Concordance Between Cerebrospinal Fluid Biomarkers with Alzheimer’s Disease Pathology Between Three Independent Assay Platforms

Doecke, James D.; Rembach, Alan; Villemagne, Victor L.; Varghese, Shiji; Rainey-Smith, Stephanie R.; Sarros, Shannon; Evered, Lisbeth; Fowler, Christopher; Pertile, Kelly K.; Rumble, Rebecca; Trounson, Brett; Taddei, Kevin; Macaulay, S. Lance; Bush, Ashley I.; Ellis, Kathryn A.; Martins, Ralph N.; Ames, David; Silbert, Brendan; Vanderstichele, Hugo; Masters, Colin L.; Darby, David; Li, Qiao‐Xin; Collins, Steven J.

doi:10.3233/jad-170128

Cited by 23 publications

(16 citation statements)

References 51 publications

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“…The significant change in CSF Ab42 before the Ab PET threshold for Ab positivity (Fig 2) is in agreement with previous studies showing that CSF Ab42 becomes abnormal prior to Ab PET (Palmqvist et al, 2016Vlassenko et al, 2016). Further, the later change in Ab42/40 compared to Ab42 might be one of the explanations for the higher agreement between (dichotomous) Ab PET and Ab42/40 compared with Ab PET and Ab42 (Fig 2), which has been reported previously (Janelidze et al, 2016Lewczuk et al, 2017;Doecke et al, 2018). Although this temporal difference in Ab42 and Ab42/40 is in agreement with the spline model showing an initial drop in Ab40 followed by stable levels (Fig 3A), the A-D The biomarker data were fitted using monotone spline models for CSF Ab42 (A), Ab42/40 (B), P-tau (C), and T-tau (D) assays, where Ab PET SUVR acted as a proxy for time in AD.…”

Section: Discussionsupporting

confidence: 91%

Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease

et al. 2019

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Failures in Alzheimer's disease (AD) drug trials highlight the need to further explore disease mechanisms and alterations of biomarkers during the development of AD. Using cross‐sectional data from 377 participants in the BioFINDER study, we examined seven cerebrospinal fluid (CSF) and six plasma biomarkers in relation to β‐amyloid (Aβ) PET uptake to understand their evolution during AD. In CSF, Aβ42 changed first, closely followed by Aβ42/Aβ40, phosphorylated‐tau (P‐tau), and total‐tau (T‐tau). CSF neurogranin, YKL‐40, and neurofilament light increased after the point of Aβ PET positivity. The findings were replicated using Aβ42, Aβ40, P‐tau, and T‐tau assays from five different manufacturers. Changes were seen approximately simultaneously for CSF and plasma biomarkers. Overall, plasma biomarkers had smaller dynamic ranges, except for CSF and plasma P‐tau which were similar. In conclusion, using state‐of‐the‐art biomarkers, we identified the first changes in Aβ, closely followed by soluble tau. Only after Aβ PET became abnormal, biomarkers of neuroinflammation, synaptic dysfunction, and neurodegeneration were altered. These findings lend in vivo support of the amyloid cascade hypotheses in humans.

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Section: Discussionsupporting

confidence: 91%

Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease

et al. 2019

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“…It has been well established that the decreases in CSF Aβ42 coincide with increased brain amyloid plaque pathology (Seeburger et al, 2015; Doecke et al, 2018). In CSF, Aβ changes were detected before the changes in t-Tau in cognitively normal adults (Buchhave et al, 2012), and the change could be observed as early as middle-age (Sutphen et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Age-Dependent Relationship Between Plasma Aβ40 and Aβ42 and Total Tau Levels in Cognitively Normal Subjects

Lue

Pai

Chen

et al. 2019

Front. Aging Neurosci.

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Both amyloid plaques and neurofibrillary tangles are pathological hallmarks in the brains of patients with Alzheimer’s disease (AD). However, the constituents of these hallmarks, amyloid beta (Aβ) 40, Aβ42, and total Tau (t-Tau), have been detected in the blood of cognitively normal subjects by using an immunomagnetic reduction (IMR) assay. Whether these levels are age-dependent is not known, and their interrelation remains undefined. We determined the levels of these biomarkers in cognitively normal subjects of different age groups. A total of 391 cognitively normal subjects aged 23–91 were enrolled from hospitals in Asia, Europe, and North America. Healthy cognition was evaluated by NIA-AA guidelines to exclude subjects with mild cognitive impairment (MCI) and AD and by cognitive assessment using the Mini Mental State Examination and Clinical Dementia Rating (CDR). We examined the effect of age on plasma levels of Aβ40, Aβ42, and t-Tau and the relationship between these biomarkers during aging. Additionally, we explored age-related reference intervals for each biomarker. Plasma t-Tau and Aβ42 levels had modest but significant correlations with chronological age (r = 0.127, p = 0.0120 for t-Tau; r = −0.126, p = 0.0128 for Aβ42), ranging from ages 23 to 91. Significant positive correlations were detected between Aβ42 and t-Tau in the groups aged 50 years and older, with Rho values ranging from 0.249 to 0.474. Significant negative correlations were detected between Aβ40 and t-Tau from age 40 to 91 (r ranged from −0.293 to −0.582) and between Aβ40 and Aβ42 in the age groups of 30–39 (r = −0.562, p = 0.0235), 50–59 (r = −0.261, p = 0.0142), 60–69 (r = −0.303, p = 0.0004), and 80–91 (r = 0.459, p = 0.0083). We also provided age-related reference intervals for each biomarker. In this multicenter study, age had weak but significant effects on the levels of Aβ42 and t-Tau in plasma. However, the age group defined by decade revealed the emergence of a relationship between Aβ40, Aβ42, and t-Tau in the 6th and 7th decades. Validation of our findings in a large-scale and longitudinal study is warranted.

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“…Strong concordance has been observed between CSF markers (Aβ 42 , tau, and pTau181) and PET-Aβ-amyloid status, as measured by the Roche Elecsys and INNOtest assays [ 30, 31 ]. A high correlation of CSF biomarkers on the AlzBio3 and EUROIMMUNE platforms has also been reported [ 101 ]. Methodologically, no difference in these biomarkers was observed from CSF collected using gravity or aspiration techniques [ 102 ].…”

Section: Resultsmentioning

confidence: 98%

Fifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer’s Disease

Fowler¹,

Rainey‐Smith²,

Bird³

et al. 2021

ADR

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Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer’s disease dementia (AD)) as an ‘Inception cohort’ who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an ‘Enrichment cohort’ (as of 10 April 2019). Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.

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Concordance Between Cerebrospinal Fluid Biomarkers with Alzheimer’s Disease Pathology Between Three Independent Assay Platforms

Abstract: This study confirms strong concordance between CSF biomarkers and PET Aβ-amyloid status is independent of immunoassay platform, supporting their utility as biomarkers in clinical practice for the diagnosis of AD and for participant enrichment in clinical trials.

Cited by 23 publications

References 51 publications

Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease

Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease

Age-Dependent Relationship Between Plasma Aβ40 and Aβ42 and Total Tau Levels in Cognitively Normal Subjects

Fifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer’s Disease

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