Klinikum rechts der Isar
Technische Universität München
Efficiency of the ratio of cerebrospinal fluid Aβ42/Aβ40 concentrations
inLaura
detecting
Alzheimer’s disease. A step forwards?
Kriett1, Bernhard Haller2, Stefan Förster1, Elisabeth Klupp1,
Panagiotis Alexopoulos,
Tamara Eisele
Drzezga1, Andreas
Fellgiebel4, Igor Yakushev1
Panos Alexopoulos3, Alexander
Department of Psychiatry and Psychotherapy
Introduction / Aims
According to its new conceptualization, Alzheimer’s disease (AD) can be diagnosed independently
of its clinical symptoms. As a consequence, biomarkers play a crucial role for diagnosing AD, since
they are capable to detect AD pathophysiological processes in oligosymptomatic or even
preclinical stages of the disease course. Markers of amyloid pathology such as levels of β-amyloid
1-40 (Aβ40) and 1-42 (Aβ42) in the cerebrospinal fluid (CSF) constitute a valuable instrument not
only in the field of diagnosing AD, but also of its differential diagnosis.
Sample No.
Methods
The aim of the present investigation was to study the efficiency of the ratio of CSF concentrations
of Aβ42/Aβ40 compared to the efficiency of Aß42, as determined with two new Enzyme-linked
Immunosorbent Assays (ELISA), in detecting AD. The ELISA assays have been developed by IBL
International GmbH, Hamburg. The clinical diagnosis based on a comprehensive diagnostic
workup embodied the gold standard. The study sample consisted of 40 patients fulfilling the
National Institute on Aging – Alzheimer Association (NIA-AA) clinical criteria for dementia due to
probable AD (pAD) (age in years: 67.55±7.55, 20 men, 20 women) and 43 cognitively healthy
elderly individuals (controls) with normal test results and no history of subjective memory
complaints and no dependency with regards to their activities of daily living (age in years:
65.74±8.98, 31 men, 12 women). The intraindividual coefficient of variation (CV) was studied in five
samples in each of which Aβ42 and Aβ40 were measured twenty times. A receiver operating
characteristic (ROC) curve analysis was employed, in order to select the optimal cut-off value of
the ratio Aβ42/Aβ40 and the Aß42 below which an individual has a very high chance of suffering
from pAD and to calculate sensitivity and specificity.
Results
The intraindividual CV varied between 3.1-9.1% (mean 4.9%) and 3.7-6.5% (mean 5.0%) for Aβ42
and Aβ40 respectively (Table 1). The Aβ42/Aβ40 optimal cut-off value was 0.05. The sensitivity was
98% and the specificity was 91%, whilst the sensitivity and specificity of CSF Aβ42 levels was 85%
and 86%, respectively, based on a cut-off of 640 pg/mL (Table 2).
Conclusions
The results of the present study point to a higher efficiency of the CSF Aβ42/Aβ40 ratio in
detecting AD pathophysiological alterations compared to CSF Aβ42 levels and highlight the
reliability of the new essays, which can increase our capacity to detect AD. They are in line with
the findings of previous studies which indicate that the association of two or three different
biomarkers yields higher sensitivity and specificity than each biomarker alone. Nonetheless,
further investigations focused on the efficiency of the ratio in the differential diagnosis of pAD and
in detecting in AD in oligosymptomatic and preclinical stages are warranted.
1
2
3
4
5
N
20
20
20
20
20
Table 1: Coefficient of Variation
Aβ40
concentration
(mean ±
standard
Coefficient
deviation)
of
(pg/mL)
variation
2244 ± 141
6.3%
5157 ± 223
4.3%
6164 ± 231
3.7%
17832 ± 1163
6.5%
8892 ± 348
3.9%
Aβ42
concentratio
n (mean±
standard
Coefficient
deviation)
of variation
(pg/mL)
117 ± 16
9.1%
474 ± 21
4.4%
478 ± 15
3.1%
661 ± 22
3.3%
700 ± 33
4.7%
Table 2: Efficiency in detecting Alzheimer‘s disease
Aβ1-42/ Aβ1-40
Aβ1-42 (pg/mL)
Mean ± standard deviation
0.06 ± 0.02
798.67 ± 455.51
Cut-Off
0,05
640
False positive
4
6
True positive
39
34
False negative
1
6
True negative
39
37
Sensitivity
98%
85%
Specificity
91%
86%
Disclosure of relevant financial relationships
The authors serve as consultants of IBL International GmbH
References
Ferreira D, Perestelo-Perez L, et al. Meta-review of CSF core biomarkers in Alzheimer’s disease:
the state-od-the-art after the new revised diagnostic criteria. Front Aging Neurosci 2014; 6:47