD, PD and ALS when used as autologous therapy in high doses when administered intravenously every 3 weeks over an extended treatment period. Evinco has demonstrated that NK‑cell–derived extracellular vesicles (NK‑EVs) possess potent neurotrophic and immunomodulatory properties. NK‑EVs rejuvenate microglia and shift them toward anti‑inflammatory, reparative states, enhance β‑amyloid clearance and metabolic processing, deliver microRNA cargo that suppresses tau phosphorylation and neurofibrillary tangle formation and support neuronal resilience and synaptic maintenance.

NK‑EVs can be delivered intranasally, enabling direct CNS entry. We also observe robust trafficking of NK‑EVs along the brain–gut neuroimmune axis, consistent with a natural route of communication between peripheral immune cells and CNS glial networks.

This signalling pathway may represent a fundamental mechanism by which the immune system maintains brain health across the lifespan – a mechanism that becomes dysregulated during ageing and contributes to neurodegeneration. Evinco’s therapeutic strategy aims to restore balanced immune–glial communication, recalibrate microglial function, and re‑establish the neuroimmune homeostasis required for healthy brain ageing.