Biomarker-guided therapy is an emerging precision medicine approach that uses measurable biological indicators — from blood, cerebrospinal fluid (CSF), neuroimaging, or genetic testing — to guide treatment selection, dosing, timing, and monitoring in neurodegenerative diseases. Rather than treating all patients with the same diagnosis identically, biomarker-guided approaches stratify patients by their specific molecular and pathological profile, enabling targeted interventions matched to individual disease biology [1].
The 2024 revision of the NIA-AA diagnostic criteria for Alzheimer's disease marked a paradigm shift, formally defining AD by its biological markers rather than clinical symptoms alone. This transition from syndromic to biological diagnosis sets the stage for biomarker-guided therapeutic decision-making analogous to precision oncology [2].
Blood-based biomarkers have transformed the field by enabling minimally invasive, scalable disease detection and monitoring:
- CSF Aβ42, p-tau, total tau: The "AD CSF signature" — decreased Aβ42 with increased p-tau and t-tau
- CSF NfL: Neuronal damage marker used in clinical trials for ALS and FTD
- CSF TREM2: Soluble TREM2 reflects microglial
- MAPT testing: Identifies tau-mutant FTD patients eligible for tau-targeted therapeutics](/treatments/tau-targeted-therapeutics)
- CSF NfL: Prognostic biomarker and clinical trial endpoint
Modern precision medicine approaches increasingly use multi-biomarker panels rather than single markers:
| Biomarker Combination |
Clinical Application |
| p-tau217 + Aβ42/40 + NfL + GFAP |
AD screening, staging, and prognosis |
| alpha-synuclein SAA + DAT-SPECT + GBA1 genotype |
PD subtype classification and trial matching |
| NfL + SOD1/C9orf72 genetics + muscle biomarkers |
ALS diagnosis, subtyping, and therapy selection |
| Amyloid PET + tau PET + MRI volumetrics + APOE genotype |
Comprehensive AD staging for treatment planning |
A "combinatorial strategy" integrating blood-based biomarkers, neuroimaging, and genetic data is increasingly viewed as the most realistic approach for individualized treatment planning [8].
Biomarkers have transformed clinical trial design in neurodegeneration:
- Enrichment: Selecting biomarker-positive participants (e.g., amyloid-PET-positive for AD trials) increases the probability of detecting treatment effects
- Stratification: Randomizing participants by biomarker profile (e.g., APOE genotype) ensures balanced groups
- Surrogate endpoints: Biomarker changes (amyloid clearance, NfL reduction) serve as accelerated approval endpoints
- Adaptive designs: Biomarker data guides dose selection, population enrichment, and early futility analysis during trials
- Basket trials: Testing therapies across diseases unified by a common biomarker (e.g., NfL-positive neurodegeneration)
¶ Regulatory Landscape
- FDA accelerated approval has been granted based on biomarker endpoints: lecanemab (amyloid clearance as surrogate), tofersen (NfL reduction as surrogate)
- The 2024 NIA-AA criteria establish biomarker-defined AD as the standard for clinical research
- Blood-based biomarkers are being validated for regulatory use as pre-screening tools, reducing the need for expensive PET scans
- Access and equity: PET scans cost $5,000–$8,000; blood tests may democratize access if validated and approved
- Standardization: Different assay platforms yield different results; reference standards needed
- Pre-symptomatic treatment: Biomarkers detect disease years before symptoms — ethical implications of early diagnosis and treatment
- Multi-pathology: Many patients have mixed pathologies (AD + Lewy body + vascular); single-disease biomarkers may miss co-existing conditions
- Dynamic monitoring: Biomarker levels change over disease course and with treatment — establishing trajectories requires longitudinal data
The study of Biomarker Guided Therapy In Neurodegenerative Disease has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- [Hansson O. "Biomarker-guided decision making in clinical drug development for neurodegenerative disorders." Nat Rev Drug Discov. 2025. DOI
- [Jack CR Jr, et al. "Revised criteria for diagnosis and staging of Alzheimer's Disease." Alzheimers Dement. 2024;20(8):5633-5667. DOI
- [Palmqvist S, et al. "Blood biomarkers to detect Alzheimer's Disease in primary care and secondary care." JAMA. 2024;332(15):1245-1257. DOI
- [Khalil M, et al. "Neurofilaments as biomarkers in neurological disorders." Nat Rev Neurol. 2018;14(10):577-589. DOI
- [Sperling RA, et al. "Association of factors with elevated amyloid burden in clinically normal older individuals." JAMA Neurol. 2020;77(6):735-745. DOI
- [Miller TM, et al. "Trial of antisense oligonucleotide tofersen for SOD1 ALS." N Engl J Med. 2022;387(12):1099-1110. DOI
- [van Dyck CH, et al. "Lecanemab in early Alzheimer's Disease." N Engl J Med. 2023;388(1):9-21. DOI
- [Teunissen CE, et al. "Blood-based biomarkers for Alzheimer's Disease: towards clinical implementation." Lancet Neurol. 2022;21(1):66-77. DOI