Addition of the Aβ42/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer's disease dementia in mild cognitive impairment

Background: Cerebrospinal fluid (CSF) biomarkers have been used to increase the evidence of underlying Alzheimer's disease (AD) pathology in mild cognitive impairment (MCI). However, CSF biomarker-based classification often results in conflicting profiles with controversial prognostic value. Normalization of the CSF A beta 42 concentration to the level of total amyloid beta (A beta), using the A beta 42/40 ratio, has been shown to improve the distinction between AD and non-AD dementia. Therefore, we evaluated whether the A beta 42/40 ratio would improve MCI categorization and more accurately predict progression to AD. Methods: Our baseline population consisted of 197 MCI patients, of which 144 had a follow-up >= 2 years, and comprised the lonitudinal study group. To establish our own CSF A beta 42/40 ratio reference value, a group of 168 AD-dementia patients and 66 neurological controls was also included. CSF biomarker-based classification was operationalized according to the framework of the National Institute of Aging-Alzheimer Association criteria for MCI. Results: When using the core CSF biomarkers (A beta 42, total Tau and phosphorylated Tau), 30% of the patients fell into the high-AD-likelihood (HL) group (both amyloid and neurodegeneration markers positive), 30% into the low-AD-likelihood group (all biomarkers negative), 28% into the suspected non-Alzheimer pathophysiology (SNAP) group (only neurodegeneration markers positive) and 12% into the isolated amyloid pathology group (only amyloid-positive). Replacing A beta 42 by the Aa42/40 ratio resulted in a significant increase in the percentage of patients with amyloidosis (42-59%) and in the proportion of interpretable biological profiles (61-75%), due to a reduction by half in the number of SNAP cases and an increase in the proportion of the HL subgroup. Survival analysis showed that risk of progression to AD was highest in the HL group, and increased when the A beta 42/40 ratio, instead of A beta 42, combined with total Tau and phosphorylated Tau was used for biomarker-based categorization. Conclusions: Our results confirm the usefulness of the CSF A beta 42/40 ratio in the interpretation of CSF biomarker profiles in MCI patients, by increasing the proportion of conclusive profiles and enhancing their predictive value for underlying AD.