Early Phase Unit, Worldwide Clinical Trials
Neurodegenerative diseases represent a diverse group of progressive disorders characterized by the loss of structure and function of neurons. Despite their clinical heterogeneity, these diseases often share overlapping pathological mechanisms, including protein misfolding and aggregation, synaptic dysfunction, neuroinflammation, and axonal degeneration. Accurate diagnosis and effective disease monitoring remain challenging, particularly in the early stages, underscoring the critical need for robust biomarkers.
Biomarkers—measurable indicators of biological processes or pharmacologic responses—play a vital role in enhancing diagnostic accuracy, tracking disease progression, evaluating therapeutic efficacy, and enabling precision medicine approaches. In recent years, advances in molecular techniques and ultra-sensitive detection platforms have led to the identification and validation of fluid and imaging biomarkers across multiple neurodegenerative disorders.
This blog provides an overview of key biomarkers for five major neurodegenerative diseases: Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Huntington’s disease (HD). For each condition, we highlight core biomarkers, their biological relevance, current clinical applications, and emerging opportunities for integration into research and care pathways.
Alzheimer’s Disease
AD is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. The amyloid-tau hypothesis remains the prevailing model of AD pathogenesis, proposing that the accumulation of amyloid-beta (Aβ) initiates a cascade of pathological events, with subsequent tau hyperphosphorylation and aggregation contributing to synaptic dysfunction, neuroinflammation, and neuronal loss.
Core fluid biomarkers include Aβ42 and phosphorylated tau (p-tau181, p-tau217, and p-tau231), which are instrumental in identifying AD pathology, supporting early diagnosis, and monitoring therapeutic response. These biomarkers are typically measured in cerebrospinal fluid (CSF), which directly reflects central nervous system (CNS) pathology and remains the reference standard. However, recent advances in ultra-sensitive assay platforms, including single molecule array (Simoa) and mass spectrometry, have enabled reliable detection in plasma, facilitating broader clinical implementation through minimally invasive sampling.
In vivo imaging using positron emission tomography (PET) provides spatial resolution of amyloid and tau deposition. Amyloid PET and tau PET complement fluid biomarkers by offering anatomical and regional information. Despite their high specificity, cost and accessibility constraints currently limit their routine clinical use.
Markers of neurodegeneration, particularly neurofilament light chain (NfL), are increasingly utilized to quantify neuronal injury. NfL levels in CSF and plasma are associated with disease severity and progression, although they lack disease specificity. When interpreted alongside amyloid and tau biomarkers, NfL enhances the overall assessment of disease burden and longitudinal change.
Parkinson’s Disease
PD is a neurodegenerative disorder primarily affecting motor function due to the loss of dopaminergic neurons in the substantia nigra. The alpha-synuclein hypothesis underpins the current understanding of PD pathology, implicating the misfolding and aggregation of alpha-synuclein (α-syn) into Lewy bodies and neurites as a key driver of neurodegeneration.
Pathological forms of α-syn, including oligomeric and phosphorylated species (particularly at serine-129), are under investigation as diagnostic biomarkers. These forms are detectable in CSF, with limited utility in blood or peripheral tissues. CSF remains the preferred matrix due to higher sensitivity and specificity, though ongoing development of sensitive detection methods such as real-time quaking-induced conversion (RT-QuIC) and advanced immunoassays may support future implementation of blood-based assays.
Imaging modalities, particularly dopamine transporter (DAT) single-photon emission computed tomography (SPECT), are widely employed to visualize striatal dopaminergic deficits and assist in differential diagnosis. Although PET tracers for α-syn are in development, they are not yet available for clinical use.
NfL, while not specific to PD, is elevated in atypical Parkinsonian syndromes and later-stage PD. It serves as a supplementary biomarker, offering insight into the degree of axonal damage and disease progression.
Amyotrophic Lateral Sclerosis
ALS is a rapidly progressive neurodegenerative disease affecting upper and lower motor neurons. While its etiology is heterogeneous, cytoplasmic aggregation of TDP-43 is the predominant pathological hallmark in most sporadic and familial cases. Mutations in genes such as SOD1, C9orf72, FUS, and TARDBP further support the role of proteinopathy and RNA dysregulation in ALS pathogenesis.
Although disease-specific fluid biomarkers are lacking, NfL and neurofilament heavy chain (NfH) have emerged as robust indicators of axonal injury. These markers are reliably quantified in CSF and plasma using sensitive platforms such as Simoa and electrochemiluminescence (ECL). Plasma NfL levels correlate strongly with disease severity, progression rate, and prognosis, supporting their application in patient stratification and therapeutic monitoring.
Structural imaging using magnetic resonance imaging (MRI) can reveal degeneration in motor pathways but lacks the sensitivity and specificity required for early diagnosis. No PET tracers targeting ALS-specific protein aggregates are currently available, though ongoing research aims to develop tracers for TDP-43 or markers of neuroinflammation. Integration of fluid biomarkers, imaging, and genetic profiling enhances diagnostic precision and provides valuable tools for clinical trials in ALS.
Multiple Sclerosis
MS is a chronic, immune-mediated demyelinating disease of the central nervous system. The disease course may be relapsing-remitting or progressive, characterized by immune cell infiltration, myelin loss, and neuroaxonal damage.
CSF-restricted oligoclonal bands (OCBs), representing intrathecal IgG synthesis, are a long-established diagnostic biomarker. In recent years, NfL has become a leading fluid biomarker of axonal injury. Elevated NfL levels in CSF and serum correlate with disease activity, brain atrophy, and long-term disability. Serum NfL, quantifiable via Simoa technology, offers a less invasive approach for longitudinal disease monitoring. Glial fibrillary acidic protein (GFAP) is also under investigation as a marker of astrocyte activation and is particularly relevant in progressive MS subtypes.
MRI remains the cornerstone of MS diagnosis and monitoring, providing detailed visualization of demyelinating lesions, lesion burden, and brain atrophy. Combined assessment using MRI, CSF OCBs, and blood-based biomarkers such as NfL offers a comprehensive approach to evaluating disease status and therapeutic response.
Huntington’s Disease
HD is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, resulting in the production of mutant huntingtin (mHTT) protein. This process leads to progressive neuronal dysfunction and degeneration, particularly in the striatum and cortex, manifesting as motor, cognitive, and psychiatric disturbances.
mHTT is the most specific biomarker for HD and is detectable in CSF and, more recently, in plasma using ultrasensitive assays such as Simoa or immunoassays incorporating protein enrichment techniques. CSF mHTT concentrations correlate with disease stage and are being utilized in clinical trials to assess pharmacodynamic responses to HTT-lowering therapies.
NfL is a complementary biomarker, with elevated levels in CSF and plasma serving as indicators of axonal injury. NfL is predictive of clinical progression and brain atrophy, including in premanifest individuals, and is suitable for tracking disease evolution.
MRI provides structural imaging biomarkers, particularly sensitive to early atrophy in the caudate and putamen. While PET tracers targeting mHTT aggregates are not yet available, PET may be used in research settings to assess cerebral metabolism and neuroinflammation. Together, genetic confirmation, fluid biomarkers, and neuroimaging form an integrated framework for diagnosis, disease monitoring, and therapeutic development in HD.
Discover More About Biomarker Selection in Neurodegenerative Diseases
The development and application of biomarkers have significantly advanced our understanding of neurodegenerative diseases, offering critical tools for early diagnosis, prognosis, and therapeutic monitoring. While several biomarkers—such as Aβ, tau, α-synuclein, NfL, and mHTT—have shown strong clinical utility, others remain in exploratory phases with promising potential.
Continued efforts to validate and integrate these biomarkers across fluid and imaging modalities will be essential for improving patient care and accelerating therapeutic development in neurodegenerative disorders. Learn more about how biomarkers play a crucial role in the development of these conditions and how to best measure them in your next clinical trial in our white paper.
Alzheimer’s Disease
| Biomarker | Function | Clinical Relevance |
| Aβ42 | Marker of amyloid plaque deposition | High |
| Aβ40 | Supportive amyloid marker; used to calculate Aβ42/Aβ40 ratio | High |
| Aβ42/Aβ40 ratio | Improves diagnostic specificity for amyloid pathology | High |
| p-tau181 | Marker of early tau pathology and disease progression | High |
| p-tau217 | Highly specific tau biomarker; correlates with amyloid and cognitive decline | High |
| p-tau231 | Early tau change; useful in preclinical AD detection | Moderate |
| t-tau | General marker of neurodegeneration | Moderate |
| NfL | Indicator of axonal injury and disease progression | High |
| GFAP | Reflects astrocytic activation and neuroinflammation | Moderate |
Parkinson’s Disease
| Biomarker | Function | Clinical Relevance |
| p-α-syn (Ser129) | Pathologic form of α-synuclein; indicates Lewy body pathology | High |
| RT-QuIC α-syn | Detects α-synuclein seeding activity with high specificity | High |
| DJ-1 | Oxidative stress marker related to PD | Moderate |
| NfL | Marker of axonal injury | High |
| GFAP | Reflects astrocyte activation | Moderate |
| GBA activity | Enzyme activity linked to lysosomal dysfunction and genetic PD risk | Moderate |
Amyotrophic Lateral Sclerosis
| Biomarker | Function | Clinical Relevance |
| NfL | Indicator of axonal damage and progression | High |
| NfH | Marker of neuroaxonal breakdown; often used in trials | High |
| TDP-43 | Primary pathology protein in most ALS cases | High |
| CK | Elevated due to muscle breakdown | Moderate |
| IL-6 | Pro-inflammatory cytokine; involved in neuroinflammation | Moderate |
| IL-8 | Cytokine marker of inflammation | Moderate |
| TNF-α | Inflammatory cytokine elevated in ALS | Moderate |
| CHI3L1/YKL-40 | Marker of microglial activation and neuroinflammation | Moderate |
Multiple Sclerosis
| Biomarker | Function | Clinical Relevance |
| OCBs | Diagnostic marker of intrathecal IgG synthesis | High |
| NfL | Marker of axonal injury and disease activity | High |
| GFAP | Astrocytic activation marker; especially in progressive MS | High |
| CXCL13 | Reflects B-cell chemotaxis and inflammation | Moderate |
| sCD27 | T-cell activation marker | Moderate |
| CHI3L1/YKL-40 | Glial activation and progression marker | High |
| MBP | Indicates active demyelination | Moderate |
Huntington’s Disease
| Biomarker | Function | Clinical Relevance |
| mHTT | Causative and specific marker of Huntington’s pathology | High |
| NfL | Axonal injury marker correlating with disease onset and severity | High |
| t-tau | General neurodegeneration marker | Moderate |
| p-tau | Tau pathology associated with neurodegeneration | Moderate |
| YKL-40 | Marker of glial activation | Moderate |
| BDNF | Decreased levels indicate impaired neurotrophic support | Moderate |
For any questions, contact Worldwide Clinical Trials to find out how our rigorous approach to biomarker selection and measurement is helping us develop targeted therapies for patients around the globe.
