Biofluid biomarkers in Alzheimer’s disease and other neurodegenerative dementias
Summary
This comprehensive review surveys the current state of biofluid biomarkers across Alzheimer’s disease (AD) and related neurodegenerative dementias. It covers established markers (CSF and plasma Aβ42/Aβ40, phosphorylated tau species, neurofilament light chain), emerging candidates (MTBR-tau243, brain-derived tau, beta-synuclein, synaptic markers), and pathology-specific assays (alpha-synuclein and TDP-43 seed amplification assays). The article also discusses analytical advances, pre-analytical standardisation, confounders (for example renal function and comorbidities), and the role of biomarkers in diagnosis, staging and therapeutic trials, including how disease-modifying anti‑amyloid antibodies affect downstream biomarkers.
Key Points
- Plasma Aβ42/Aβ40 and several p-tau assays (p-tau181, p-tau217, p-tau212 and others) now provide robust, minimally invasive detection of cerebral amyloid and tau pathology.
- New tau measures (for example MTBR‑tau243, tau368/total‑tau ratios) promise better specificity for tau tangle pathology and staging across the AD continuum.
- Neurofilament light (NfL) is a sensitive marker of neurodegeneration but is not disease-specific; levels are influenced by comorbidities and renal function.
- Glial and inflammatory markers (GFAP and other proteomic signals) complement amyloid/tau panels and may reflect astrocytic or neuroinflammatory responses.
- Synaptic biomarkers (NPTX2, SV2A-related measures, beta‑synuclein) offer insight into synaptic dysfunction and may predict cognitive decline beyond amyloid burden.
- Seed amplification assays (alpha‑synuclein, TDP‑43) give high diagnostic accuracy for synucleinopathies and TDP‑43 proteinopathies, with growing clinical validation.
- Pre-analytical variables, assay harmonisation and population differences (ethnicity, comorbid disease, kidney function) remain critical challenges for clinical rollout.
- Biofluid biomarkers are increasingly useful in clinical trials — for patient selection, target engagement and monitoring downstream biology after anti-amyloid therapies.
- There is intense ongoing work on multiplex proteomic platforms, dried‑blood and finger‑prick sampling, and standardisation projects to enable broader, equitable access.
Why should I read this
Look — if you care about where AD diagnostics and trials are heading, this paper is a one‑stop catch‑up. It pulls together the messy literature on blood and CSF markers, flags what actually works (and what doesn’t), and tells you which assays might matter in the clinic or a trial next. Short version: saves you hours of reading and points you to the bits that will change practice soon.
Context and relevance
The review is highly relevant for clinicians, trialists and researchers as blood‑based biomarkers move from research into routine use. It situates assay advances within the broader shifts in AD care: earlier detection, biomarker-based staging, and biomarker endpoints for disease‑modifying treatments. The paper also highlights translational obstacles — assay standardisation, confounders such as renal impairment or other comorbidities, and ethical issues around disclosure — which must be solved for equitable clinical implementation.