By Dr. Sandra Langer et al., Fujirebio
Previous posts in this series:
- Use of the Aβ1-42/Aβ1-40 ratio to improve accuracy of AD diagnosis
- Aβ1-42/Aβ1-40 ratio for interpretation of discordant results
- Improvement of AD risk scores by use of the Aβ1-42/Aβ1-40 ratio
- How to work with Aβ1-42/Aβ1-40 ratio
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- Combinations of different biomarkers outperform the use of individual biomarkers alone.
- Several biomarker combinations have been tested and used in different kinds of ratios for AD diagnostics (t-Tau/Aβ1-42 ratio, p-Tau/Aβ1-42 ratio, Aβ1-42/Aβ1-38 ratio) with good sensitivity and specificity.
- However, combining different physiopathologies (e.g. Tau and amyloid), the ratios must be used in a very strict context, according to a well-defined clinical question.
- CSF Aβ1-42/Aβ1-40 can be used as a tool to normalize values of amyloid levels, other ratios might be seen more as interpretation tools.
CSF Aβ1-42/Aβ1-40 is a tool to normalize values of patients with different amyloid levels, as other ratios might be seen more as interpretation tools which allow to compare different biomarker results.
Whereas other ratios combine different pathological features, the Aβ1-42/Aβ1-40 ratio is a combination of two markers reflecting the same pathology. As soon as other biomarkers such as tTau or pTau are included, it must be taken into consideration that Tau and Aβ might not have a linear relationship all over the course of the disease as they are parts of different pathological pathways. Therefore, every use of a ratio combining different pathologies needs to be evaluated and assessed very critical with regard to its value and result at different states of the disease and lifespan of the patient.
Tau / amyloid ratios
Among the scientific community it is generally widely accepted that combinations of different biomarkers outperform the use of individual biomarkers alone. The ongoing discussions are more related to the question about the best combination to predict or differentially diagnose AD.
Based on the sensitivity of the best performing regression formulas, Duits et al. (2015) recommend the use of a tTau/Aβ1-42 ratio, as the use of this combination constitutes a robust CSF AD Alzheimer profile. They also evaluated pTau/Aβ1-42 ratio, which was found to predict AD with a sensitivity of 91%–93%, and a specificity of 81%–84%. The same combinations (tTau/Aβ1-42 and pTau/Aβ1-42) best predicted cognitive decline in mild cognitive impairment patients. Validation confirmed these results, especially regarding the tTau/Aβ1-42 ratio.4
The Alzheimer Disease Neuroimaging Initiative (ADNI), an international consortium, has been a key cohort study for predicting the progression from MCI to AD using biomarkers, and demonstrated that the tTau/Aβ1-42 ratio could be used to predict conversion from MCI to AD dementia, revealing a sensitivity of 86% and specificity of 85%.1;2
Nevertheless, since there are other pathologies (e.g. Tau), and other ratios that can combine different pathological models to evaluate the AD risk, all ratios must be used in strict context, according to a well-defined clinical question.
Other amyloid / amyloid ratios
It seems that between Aβ1-42/Aβ1-40 ratio and Aβ1-42/Aβ1-38 ratio there is not much difference. Aβ1-38 may be increased in neuroinflammatory diseases.3 But since the assays for Aβ1-40 are well-established, which is not the case for Aβ1-38, and in addition there is not enough data on Aβ1-38, Aβ1-42/Aβ1-40 ratio seems to be the better option in this comparison.
- Petersen, R. C., et al. "Alzheimer's disease neuroimaging initiative (ADNI): clinical characterization." Neurology 74.3 (2010): 201-209.
- Ritchie, Craig, et al. "CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI)." Cochrane Database of Systematic Reviews 3 (2017).
- Wiltfang, Jens, et al. "Highly conserved and disease‐specific patterns of carboxyterminally truncated Aβ peptides 1–37/38/39 in addition to 1–40/42 in Alzheimer's disease and in patients with chronic neuroinflammation." Journal of neurochemistry 81.3 (2002): 481-496.
- Duits, Flora H., et al. "The cerebrospinal fluid “Alzheimer profile”: easily said, but what does it mean?" Alzheimer's & Dementia 10.6 (2014): 713-723.