Understanding the Aβ1-42/Aβ1-40 ratio in relation to Alzheimer’s Disease

A study by Wiltfgang et al. found that in a population of cognitively normal individuals and individuals with AD, the distribution of total Aβ (40 and 42) follows a Gaussian distribution, with Aβ1-40 making up about 70% of total Aβ load.¹ Although most cases fell within +/- 2SD of the Gaussian distribution, with the majority having normal total Aβ, outliers were still present. Some individuals had high total Aβ and some had low total Aβ. This was true for both normal and AD subjects.

This means that AD patients with a high total Aβ load could be identified incorrectly as amyloid negative and vice versa; normal subjects with low total Aβ could be diagnosed as amyloid positive, if only Aβ1-42 is used.

In all three manifestations of amyloid production (normal, low, and high total Aβ) the ratio could correctly interpret abnormal amyloid deposition in more cases than Aβ1-42 alone.

In a proof-of-principle study carried out in 2007, Wiltfang et al. concluded that the amyloid β concentration ratio should replace the ‘raw’ concentrations of corresponding Aβ peptides to improve reliability of the neurochemical dementia diagnosis².

More recently, several studies demonstrated added value for CSF Aβ1-40 or the CSF Aβ1-42/Aβ1-40 ratio to distinguish AD when presented with ambiguous AD CSF biomarker profiles^3–5. Dementia with Lewy bodies (DLB), the second most common dementia in the elderly, after Alzheimer’s disease (AD), presents similar symptoms to AD, making clinical differentiation difficult. A retrospective analysis from Bousige et al. found that Aβ1-42/1-40 concentrations observed in DLB were clearly distinct from AD Aβ1-42/1-40 concentrations at both early and late stages of disease, whereas concentrations of Aβ1-42 alone in patients with demented DLB overlapped with those seen in AD.

These and other results show that use of the Aβ1-42/1-40 ratio significantly improves understanding of amyloid deposition over the use of Aβ1-42 alone.