Research Article: 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

Date Published: March 20, 2018

Publisher: BioMed Central

Author(s): Inês Baldeiras, Isabel Santana, Maria João Leitão, Helena Gens, Rui Pascoal, Miguel Tábuas-Pereira, José Beato-Coelho, Diana Duro, Maria Rosário Almeida, Catarina Resende Oliveira.


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 Aβ42 concentration to the level of total amyloid beta (Aβ), using the Aβ42/40 ratio, has been shown to improve the distinction between AD and non-AD dementia. Therefore, we evaluated whether the Aβ42/40 ratio would improve MCI categorization and more accurately predict progression to AD.

Our baseline population consisted of 197 MCI patients, of which 144 had a follow-up ≥ 2 years, and comprised the longitudinal study group. To establish our own CSF Aβ42/40 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.

When using the core CSF biomarkers (Aβ42, 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 Aβ42 by the Aβ42/40 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 Aβ42/40 ratio, instead of Aβ42, combined with total Tau and phosphorylated Tau was used for biomarker-based categorization.

Our results confirm the usefulness of the CSF Aβ42/40 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.

The online version of this article (10.1186/s13195-018-0362-2) contains supplementary material, which is available to authorized users.

Partial Text

Alzheimer’s disease (AD) is the leading cause of dementia worldwide and the most common neurodegenerative disease, affecting 4.6–8.7% of people over the age of 60 [1]. The pathophysiological process of AD is thought to begin many years before its clinical diagnosis [2, 3] and is generally hypothesized to be initiated by abnormal amyloid processing, followed by neuronal dysfunction and structural brain changes, which ultimately lead to cognitive impairment and dementia [4]. The interest in capturing the earliest stages of AD has been supported by the development of biomarkers of the disease like the core cerebrospinal fluid (CSF) AD biomarkers, amyloid positron emission tomography (PET) imaging and evidence of hippocampal atrophy on MRI. These biomarkers, reflecting both amyloid deposition and neuronal injury, have been incorporated into new diagnostic criteria, like those proposed by the National Institute of Aging–Alzheimer Association (NIA-AA) for AD dementia [5], mild cognitive impairment (MCI) [6] or preclinical states [7].

In this study we investigated the effect of using the CSF Aβ42/40 ratio, instead of Aβ42 levels, both combined with Tau and p-Tau, in MCI classification according to the NIA-AA criteria. Our main findings were that the percentage of patients with amyloidosis (HL + IAP) significantly increased from 42 to 59%, reaching a similar percentage to the patients with injury markers (HL + SNAP, 56%). The proportion of interpretable biological profiles also increased significantly from 61% to 75%, particularly due to a reduction to half in the number of SNAP cases.

Our results confirm the usefulness of the addition of the CSF Aβ42/40 ratio in the interpretation of the CSF profile of MCI patients, as it increases the proportion of patients with conclusive profiles, therefore enhancing their predictive value for underlying AD dementia.




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