Clinical usefulness of cerebrospinal fluid biomarkers in Alzheimer's disease

Abstract

Background Alzheimer's disease (AD) is a complex disease that shares clinical features with other dementias. It is important to establish a specific and reliable diagnosis. Nowadays, AD diagnosis is based on cerebrospinal fluid (CSF) biomarkers. However, the corresponding cut‐offs differ amongst studies. This study aims to evaluate the CSF biomarkers in the AD differential diagnosis. Methods Clinical relevant biomarkers (amyloid β42 (Aβ42), t‐Tau, p‐Tau, amyloid β40 (Aβ40), neurofilament light chain (NfL)) were determined in CSF samples from participants classified as AD (n = 124) and non‐AD (n = 148) patients from the Neurology Unit. They were included and evaluated consecutively (August 2018–October 2020). The clinical utility of these biomarkers was evaluated by AUC‐ROC curves and the corresponding cut‐off points were defined. Results The results showed satisfactory accuracy (AUC‐ROC 0.91 for Aβ42, 0.890 for t‐Tau and 0.933 for p‐Tau); whilst Aβ40 and NfL did not show good discriminatory capacity (AUC‐ROC 0.557 and 0.738, respectively). The ratios Aβ42/Aβ40 and t‐Tau/Aβ42 improved the diagnosis indices of each individual biomarker, with AUC‐ROC of 0.980 and 0.971, respectively. Also, elevated levels of NfL were found in the frontotemporal dementia group compared with the other participant groups. Conclusions The ratio Aβ42/Aβ40 showed the highest discriminating capacity between AD and non‐AD patients and might be useful in clinical practice. Regarding NfL, it is not a specific biomarker for AD; however, it might be helpful for the differential diagnosis of frontotemporal dementia. Nevertheless, further analysis in an external cohort is required in order to validate these results.

Biomarkers associated with the pathogenesis of Alzheimer’s disease

“…As mentioned previously, previous reports have shown that declines in p-tau levels and t-tau protein concentrations in the cerebral fluid of AD patients were not altered in a statistically significant way. In contrast, no significant longitudinal changes in p-tau and t-tau were found in the authors’ assay ( Lleo et al, 2019 ; Pena-Bautista et al, 2023 ).…”

“…Aβ exists mainly as Aβ40 and Aβ42 subtypes, and under normal conditions, the production and clearance of Aβ40 is in dynamic balance; Aβ42 is neurotoxic and accumulates in AD sufferers’ brains to produce senile plaques, showing good accuracy in detecting AD ( Hansson et al, 2018 ). Pena-Bautista et al (2023) statistically found decreased concentrations of Aβ42 in the CSF of those with AD, and lower CSF Aβ42 concentrations distinguished AD patients from healthy controls. Different illness conditions had different amounts of Aβ42 in the CSF, and AD could be distinguished from other forms of dementia based on the levels of Aβ42.…”

“…Overexpression of sTREM2 attenuated tau pathology and cognitive impairment in tau P301S transgenic mice. In addition, sTREM2 ( Laske et al, 2017 ; Hampel et al, 2018 ; Hansson et al, 2018 ; Lleo et al, 2019 ; Doecke et al, 2020 ; Aamodt et al, 2021 ; Clark et al, 2021 ; Simrén et al, 2021 ; Park et al, 2022 ; Zhang et al, 2022 ; Delaby et al, 2023 ; Dinoto et al, 2023 ; Pena-Bautista et al, 2023 ) is the smallest sTREM2 sequence that activates TG2 ( Zhang et al, 2023 ). This active peptide mimics the protective effects of sTREM2 both in vitro and in vivo .…”

“…The development of highly sensitive techniques to detect even low levels of NFL in the blood has made NFL an accessible and reliable biomarker of neurodegenerative disease ( Dinoto et al, 2023 ). NFL is a non-specific marker of neuronal damage and might help with the differential diagnosis of frontotemporal dementia and be useful in the differential diagnosis of frontotemporal dementia, as NFL concentrations in CSF are higher in AD patients than in those with normal cognitive function and increase with cognitive deterioration ( Pena-Bautista et al, 2023 ). In addition, NFL in CSF was significantly correlated with tau protein and Aβ levels, suggesting that NFL could be used as a biomarker for predicting cerebrospinal fluid in AD ( Aamodt et al, 2021 ).…”

Early Alzheimer’s Disease Screening Approach Using Plasma Biomarkers

“…The CSF samples were analyzed by chemiluminescence (CLIA) immunoassay (Lumipulse ® Fujirebio, Japan) in the clinical diagnosis service from Hospital La Fe. The cut-off values used for each biomarker were (reference level) >830 pg mL −1 for Aβ42, <380 pg mL −1 for t-Tau, <60 pg mL −1 for p-Tau181, >0.069 Aβ42/Aβ40, <0.41 t-Tau/Aβ42, and <810 pg mL −1 for NfL [ 74 ].…”