| Autor: |
Marlies Oosthoek, Lisa Vermunt, Arno de Wilde, Bram Bongers, Daniel Antwi-Berko, Philip Scheltens, Pieter van Bokhoven, Everard G. B. Vijverberg, Charlotte E. Teunissen |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Alzheimer’s Research & Therapy, Vol 16, Iss 1, Pp 1-13 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
1758-9193 |
| DOI: |
10.1186/s13195-024-01456-1 |
| Popis: |
Abstract Background Clinical trials in Alzheimer’s disease (AD) had high failure rates for several reasons, including the lack of biological endpoints. Fluid-based biomarkers may present a solution to measure biologically relevant endpoints. It is currently unclear to what extent fluid-based biomarkers are applied to support drug development. Methods We systematically reviewed 272 trials (clinicaltrials.gov) with disease-modifying therapies starting between 01–01-2017 and 01–01-2024 and identified which CSF and/or blood-based biomarker endpoints were used per purpose and trial type. Results We found that 44% (N = 121) of the trials employed fluid-based biomarker endpoints among which the CSF ATN biomarkers (Aβ (42/40), p/tTau) were used most frequently. In blood, inflammatory cytokines, NFL, and pTau were most frequently employed. Blood- and CSF-based biomarkers were used approximately equally. Target engagement biomarkers were used in 26% (N = 72) of the trials, mainly in drugs targeting inflammation and amyloid. Lack of target engagement markers is most prominent in synaptic plasticity/neuroprotection, neurotransmitter receptor, vasculature, epigenetic regulators, proteostasis and, gut-brain axis targeting drugs. Positive biomarker results did not always translate to cognitive effects, most commonly the small significant reductions in CSF tau isoforms that were seen following anti-Tau treatments. On the other hand, the positive anti-amyloid trials results on cognitive function were supported by clear effect in most fluid markers. Conclusions As the field moves towards primary prevention, we expect an increase in the use of fluid-based biomarkers to determine disease modification. Use of blood-based biomarkers will rapidly increase, but CSF markers remain important to determine brain-specific treatment effects. With improving techniques, new biomarkers can be found to diversify the possibilities in measuring treatment effects and target engagement. It remains important to interpret biomarker results in the context of the trial and be aware of the performance of the biomarker. Diversifying biomarkers could aid in the development of surrogacy biomarkers for different drug targets. |
| Databáze: |
Directory of Open Access Journals |
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