High cerebrospinal amyloid-β 42 is associated with normal cognition in individuals with brain amyloidosis

Abstract

Background Brain amyloidosis does not invariably predict dementia. We hypothesized that high soluble 42-amino acid β amyloid (Aβ42) peptide levels are associated with normal cognition and hippocampal volume despite increasing brain amyloidosis. Methods This cross-sectional study of 598 amyloid-positive participants in the Alzheimer's Disease Neuroimaging Initiative cohort examined whether levels of soluble Aβ42 are higher in amyloid-positive normal cognition (NC) individuals compared to mild cognitive impairment (MCI) and Alzheimer's disease (AD) and whether this relationship applies to neuropsychological assessments and hippocampal volume measured within the same year. All subjects were evaluated between June 2010 and February 2019. Brain amyloid positivity was defined as positron emission tomography-based standard uptake value ratio (SUVR) ≥1.08 for [18] F-florbetaben or 1.11 for [18] F-florbetapir, with higher SUVR indicating more brain amyloidosis. Analyses were adjusted for age, sex, education, APOE4, p -tau, t -tau, and centiloids levels. Findings Higher soluble Aβ42 levels were observed in NC (864.00 pg/ml) than in MCI (768.60 pg/ml) or AD (617.46 pg/ml), with the relationship between NC, MCI, and AD maintained across all amyloid tertiles. In adjusted analysis, there was a larger absolute effect size of soluble Aβ42 than SUVR for NC (0.82 vs. 0.40) and MCI (0.60 vs. 0.26) versus AD. Each standard deviation increase in Aβ42 was associated with greater odds of NC than AD (adjusted odds ratio, 6.26; p < 0.001) or MCI (1.42; p = 0.006). Higher soluble Aβ42 levels were also associated with better neuropsychological function and larger hippocampal volume. Interpretation Normal cognition and hippocampal volume are associated with preservation of high soluble Aβ42 levels despite increasing brain amyloidosis. Funding Please refer to the Funding section at the end of the article.

Staging Disease Severity Using the Alzheimer’s Disease Composite Score (ADCOMS): A Retrospective Data Analysis

“…Table 8 presents values of the biomarkers total tau, tau phosphorylated at threonine 181 (p-tau 181 ), and amyloid β 1–42 as measured in CSF at baseline and the number of patients carrying the apolipoprotein ε4 allele (APOE4) gene according to ADCOMS staging groups. People staged as having normal cognition using the ADCOMS have significantly lower mean tau and p-tau 181 levels and significantly higher mean amyloid β 1–42 values than those staged as having early AD (soluble amyloid β 1–42 is known to decrease as patients progress[ 21 ]). Additionally, the likelihood of being an APOE4 carrier increased across the ADCOMS staging groups, such that people staged as having moderate/severe AD had the highest likelihood of carrying this gene.…”

Prefrontally Modulated Vagal Tone Inhibits Inflammatory Responses to Prevent Telomere Damage in Healthy Participants

“…The role of amyloid plaque in Alzheimer's disease is undecided with accumulating evidence indicating that it might not be the pathogenic trigger driving the neurodegenerative cascade (e.g. Sturchio et al, 2021). Alternative explanatory mechanisms that trigger and interact with known antecedents to neurodegenerative pathology are thus needed.…”

Aducanumab for Alzheimer’s disease: A regulatory perspective

“…Despite both drugs demonstrated convincing Aβ target engagement, gantenerumab failed to show a beneficial effect on cognitive measures, whereas solanezumab-treated group even exhibited a greater cognitive decline on some measures compared to placebo [9]. One week later, a cross sectional study conducted on 598 amyloid-positive participants patients was published and revealed that soluble Aβ 42 levels above 800 pg/ml were correlated with normal cognition irrespective of (and despite increasing) brain amyloid burden, implying that increasing soluble Aβ 42 , rather than reducing Aβ plaques, might represent a better therapeutic option [11]. We believe that these evidences should be taken into account for the future regulatory decision-making.…”