Biofluid-based biomarkers – realizing their potential in Alzheimer’s disease

Henrik Zetterberg, University of Gothenberg, Sweden and University College London, UK, during the first plenary session at this year’s AAIC, gave an upbeat assessment of the current literature on biofluid-based biomarkers for use in assessing Alzheimer’s disease-related pathologies.

Amyloid pathology

CSF Aβ42 levels are low in Alzheimer’s disease (AD) versus controls such that CSF Aβ42 is considered a reliable marker of senile plaque pathology.1-3 However, because CSF Aβ42 levels also decline in other conditions, measurement of the CSF Aβ42:Aβ40 ratio appears to be a more robust plaque pathology marker for AD than CSF Aβ42 alone. Indeed, longitudinal data support its value as a marker of disease in AD – the ratio fully changes before symptoms appear and does not change over time in symptomatic disease.4-5

Thus, as a marker of AD, CSF Aβ42:Aβ40 is relatively straightforward to interpret and, indeed, certified reference methods and materials for CSF Aβ42 are available.

CSF Aβ42:Aβ40 is relatively straightforward to interpret and certified reference methods and materials for CSF Aβ42 are available

Is there a more convenient assay method? While plasma Aβ assays start to look promising, robustness is currently an issue for biological reasons. Assays for brain-derived Aβ (e.g. pyroGluAβ) could possibly solve this issue. Nevertheless, fully-automated clinical chemistry tests with very low analytical variation have been developed and are entering clinical laboratory practice now.


Tau pathology

It has been known for some time that CSF phospho-tau (P-tau) is increased in AD but not in other tauopathies but the variation in forms of P-tau correlates weakly with the underlying pathology associated with AD.6 However, different phospho-forms of tau can be measured in plasma and, in combination with other accessible measures such as brief cognitive tests and APOE genotyping, may offer a diagnostic means of predicting AD.7

Thus, Professor Zetterberg suggested, CSF and plasma P-tau measurements may offer a direct marker of Aβ- induced tau phosphorylation and release from neurons and, thus, a predictive marker of tangle pathology.

CSF and plasma P-tau measurements may offer a direct marker of Aβ- induced tau phosphorylation and release from neurons predictive of tangle pathology.



High levels present in CSF and plasma of serum neurofibrillary light chain (NfL) molecules are dynamic, if slow, biomarkers for active neurodegeneration and/or neuroaxonal injury.8

Therefore, drugs slowing down neurodegeneration should reduce or stabilize NfL levels. Indeed, CSF NfL dynamics appear normalized in response to treatments used in MS, spinal muscular atrophy and in Huntington’s disease.9-11 

A proof of concept study of CSF NfL dynamics in anti-Aβ antibody treatment suggests that such therapy may eventually be effective in AD although the data to date are not as encouraging as those for other conditions.12 

CSF NfL dynamics appear normalized in response to treatments used in MS, spinal muscular atrophy and in Huntington’s disease


Glial activation

Glial activation is another promising avenue currently being investigated in AD. Glial fibrillary acidic protein (GFAP) is an astrocytic activation marker - with greater efficacy in plasma than in CSF  - to indicate levels of accumulated amyloid and so neurological damage in the brain.13  


Synuclein pathology

Very promising qualitative results on synuclein pathology markers in CSF have been published. Two groups have developed assays for alpha-synuclein misfolded aggregates. CSF α-synuclein seeds in patients with Parkinson’s disease (PD) and dementia with Lewy bodies fold differently from those found in controls and in those with AD. 14-15  This finding  facilitates differential diagnoses of these conditions.

Very promising qualitative results on synuclein pathology markers in CSF have been published


TDP-43 pathology

Transactive response DNA-binding protein-43 (TDP-43) is the cardinal protein in the most common subtypes of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. Pilot data available for an assay TDP-43 in CSF suggest it may be exploited as a disease biomarker in these patients.16



The whole set of CSF biomarkers should inform on the clinical importance of AD and non-AD pathologies. Already useful biomarkers are available in CSF and blood and much work has been done on standardization and implementation in clinical laboratory practice The blood biomarkers should be useful as early diagnostic test to determine who is likely to benefit from disease-modifying treatment and to monitor treatments but more data on diverse populations are needed.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

  1. AlzBiomarker database
  2. Strozyk D et al. CSF Abeta 42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology 2003;60:652-656.
  3. Palmqvist S et al. Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid β-amyloid 42: a cross-validation study against amyloid positron emission tomography. JAMA Neurology 2014;71:1282-9.
  4. Jenelidze S et al. CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios: better diagnostic markers of Alzheimer’s disease. Ann Clin Transl Neurol 2016;3:154-65.
  5. Betthauser T et al. AAIC 2021.
  6. Itoh N et al. Large-scale, multicenter study of cereobrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer’s disease. Ann Neurol 2001;50:150-6.
  7. Palmqvist S et al. Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures. Nature Medicine 2021;27:1034-1042
  8. Zetterberg H et al. Association of cerebrospinal fluid neurofilament light concentration with Alzheimer’s disease progression. JAMA Neurol 2016;73:60-7.
  9. Gunnarson M et al. Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. Ann Neurol 2011; 69:83-89.
  10. Olsson B et al. NFL is a marker of treatment response in children with SMA treated with nusinersen. J Neurol 2019;266:2129-2136.
  11. Tabrizi SJ et al. Targeting huntingtin expression in patients with Huntington’s disease. NEJM 2019;380:2307-2316.
  12. Swanson et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimer’s Research and Therapy 2021;
  13. Benedet et al. AAIC 2021
  14. Fairfoul G et al. Alpha-synuclein RT-QulC in the CSF of patients with alpha-synucleinopathies. Annals of Clinical and Translational Neurology 2016;3:812-818.
  15. Shahnawaz M et al. Development of a biochemical diagnosis of Parkinson Disease by detection of α-synuclein misfolded aggregates in cerebrospinal fluid. JAMA Neurol 2017;74:163-172;
  16. Scialó C et al. TDP-43 real-time quaking induced conversion reaction optimization and detection of seeding activity in CSF and amylotrophic lateral sclerosis and frontotemporal dementia patients. Brain Comm 2020. Doi:10.1093/braincomms/fcaa 142
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