Cerebrospinal fluid A beta 1–40 peptides increase in Alzheimer’s disease and are highly correlated with phospho-tau in control individuals

Abstract

Background Amyloid pathology, which is one of the characteristics of Alzheimer’s disease (AD), results from altered metabolism of the beta-amyloid (Aβ) peptide in terms of synthesis, clearance, or aggregation. A decrease in cerebrospinal fluid (CSF) level Aβ1–42 is evident in AD, and the CSF ratio Aβ42/Aβ40 has recently been identified as one of the most reliable diagnostic biomarkers of amyloid pathology. Variations in inter-individual levels of Aβ1–40 in the CSF have been observed in the past, but their origins remain unclear. In addition, the variation of Aβ40 in the context of AD studied in several studies has yielded conflicting results. Methods Here, we analyzed the levels of Aβ1–40 using multicenter data obtained on 2466 samples from six different cohorts in which CSF was collected under standardized protocols, centrifugation, and storage conditions. Tau and p-tau (181) concentrations were measured using commercially available in vitro diagnostic immunoassays. Concentrations of CSF Aβ1–42 and Aβ1–40 were measured by ELISA, xMAP technology, chemiluminescence immunoassay (CLIA), and mass spectrometry. Statistical analyses were calculated for parametric and non-parametric comparisons, linear regression, correlation, and odds ratios. The statistical tests were adjusted for the effects of covariates (age, in particular). Results Regardless of the analysis method used and the cohorts, a slight but significant age-independent increase in the levels of Aβ40 in CSF was observed in AD. We also found a strong positive correlation between the levels of Aβ1–40 and p-tau (181) in CSF, particularly in control patients. Conclusions These results indicate that an increase in the baseline level of amyloid peptides, which are associated with an increase in p-tau (181), may be a biological characteristic and possibly a risk factor for AD. Further studies will be needed to establish a causal link between increased baseline levels of Aβ40 and the development of the disease.

P-tau subgroups in AD relate to distinct amyloid production and synaptic integrity profiles

“…We found that p-tau subgroups 2–4 had increasingly higher CSF markers of amyloid production and synaptic integrity markers, which is in line with studies that reported continuous associations of tau with biomarkers reflecting these processes (i.e., Aβ40 [ 36 ] and BACE1 [ 12 , 13 ], NRGN [ 8 , 18 – 22 ], and VAMP2 [ 16 ]). A previous study also showed tau and amyloid metabolism may have overlapping causal mechanisms, as in cognitively intact monozygotic twins, amyloid production markers in one twin were related to p-tau levels of the other twin [ 37 ].…”

Amyloid pathology but notAPOEε4 status is permissive for tau-related hippocampal dysfunction

“… 25 ). Also, a recent report showed that Aβ40 levels tend to increase together with increasing p-tau pathology, 26 raising the possibility that Aβ42/40 levels would show stronger collinearity with CSF-tau measures than Aβ42 alone. Aβ42 levels have previously been used to determine amyloid positivity in SCD.…”

Blood amyloid and tau biomarkers as predictors of cerebrospinal fluid profiles

“…All participants had received neurological and neuropsychological evaluation and provided CSF and plasma samples. The Montpellier cohort included 161 patients recruited from September 2009 to June 2017 (Lehmann et al 2020 ). All patients underwent a thorough clinical examination including biological laboratory tests, neuropsychological assessments, and brain imaging.…”

“…CSF Aβ 1–42 , Aβ 1–40 , total tau and phosphorylated tau 181 [p-tau(181)] were measured using Fujirebio Lumipulse or Innotest assay as described (Lehmann et al 2020 ). The cutoff values were initially obtained from groups of patients clinically diagnosed with AD (whose clinical diagnoses were made blind to biomarker results) and, for the Barcelona cohort, from amyloid-PET positive and amyloid-PET negative participants (Alcolea et al 2019 , PMID 31464088) or, for Montpellier, from control population of the memory clinic with various etiology (Lehmann et al 2013 , 2018 ).…”