Total tau or total tau and phosphorylated-tau 181 and Alzheimer's disease

Three core CSF biomarkers for Alzheimer's disease have been developed, each correlating to one of the key characteristics of Alzheimer's disease pathology (1):

• low levels of CSF amyloid-beta1-42 correlate with greater plaque load
• high levels of total tau correlate with greater intensity of neuronal degeneration
• high levels of phosphorylated tau correlate with neurofibrillary tangle pathology.

In the context of a clinical presentation consistent with Alzheimer's disease

• presence of low levels of amyloid-beta1-42 in combination with high levels of total tau and phosphorylated tau provide support for the diagnosis with a sensitivity of 80-93% and specificity of 82-90% against cognitively normal controls (1)
  • other common dementia disorders can overlap with Alzheimer's disease both in terms of symptoms and CSF profile, and mixed pathologies are common.

A study by Skillback et al found (1):

• frontotemporal dementia
  • highest cerebrospinal fluid levels of amyloid-beta1-42 and the lowest levels of total tau and phosphorylated tau
    
• Alzheimer's disease
  • highest levels of total tau and phosphorylated tau and the lowest levels of amyloid-beta1-42 and amyloid-beta1-42:phosphorylated tau ratios were found
  • low amyloid-beta1-42, high total tau and high phosphorylated tau correlated with low Mini-Mental State Examination scores in Alzheimer's disease
    
• in Parkinson's disease dementia and vascular dementia
  • low cerebrospinal fluid amyloid-beta1-42 was associated with low Mini-Mental State Examination score
    
• cerebrospinal fluid biomarkers were strongly associated with specific clinical dementia diagnoses with Alzheimer's disease and frontotemporal dementia showing the greatest difference in biomarker levels
  
• cerebrospinal fluid amyloid-beta1-42, total tau, phosphorylated tau and the amyloid-beta1-42:phosphorylated tau ratio all correlated with poor cognitive performance in Alzheimer's disease, as did cerebrospinal fluid amyloid-beta1-42 in Parkinson's disease dementia and vascular dementia.

NICE states (2):

• further tests for Alzheimer's disease
  • if the diagnosis is uncertain and Alzheimer's disease is suspected, consider either:
    • FDG-PET (fluorodeoxyglucose-positron emission tomography-CT), or perfusion SPECT (single-photon emission CT) if FDG-PET is unavailable or
    • examining cerebrospinal fluid for:
      • either total tau or total tau and phosphorylated-tau 181 AND
      • either amyloid beta 1-42 or amyloid beta 1-42 and amyloid beta 1-40.

Reference:

• (1) Skillback T et al. Cerebrospinal fluid tau and amyloid-beta1-42 in patients with dementia.Brain. 2015 Sep;138(Pt 9):2716-31
• (2) NICE (June 2018). Dementia: assessment, management and support for people living with dementia and their carers. (Accessed 15 March 2022)