Tau-targeting Immunotherapy in Neurodegenerative Diseases

Tau-targeting immunotherapy seeks to modify the course of Alzheimer’s disease and related tauopathies by intervening in the processes that underlie tau aggregation, spread and neurotoxicity. Pathological tau undergoes hyperphosphorylation and misfolding, forming neurofibrillary tangles that correlate closely with neuronal dysfunction and cognitive decline. Both active and passive immunisation strategies have been developed to engage pathogenic tau species in the extracellular space or within cells, harnessing humoral responses or exogenously administered antibodies. In parallel, oligonucleotide-based approaches aim to reduce tau expression at the messenger RNA level. Preclinical models have demonstrated that antibodies can facilitate tau clearance via microglial uptake or neuronal endocytosis, delay symptom onset and improve behaviour. Clinical trials have begun to assess safety, target engagement and biomarker changes, marking a transition from experimental to translational research. The global significance of tau immunotherapy lies in its potential to deliver disease-modifying effects where symptomatic treatments have so far failed. Close integration of biomarker development, dosing strategies and patient stratification will be critical to realise practical applications across diverse neurodegenerative syndromes.

Research from Nature Portfolio

Recent phase 1b studies of a tau-targeting antisense oligonucleotide administered by intrathecal bolus reported dose-dependent reductions of total-tau protein in cerebrospinal fluid with a favourable safety profile, establishing proof of mechanism for lowering tau synthesis in mild Alzheimer’s disease. In a parallel phase 2 monoclonal antibody trial targeting the N-terminus of tau, long-term administration was well tolerated and achieved significant suppression of unbound tau in cerebrospinal fluid, though no cognitive benefit emerged at the primary end point. These developments underscore the ability to engage tau pathology in humans and refine strategies for antibody design, dosing frequency and patient selection ahead of efficacy studies.

Tau-targeting Immunotherapy in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in tau-targeting immunotherapy in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Tau protein: A microtubule-associated protein that stabilises neuronal cytoskeleton and forms pathological aggregates when hyperphosphorylated.

Monoclonal antibody: A uniform immunoglobulin molecule engineered to recognise a single epitope on tau, used for passive immunotherapy.

Antisense oligonucleotide: A short synthetic strand of nucleic acid designed to bind MAPT mRNA and reduce tau synthesis.

Passive immunotherapy: Administration of exogenous antibodies to target and clear pathological tau species.

Active immunisation: Vaccination that induces an endogenous immune response against specific tau epitopes.

Neurofibrillary tangle: Intraneuronal aggregates of hyperphosphorylated tau that disrupt cell function and correlate with disease progression.

References

1. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial. Nature Medicine (2023).
2. TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer’s disease. Nature Aging (2023).
3. Passive immunotherapy for Alzheimer's disease. Ageing Research Reviews (2024).
4. A walk through tau therapeutic strategies. Acta Neuropathologica Communications (2019).
5. Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. Scientific Reports (2015).
6. Antibody Uptake into Neurons Occurs Primarily via Clathrin-dependent Fcγ Receptor Endocytosis and Is a Prerequisite for Acute Tau Protein Clearance*. Journal of Biological Chemistry (2013).