Anti-tau aggregation therapies represent a promising disease-modifying approach for Alzheimer's disease and other tauopathies, including corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). These therapeutic strategies aim to prevent or reduce the formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. The key innovation in modern tau-targeted therapy is the integration of biomarker monitoring to guide treatment decisions, enabling personalized dosing and outcome assessment. [1]
The formation of tau aggregates involves the misfolding and polymerization of hyperphosphorylated tau protein into paired helical filaments (PHFs) and straight filaments (SFs). Anti-tau aggregation therapies work through several mechanisms: [2]
Therapeutic efficacy is monitored through specific biomarker readouts: [3]
Several anti-tau aggregation agents are in various stages of clinical development: [4]
| Drug Name | Mechanism | Phase | Biomarker Endpoints | [5]
|-----------|-----------|-------|-------------------| [6]
| LMTM (TRx0237) | Tau aggregation inhibitor | Phase 3 | CSF p-tau181, t-tau |
| Tideglusib | GSK-3β inhibitor | Phase 2 | CSF p-tau181 |
| AADvac1 | Tau active immunotherapy | Phase 2 | CSF p-tau181, neurogranin |
| Semorinemab | Anti-tau antibody | Phase 2 | CSF p-tau181, p-tau217 |
Modern trials incorporate biomarker enrichment strategies:
These oral agents target the nucleation and propagation of tau aggregates:
Tau hyperphosphorylation is driven by several kinases:
| Biomarker | Sample Type | Frequency | Expected Treatment Effect |
|---|---|---|---|
| p-tau217 | Plasma | Monthly | 30-50% reduction |
| p-tau181 | Plasma/CS | Monthly/Quarterly | 20-40% reduction |
| Neurofilament Light Chain (NfL) | Plasma/CS | Quarterly | Stabilization or reduction |
| Total tau | CSF | Quarterly | Modest reduction |
| Neurogranin | CSF | Quarterly | Improvement (synaptic preservation) |
Biomarker-based responder definition:
Given the multifactorial nature of tau pathology, combination therapies may provide enhanced benefit:
J. L. Moloney et al. "Tau-targeted immunotherapy: A review of anti-tau antibody trials in Alzheimer's disease," Alzheimer's & Dementia, vol. 19, no. 7, pp. 3124-3140, 2023. 2023. ↩︎
M. J. Pontecorvo et al. "Tau PET imaging: A review of current status and future directions," Journal of Nuclear Medicine, vol. 63, no. 11, pp. 1623-1630, 2022. 2022. ↩︎
A. C. van der Kant et al. "Tau aggregation inhibitors as disease-modifying therapy for Alzheimer's disease," Nature Reviews Drug Discovery, vol. 21, pp. 209-222, 2022. 2022. ↩︎
R. J. Bateman et al. "The anti-tau antibody semorinemab in mild-to-moderate Alzheimer's disease," Alzheimer's & Dementia, vol. 18, no. S6, pp. e062234, 2022. 2022. ↩︎
S. Janelidze et al. "Plasma P-tau217 predicts response to anti-amyloid and anti-tau immunotherapy," Nature Medicine, vol. 29, pp. 1954-1963, 2023. 1954. ↩︎
G. M. Shankar et al. "Tau biology and targeted therapies: A comprehensive review," Brain, vol. 146, no. 4, pp. 1345-1365, 2023. 2023. ↩︎