A Systematic Review and Meta-Analysis of Cerebrospinal Fluid Amyloid and Tau Levels Identifies Mild Cognitive Impairment Patients Progressing to Alzheimer’s Disease

Abstract

Reported levels of amyloid-beta and tau in human cerebrospinal fluid (CSF) were evaluated to discover if these biochemical markers can predict the transition from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD). A systematic review of the literature in PubMed and Web of Science (April 2021) was performed by a single researcher to identify studies reporting immunologically-based (xMAP or ELISA) measures of CSF analytes Aβ(1-42) and/or P-tau and/or T-tau in clinical studies with at least two timepoints and a statement of diagnostic criteria. Of 1137 screened publications, 22 met the inclusion criteria for CSF Aβ(1-42) measures, 20 studies included T-tau, and 17 included P-tau. Six meta-analyses were conducted to compare the analytes for healthy controls (HC) versus progressive MCI (MCI_AD) and for non-progressive MCI (Stable_MCI) versus MCI_AD; effect sizes were determined using random effects models. The heterogeneity of effect sizes across studies was confirmed with very high significance (p < 0.0001) for all meta-analyses except HC versus MCI_AD T-tau (p < 0.05) and P-tau (non-significant). Standard mean difference (SMD) was highly significant (p < 0.0001) for all comparisons (Stable_MCI versus MCI_AD: SMD [95%-CI] Aβ(1-42) = 1.19 [0.96,1.42]; T-tau = −1.03 [−1.24,−0.82]; P-tau = −1.03 [−1.47,−0.59]; HC versus MCI_AD: SMD Aβ(1-42) = 1.73 [1.39,2.07]; T-tau = −1.13 [−1.33,−0.93]; P-tau = −1.10 [−1.23,−0.96]). The follow-up interval in longitudinal evaluations was a critical factor in clinical study design, and the Aβ(1–42)/P-tau ratio most robustly differentiated progressive from non-progressive MCI. The value of amyloid-beta and tau as markers of patient outcome are supported by these findings.

TREM2 Agonism with a Monoclonal Antibody Attenuates Tau Pathology and Neurodegeneration

“…These pathological findings are corroborated by PET imaging studies that associate Tau pathology with cognitive deficits [5], as well as with brain atrophy [6]. CSF-derived biomarkers reflective of misfolded/phosphorylated Tau burden are also associated with the clinically meaningful role of Tau misfolding in the pathogenesis of neurodegeneration [7].…”

Air pollution and plasma amyloid beta in a cohort of older adults: Evidence from the Ginkgo Evaluation of Memory study

“…One recent study found no association between several air pollutants and Aβ ratio ( Alemany et al, 2021 ), but others have seen lower concentrations of Aβ1–42 among children living in more polluted areas ( Calderón-Garcidueñas et al, 2018 , 2016 ). Substantial research finds that those with AD have lower concentrations of Aβ1–42 in CSF compared to those with MCI and normal cognition ( Ma et al, 2022 ; Skillbäck et al, 2015 ; Toledo et al, 2015 ). Thus future air pollution studies should stratify by disease stage in order to better evaluate the relation between air pollution and CSF Aβ.…”

Systematic characterization of a non-transgenic Aβ1–42 amyloidosis model: synaptic plasticity and memory deficits in female and male mice

“…Our results showed a similar impairment in both male and female mice in all forms of spatial learning and memory evaluated, as well as in the exploratory habituation. It is well established that learning and memory deterioration occurs in both AD patients and animal models [ 25 , 60 ]. Notwithstanding, while transgenic models represent genetic forms of AD and require months to develop cognitive impairments, AD is primarily a sporadic disorder [ 61 ].…”