Blood-based biomarkers are now central to neurodegenerative-disease diagnostics because they can be sampled repeatedly, at lower cost, and with less procedural burden than lumbar puncture or PET imaging.[@blennow2022][@teunissen2022] Their core clinical value is triage and probability refinement: they help clinicians decide who needs confirmatory testing, who may qualify for biologically targeted trials, and how quickly disease biology is changing over time.[@hansson2023][@cummings2023]
For Alzheimer's Disease, plasma amyloid and phosphorylated tau assays increasingly support biologic diagnosis workflows.[@hansson2023][@palmqvist2020] For Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and atypical parkinsonism such as Corticobasal Syndrome (CBS) and Progressive Supranuclear Palsy (PSP), blood markers are most useful as multimarker panels rather than one-marker answers.[@simren2021][@ashton2021]
A useful mechanistic framing is that blood biomarkers represent different biological compartments:
Blood-based biomarkers are now central to neurodegenerative-disease diagnostics because they can be sampled repeatedly, at lower cost, and with less procedural burden than lumbar puncture or PET imaging.[@blennow2022][@teunissen2022] Their core clinical value is triage and probability refinement: they help clinicians decide who needs confirmatory testing, who may qualify for biologically targeted trials, and how quickly disease biology is changing over time.[@hansson2023][@cummings2023]
For Alzheimer's Disease, plasma amyloid and phosphorylated tau assays increasingly support biologic diagnosis workflows.[@hansson2023][@palmqvist2020] For Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and atypical parkinsonism such as Corticobasal Syndrome (CBS) and Progressive Supranuclear Palsy (PSP), blood markers are most useful as multimarker panels rather than one-marker answers.[@simren2021][@ashton2021]
A useful mechanistic framing is that blood biomarkers represent different biological compartments:
Plasma Aβ42/40 ratio decreases as cerebral amyloid burden increases, with performance that improves when mass-spectrometry methods and multimarker models are used.[@nakamura2018][@schindler2019] Aβ42/40 is useful for AD triage but should be interpreted with assay-specific cutoffs and in combination with tau markers.[@hansson2023]
Plasma Phosphorylated Tau 181 (p-tau 181), Phosphorylated Tau 217 (p-tau217), and p-tau231 track AD-type tau biology with different stage sensitivities.[@palmqvist2020][@karikari2020] p-tau217 often provides the strongest AD vs non-AD discrimination in mixed memory-clinic cohorts.[@palmqvist2020]
Neurofilament Light Chain (NfL) - Biomarker is a robust indicator of neuroaxonal damage and progression intensity across multiple neurodegenerative syndromes.[@gaetani2019][@benatar2018] It is highly informative for prognosis and trajectory but is not disease-specific by itself.[@gaetani2019]
Plasma GFAP (Glial Fibrillary Acidic Protein) - Biomarker is linked to astroglial activation and appears especially informative in early AD biological change.[@benedet2021] Inflammatory markers such as cytokine panels can add context but often show larger between-laboratory variability and lower disease specificity.[@heneka2015]
Synaptic markers, including selected neuronal proteins and exosome-associated analytes, may provide complementary signal about network-level dysfunction and early neuronal stress.[@kvartsberg2014][@fiandaca2014] These remain promising but less standardized than core AD biomarkers.
In AD workflows, blood biomarkers are now used for:
Multimarker models that combine p-tau species, Aβ42/40, NfL, and GFAP generally outperform single-analyte strategies.[@palmqvist2020][@benedet2021]
In PD, blood biomarker interpretation focuses on progression, phenotype heterogeneity, and differential diagnosis rather than a single definitive diagnostic assay.[@simren2021][@mollenhauer2020] NfL can provide progression information, while alpha-synuclein assay development remains an active research frontier with ongoing matrix and assay-standardization challenges.[@simren2021][@majbour2016]
For ALS and ALS-FTD spectrum disease, NfL is one of the strongest blood-based prognostic tools and can support trial enrichment and progression monitoring.[@benatar2018][@verde2018] Additional markers for TDP-43 biology remain under development, and multimodal integration with clinical and electrophysiologic data is still required.[@verde2018]
For CBS/PSP pathways, blood biomarker panels are most useful for identifying co-pathology and triaging additional testing, not for replacing syndrome-level diagnosis.[@ashton2021][@jabbari2019] Elevated AD-linked plasma tau signals may suggest AD co-pathology in atypical parkinsonism phenotypes, while NfL may reflect disease intensity.[@ashton2021]
A pragmatic workflow for blood biomarkers in specialty clinics:
Blood biomarkers are highly sensitive to implementation details.[@teunissen2022]
Important constraints:
Blood biomarkers are increasingly used to support therapeutic selection and monitoring frameworks in AD programs and to stratify risk in non-AD neurodegenerative diseases.[@cummings2023][@mollenhauer2020] Their highest-value role is decision support inside a multimodal model:
Key remaining gaps include:
For CBS/PSP clinical care, blood biomarkers should be used as an evidence-weighting layer: they can refine probability of AD co-pathology, estimate injury burden, and prioritize advanced testing, but they do not replace expert syndrome diagnosis.[@ashton2021][@jabbari2019] In practice, panel-based interpretation with explicit uncertainty communication is the safest strategy.
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