Amyloid β-Protein (1-37)

Objective: Alzheimer's disease (AD) involves a series of pathological changes and some biomarkers were reported to assist in monitoring and predicting disease progression before the emergence of clinical symptoms. We aimed to identify prospective biomarkers and quantify their effect on AD progression. Methods: PubMed, EMBASE and Web of Science databases were searched for prospective cohort studies published up to October 2021. Eligible studies were included, and the available data were extracted. Meta-analyses were conducted based on random-effect models. Relative risk (RR) with 95% confidence interval (CI) was adopted as the final effect size. Results: Totally 48,769 articles were identified, of which 84 studies with 20 prospective biomarkers were included in meta-analyses. In the present study, 15 biomarkers were associated with AD progression, comprising CSF Aβ42 (RR=2.49, 95%CI=1.68-3.69), t-tau (RR=1.88, 95%CI=1.49-2.37), p-tau (RR=1.74, 95%CI=1.37-2.21), tau/Aβ42 ratio (RR=5.11, 95%CI=2.01-13.00); peripheral blood Aβ42/Aβ40 (RR=1.26, 95%CI=1.05-1.51), t-tau (RR=1.33, 95%CI=1.08-1.64), NFL (RR=1.75, 95%CI=1.07-2.87); whole, left and right hippocampal volume (HV) (whole: RR=1.65, 95%CI=1.39-1.95; left: RR=2.60, 95%CI=1.02-6.64; right: RR=1.43, 95%CI=1.23-1.66), entorhinal cortex (EC) volume (RR=1.69, 95%CI=1.24-2.30), medial temporal lobe atrophy (MTA) (RR=1.52, 95%CI=1.33-1.74), 18 F-FDG PET (RR=2.24, 95%CI=1.29-3.89), 11 C-labeled Pittsburgh Compound B PET (11 C-PIB PET) (RR=3.91, 95%CI=1.06-14.41); APOE ε4 (RR=2.16, 1.83-2.55). A total of 70 articles were included in the qualitative review, in which 61 biomarkers were additionally associated with AD progression. Conclusion: CSF Aβ42, t-tau, p-tau, tau/Aβ42; peripheral blood t-tau, Aβ42/Aβ40, NFL; whole, left and right HV, EC volume, MTA, 18 F-FDG PET, 11 C-PIB PET; APOE ε4 may be promising prospective biomarkers for AD progression.

Importance: Depression has been associated with alterations in neurotransmitters, hormones, and inflammatory and neurodegenerative biomarkers, and biomarkers quantified in the cerebrospinal fluid (CSF) are more likely to reflect ongoing biochemical changes within the brain. However, a comprehensive overview of CSF biomarkers is lacking and could contribute to the pathophysiological understanding of depression. Objective: To investigate differences in quantified CSF biomarkers in patients with unipolar depression compared with healthy control individuals. Data sources: PubMed, EMBASE, PsycINFO, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched for eligible trials from database inception to August 25, 2021. Study selection: All studies investigating CSF biomarkers in individuals 18 years and older with unipolar depression and healthy control individuals were included. One author screened titles and abstracts, and 2 independent reviewers examined full-text reports. Studies that did not include healthy control individuals or included control individuals with recent hospital contacts or admissions that might affect CSF biomarker concentrations were excluded. Data extraction and synthesis: Data extraction and quality assessment were performed by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines. Meta-analyses were performed using standardized mean differences (SMDs) calculated with random-effects models. A third investigator was consulted if the 2 reviewers reached different decisions or when in doubt. Main outcomes and measures: Quantifiable CSF biomarkers. Results: A total of 167 studies met eligibility criteria, and 97 had available data and were included in the meta-analysis. These 97 studies comprised 165 biomarkers, 42 of which were quantified in 2 or more studies. CSF levels of interleukin 6 (7 studies; SMD, 0.35; 95% CI, 0.12 to 0.59; I2 = 16%), total protein (5 studies; SMD, 0.53; 95% CI, 0.35 to 0.72; I2 = 0%), and cortisol (2 studies; SMD, 1.23; 95% CI, 0.89 to 1.57; I2 = 0%) were higher in patients with unipolar depression compared with healthy control individuals, whereas homovanillic acid (17 studies; SMD, -0.26; 95% CI, -0.39 to -0.14; I2 = 11%), γ-aminobutyric acid (4 studies; SMD, -0.50; 95% CI, -0.92 to -0.08; I2 = 55%), somatostatin (5 studies; SMD, -1.49; 95% CI, -2.53 to -0.45; I2 = 91%), brain-derived neurotrophic factor (3 studies; SMD, -0.58; 95% CI, -0.97 to -0.19; I2 = 0%), amyloid-β 40 (3 studies; SMD, -0.80; 95% CI, -1.14 to -0.46; I2 = 0%), and transthyretin (2 studies; SMD, -0.82; 95% CI, -1.37 to -0.27; I2 = 0%) were lower. The remaining 33 biomarkers had nonsignificant results. Conclusions and relevance: The findings of this systematic review and meta-analysis point toward a dysregulated dopaminergic system, a compromised inhibitory system, hypothalamic-pituitary-adrenal axis hyperactivity, increased neuroinflammation and blood-brain barrier permeability, and impaired neuroplasticity as important factors in depression pathophysiology.

Background: Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer's disease (AD). Methods: In this randomized, double-blind, placebo-controlled phase III study, we investigated gantenerumab over 2 years. Patients were randomized to gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose. Results: Of the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, gantenerumab 105 mg, and gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints. Conclusions: The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy. Trial registration: ClinicalTrials.gov, NCT01224106 . Registered on October 14, 2010.