Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds

Abstract

BackgroundIncreased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognised, the need for further characterization of the pathophysiological mechanisms behind AD still remains.MethodsIn this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology. ResultsThe protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score.ConclusionsWe identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins’ role in AD pathophysiology.

Large‐scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease

“…Unique to this study was the inclusion of a more comprehensive set of CSF biomarkers relevant to AD, neurodegeneration, and neuroinflammation. We replicated numerous protein associations with p-tau, but found less replication for proteins previously associated with amyloid, 77,85 which could be due to differences in the exact amyloid measures used (Note S4 in supporting information). We also saw an imbalanced distribution of protein associations by biomarker, with neurogranin having by far the greatest number of protein associations and IL-6 having none (Note S5 in supporting information).…”

Large-scale proteome and metabolome analysis of CSF implicates altered glucose metabolism and succinylcarnitine in Alzheimer’s disease

“…These nominally associated proteins included many proteins known to form intracellular or extracellular deposits in disease( 71 ), including APP, TTR, B2M, APOA1, APOA2, APOA4, APOC2, APOC3, LYZ, CST3, SOD1, IGHG1, IGHG2, IGHG3, and HBB (Supplementary Table 6). Although individual protein associations and pathway enrichment have tended to be the focus of previous work, several studies have reported similar widespread enrichment among the proteome, including a case-control study of AD diagnosis with 487 of 1,968 (24.7%) of proteins nominally associated with AD diagnosis( 75 ) and a study of protein correlations with CSF total tau, ptau, and Aβ42 where 63 out of 106 proteins (59.4%) were associated with at least one of the biomarkers( 45 ). Indeed, one core feature of AD proteomics work historically has been the identification of numerous AD-associated proteins that nonetheless do not replicate upon further study( 36, 37 ).…”

“…One of the major trends in AD research has been the movement toward a biomarker-based definition of AD( 11 ). Recent CSF proteomics work in AD has explored the relationship between CSF protein levels and various AD biomarkers, especially measures of amyloid and tau pathology( 34, 45 ). We replicated numerous previously reported protein associations with CSF levels of ptau (e.g., SMOC1, BASP1, and GAP43)( 34, 45 ), but failed to replicate any of the proteins significantly associated with CSF amyloid, though we note that our analysis used Aβ42/Aβ40 as the outcome rather than Aβ42 since Aβ42/Aβ40 is considered to be a better biomarker for AD than Aβ42 alone( 46 ).…”

“…Further potential evidence implicating proteostasis was the substantial enriched association signal across the proteome, with 54.2% (496/915) of CSF proteins being nominally associated with AT category and substantial deviation from the expected null distribution across the proteome (Figure 2b). These nominally associated proteins included many proteins known to form intracellular or extracellular deposits in disease (71) (45). Indeed, one core feature of AD proteomics work historically has been the identification of numerous AD-associated proteins that nonetheless do not replicate upon further study (36,37).…”

A Machine Learning Approach for Early Diagnosis of Cognitive Impairment Using Population-Based Data

“…Studies have shown dementia to be a slowly progressive disease and lesions in the brain could be shown as early as 10-15 years before onset of clinical symptoms [9][10][11]. More recently, biomarker-based diagnostics such as amyloid-␤ and tau proteins detected using positron emission tomography (PET) scans and cerebrospinal fluid (CSF) analysis have been recognized as promising markers for pathology [12]. While these biomarkers offer high predictive ability, their high cost and invasive procedures have hindered their widespread use [13].…”