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• Use of the Aβ1-42/Aβ1-40 ratio to improve accuracy of AD diagnosis

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Aβ1-42/Aβ1-40 ratio for interpretation of discordant results

• Ambiguous results are often improved when the Aβ1-42/Aβ1-40 ratio is included.
• However, addition of the Aβ1-40 peptide concentration and the Aβ1-42/Aβ1-40 ratio does not change the conclusion when Aβ1-42 and pTau are concordant.
• The level of evidence of AD pathophysiological process or of dementia unrelated to AD can be increased by use of the Aβ1-42/Aβ1-40 ratio.

By use of the Aβ1-42/Aβ1-40 ratio, discordant results (i.e. when amyloid and tau biomarkers are not concordant) can be improved. However, while the level of evidence of AD pathophysiological process or of dementia can be increased, the addition of Aβ1-40 peptide concentration and Aβ1-42/Aβ1-40 ratio does not change the conclusion when Aβ1-42 and pTau are concordant.²

In a study from 2014, it was shown that the inclusion of Aβ1-42/Aβ1-40 ratio in the diagnostic criteria increased the level of evidence of AD pathophysiological process or dementia unlikely due to AD. Lumbar punctures (n = 386) were analysed in the lab within 2 years. One-third of the biological profiles of patients with atypical dementia were ambiguous. The addition of the Aβ1-42/Aβ1-40 ratio increased the proportion of interpretable biological profiles from 69% to 87%, without changing the conclusion when Aβ1-42 and pTau were concordant.²

They generated a decision tree, taking into account the levels of Aβ1-42 and pTau as well as the Aβ1-42/Aβ1-40 ratio (Figure 1).

In 2015, it was demonstrated in a study with 367 subjects with cognitive disorders that the assessment of Aβ1-42/Aβ1-40 ratio in patients with a discrepancy between CSF pTau and CSF Aβ1-42 led to a reliable biological conclusion in over 50% of cases that agreed with a clinician’s diagnosis. In this study 22% of the patients had indeterminate CSF profiles (i.e. when amyloid and tau biomarkers are not concordant). The systematic use of Aβ1-42/Aβ1-40 ratio instead of Aβ1-42 levels alone decreased the number of indeterminate profiles (17%; P = 0.03), but it failed to improve the classification of subjects (net reclassification improvement [NRI] = −2.1%; P = 0.64). In contrast, the use of Aβ1-42/Aβ1-40 ratio instead of Aβ1-42 levels alone in patients with a discrepancy between pTau and Aβ1-42 led to a reduction by half of the number of indeterminate profiles (10%; P < 0.001) and was further in agreement with clinician diagnosis (NRI = 10.5%; P = 0.003).¹

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