A blood-based diagnostic test incorporating plasma Aβ42/40 ratio, ApoE proteotype, and age accurately identifies brain amyloid status: findings from a multi cohort validity analysis

Abstract Background The development of blood-based biomarker tests that are accurate and robust for Alzheimer’s disease (AD) pathology have the potential to aid clinical diagnosis and facilitate enrollment in AD drug trials. We developed a high-resolution mass spectrometry (MS)-based test that quantifies plasma Aβ42 and Aβ40 concentrations and identifies the ApoE proteotype. We evaluated robustness, clinical performance, and commercial viability of this MS biomarker assay for distinguishing brain amyloid status. Methods We used the novel MS assay to analyze 414 plasma samples that were collected, processed, and stored using site-specific protocols, from six independent US cohorts. We used receiver operating characteristic curve (ROC) analyses to assess assay performance and accuracy for predicting amyloid status (positive, negative, and standard uptake value ratio; SUVR). After plasma analysis, sites shared brain amyloid status, defined using diverse, site-specific methods and cutoff values; amyloid PET imaging using various tracers or CSF Aβ42/40 ratio. Results Plasma Aβ42/40 ratio was significantly (p < 0.001) lower in the amyloid positive vs. negative participants in each cohort. The area under the ROC curve (AUC-ROC) was 0.81 (95% CI = 0.77–0.85) and the percent agreement between plasma Aβ42/40 and amyloid positivity was 75% at the optimal (Youden index) cutoff value. The AUC-ROC (0.86; 95% CI = 0.82–0.90) and accuracy (81%) for the plasma Aβ42/40 ratio improved after controlling for cohort heterogeneity. The AUC-ROC (0.90; 95% CI = 0.87–0.93) and accuracy (86%) improved further when Aβ42/40, ApoE4 copy number and participant age were included in the model. Conclusions This mass spectrometry-based plasma biomarker test: has strong diagnostic performance; can accurately distinguish brain amyloid positive from amyloid negative individuals; may aid in the diagnostic evaluation process for Alzheimer’s disease; and may enhance the efficiency of enrolling participants into Alzheimer’s disease drug trials.

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P3-025: Characterization of transthyretin isoforms in CSF from patients with Alzheimer's disease and controls by high resolution mass spectrometry

Alzheimer s & Dementia ◽

10.1016/j.jalz.2009.04.1202 ◽

2009 ◽

Vol 5 (4S_Part_11) ◽

pp. P347-P347

Author(s):

Keld Poulsen ◽

Justyna M.C. Bahl ◽

Anja H. Simonsen ◽

Gunhild Waldemar ◽

Martin R. Larsen ◽

...

Keyword(s):

Mass Spectrometry ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Resolution ◽

High Resolution Mass Spectrometry ◽

High Resolution Mass ◽

Resolution Mass

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Site-Specific Cerebrospinal Fluid Tau Hyperphosphorylation in Response to Alzheimer’s Disease Brain Pathology: Not All Tau Phospho-Sites are Hyperphosphorylated

Journal of Alzheimer s Disease ◽

10.3233/jad-210677 ◽

2021 ◽

pp. 1-15

Author(s):

Nicolas R. Barthélemy ◽

Balazs Toth ◽

Paul T. Manser ◽

Sandra Sanabria-Bohórquez ◽

Edmond Teng ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tau Phosphorylation ◽

Amyloid Pet ◽

Tau Hyperphosphorylation ◽

Cross Sectional ◽

Site Specific ◽

Treatment Objective ◽

Sectional Analysis ◽

The Relationship

Background: Understanding patterns of association between CSF phosphorylated tau (p-tau) species and clinical disease severity will aid Alzheimer’s disease (AD) diagnosis and treatment. Objective: To evaluate changes in tau phosphorylation ratios to brain imaging (amyloid PET, [18F]GTP1 PET, and MRI) and cognition across clinical stages of AD in two different cohorts. Methods: A mass spectrometry (MS)-based method was used to evaluate the relationship between p-tau/tau phosphorylation ratios on 11 sites in CSF and AD pathology measured by tau PET ([18F]GTP1) and amyloid PET ([18F]florbetapir or [18F]florbetaben). Cohort A included cognitively normal-amyloid negative (n = 6) and positive (n = 5) individuals, and amyloid positive prodromal (n = 13), mild (n = 12), and moderate AD patients (n = 10); and Cohort B included amyloid positive prodromal (n = 24) and mild (n = 40) AD patients. Results: In this cross-sectional analysis, we identified clusters of phosphosites with different profiles of phosphorylation ratios across stages of disease. Eight of 11 investigated sites were hyperphosphorylated and associated with the SUVR measures from [18F]GTP1 and amyloid PET. Novel sites 111, 153, and 208 may be relevant biomarkers for AD diagnosis to complement tau hyperphosphorylation measures on previously established sites 181, 205, 217, and 231. Hypophosphorylation was detected on residues 175, 199, and 202, and was inversely associated with [18F]GTP1 and amyloid PET. Conclusion: Hyperphosphorylated and hypophosphorylated forms of tau are associated with AD pathologies, and due to their different site-specific profiles, they may be used in combination to assist with staging of disease.

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False Memory and Alzheimer’s Disease Pathology in Patients with Amnestic Mild Cognitive Impairment: A Study with Amyloid PET

Dementia and Geriatric Cognitive Disorders Extra ◽

10.1159/000516230 ◽

2021 ◽

pp. 172-180

Author(s):

Eun-Ji Choi ◽

Bum Joon Kim ◽

Hyung-Ji Kim ◽

Miseon Kwon ◽

Noh Eul Han ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Logistic Regression ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

False Memory ◽

Visual Recognition ◽

Characteristic Curve ◽

Amnestic Mild Cognitive Impairment ◽

Amyloid Pet

Introduction: False memory, observed as intrusion errors or false positives (FPs), is prevalent in patients with Alzheimer’s disease, but has yet to be thoroughly investigated in patients with amnestic mild cognitive impairment (a-MCI) with Alzheimer’s disease pathology (ADP). We analyzed false versus veridical memory in individuals with a-MCI and measured the utility of false memory for ADP discrimination. Methods: Patients with a-MCI who received neuropsychological testing and amyloid PET were included. Patients were categorized into “with” and “without ADP” groups according to PET results. Memory tests assessed veridical and false memory, and the verity of patient responses was analyzed. A logistic regression model was used to evaluate false memory efficiency in discriminating ADP, and the sensitivity and specificity at the optimal level were estimated using the receiver-operating characteristic curve. Results: Thirty-seven ADP and 46 non-ADP patients were enrolled. The ADP group made more FPs in the recognition tests, and their response verity was significantly lower in every delayed memory test. No group difference, however, was observed in the veridical memory. The logistic regression analysis demonstrated that as the FPs increased, the risk of ADP increased 1.31 and 1.36 times in the verbal and visual recognition tests, respectively. The discriminatory accuracy of the FPs was estimated “low” to “moderate” in the visual and verbal recognition, respectively, with an optimal cutoff above 2.5. Conclusion: Increased false memory was the only feature to discriminate ADP from non-ADP in individuals with a-MCI. Further studies regarding false memory and its mechanism are warranted.

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Optimal Combinations of AT(N) Biomarkers to Determine Longitudinal Cognition in the Alzheimer's Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.718959 ◽

2021 ◽

Vol 13 ◽

Author(s):

Rong-Rong Lin ◽

Yan-Yan Xue ◽

Xiao-Yan Li ◽

Yi-He Chen ◽

Qing-Qing Tao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cortical Thickness ◽

Clinical Manifestations ◽

Cognitive Status ◽

Youden Index ◽

Amyloid Pet ◽

Cognitive Changes ◽

Neurofilament Light ◽

Tau Pet

Background: National Institute on Aging—Alzheimer's Association (NIA-AA) proposed the AT(N) system based on β-amyloid deposition, pathologic tau, and neurodegeneration, which considered the definition of Alzheimer's disease (AD) as a biological construct. However, the associations between different AT(N) combinations and cognitive progression have been poorly explored systematically. The aim of this study is to compare different AT(N) combinations using recognized biomarkers within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.Methods: A total of 341 participants were classified into cognitively unimpaired (CU; n = 200) and cognitively impaired (CI; n = 141) groups according to the clinical manifestations and neuropsychological tests. Cerebrospinal fluid (CSF) Aβ42 and amyloid-PET ([18F]flutemetamol) were used as biomarkers for A; CSF phosphorylated tau (p-tau) and tau-PET ([18F]flortaucipir) were used as biomarkers for T; CSF total tau (t-tau), hippocampal volume, temporal cortical thickness, [18F]fluorodeoxyglucose (FDG) PET, and plasma neurofilament light (NfL) were used as biomarkers for (N). Binary biomarkers were obtained from the Youden index and publicly available cutoffs. Prevalence of AT(N) categories was compared between different biomarkers within the group using related independent sample non-parametric test. The relationship between AT(N) combinations and 12-year longitudinal cognition was assessed using linear mixed-effects modeling.Results: Among the CU participants, A–T–(N)– was most common. More T+ were detected using p-tau than tau PET (p < 0.05), and more (N)+ were observed using fluid biomarkers (p < 0.001). A+T+(N)+ was more common in the CI group. Tau PET combined with cortical thickness best predicted cognitive changes in the CI group and MRI predicted changes in the CU group.Conclusions: These findings suggest that optimal AT(N) combinations to determine longitudinal cognition differ by cognitive status. Different biomarkers within a specific component for defining AT(N) cannot be used identically. Furthermore, different strategies for discontinuous biomarkers will be an important area for future studies.

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Optimal Combinations of Biomarkers to Determine AT(N) in the Alzheimer’s Disease

10.21203/rs.3.rs-118287/v1 ◽

2020 ◽

Author(s):

Rong-Rong Lin ◽

Yan-Yan Xue ◽

Xiao-Yan Li ◽

Yi-He Chen ◽

Qing-Qing Tao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cortical Thickness ◽

Clinical Stage ◽

Youden Index ◽

Amyloid Pet ◽

Clinical Dementia Rating ◽

Cognitive Changes ◽

Neurofilament Light ◽

Tau Pet

Abstract Background: National Institute on Aging—Alzheimer’s Association (NIA-AA) proposed the AT(N) system based on β-amyloid deposition, pathologic tau, and neurodegeneration, which considered the definition of Alzheimer’s disease (AD) as a biological construct. However, the associations between different AT(N) combinations and clinical stage and progression have been poorly explored systematically. The aim of this study is to compare different AT(N) combinations using recognized biomarkers within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.Methods: A total of 341 participants from ADNI cohort were classified into AT(N) groups, including 200 cognitively unimpaired (CU) participants and 141 cognitively impaired (CI) participants (101 mild cognitive impairment [MCI] and 40 Alzheimer’s disease [AD]). CSF Aβ42 and amyloid-PET ([18F]flutemetamol) were used as biomarkers for A; CSF phosphorylated tau (p-tau) and tau-PET ([18F]flortaucipir) were used as biomarkers for T; CSF total tau (t-tau), FDG-PET, hippocampal volume, temporal cortical thickness and plasma neurofilament light (NfL) were used as biomarkers for (N). Binarization of biomarkers was acquired from Youden index and public cutoffs. The relationship between different AT(N) biomarkers combinations and cognitive changes (longitudinal Mini-Mental State Examination scores and Clinical Dementia Rating Sum of Boxes) was examined using linear mixed modeling and coefficient of variation.Results: Among CU participants, A−T−(N)− variants were most common. More T+ cases were shown using p-tau than tau PET, and more N+ cases were shown using fluid biomarkers than neuroimaging. Among CI participants, A+T+(N)+ was more common. Tau PET combined with cortical thickness best predicted longitudinal cognitive decline in CI and MRI measurements in CU participants. Conclusion: These findings suggest that optimal combinations of biomarkers to determine AT(N) are differed by clinical stage. Different biomarkers within a specific component for defining AT(N) cannot be used identically. Furthermore, different strategies for discontinuous biomarkers will be an important area for the future studies.

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Comparison of amyloid PET measured in Centiloid units with neuropathological findings in Alzheimer’s Disease

10.21203/rs.2.17082/v1 ◽

2019 ◽

Author(s):

Sanka Amadoru ◽

Vincent Doré ◽

Catriona A McLean ◽

Fairlie Hinton ◽

Claire E Shepherd ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Roc Curves ◽

Neuritic Plaque ◽

Youden Index ◽

Amyloid Pet ◽

Receiver Operator Characteristic ◽

Post Mortem ◽

Neuritic Plaques ◽

Moderate Density

Abstract Background: We aimed to determine the Centiloid unit (CL) thresholds for sparse and moderate density neuritic plaques. Methods: Amyloid PET results in CL for 49 subjects were compared with post-mortem neuritic plaque density, visual read, and final clinicopathological diagnosis. A Youden Index was used to determine the optimal CL thresholds from receiver operator characteristic (ROC) curves. Results: A threshold of 20.1 CL yielded highest accuracy in detecting moderate or frequent plaque density (ROC AUC 0.97). A threshold of 9.5 CL was optimal for detecting sparse, moderate or frequent plaques (ROC AUC 0.96). Those cases with a final clinicopathological diagnosis of Alzheimer’s disease yielded a median CL result of 87.7 (IQR ±42.2) with 94% > 45 CL. Positive visual read agreed highly with results >26 CL. Conclusions: In this cohort, values <9.5 CL accurately reflected the absence of any neuritic plaques, and >20.1 CL indicated the presence of at least moderate plaque density. Clinicopathological diagnosis of AD was rare with CL <45.

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A plasma protein classifier for predicting amyloid burden for preclinical Alzheimer’s disease

Science Advances ◽

10.1126/sciadv.aau7220 ◽

2019 ◽

Vol 5 (2) ◽

pp. eaau7220 ◽

Cited By ~ 21

Author(s):

Nicholas J. Ashton ◽

Alejo J. Nevado-Holgado ◽

Imelda S. Barber ◽

Steven Lynham ◽

Veer Gupta ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Resolution Mass Spectrometry ◽

Characteristic Curve ◽

Receiver Operator Characteristic Curve ◽

Feature Model ◽

Therapeutic Trials ◽

Positron Emission ◽

Proteomic Study ◽

Peptide Fractionation

A blood-based assessment of preclinical disease would have huge potential in the enrichment of participants for Alzheimer’s disease (AD) therapeutic trials. In this study, cognitively unimpaired individuals from the AIBL and KARVIAH cohorts were defined as Aβ negative or Aβ positive by positron emission tomography. Nontargeted proteomic analysis that incorporated peptide fractionation and high-resolution mass spectrometry quantified relative protein abundances in plasma samples from all participants. A protein classifier model was trained to predict Aβ-positive participants using feature selection and machine learning in AIBL and independently assessed in KARVIAH. A 12-feature model for predicting Aβ-positive participants was established and demonstrated high accuracy (testing area under the receiver operator characteristic curve = 0.891, sensitivity = 0.78, and specificity = 0.77). This extensive plasma proteomic study has unbiasedly highlighted putative and novel candidates for AD pathology that should be further validated with automated methodologies.

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Mass spectrometry measures of plasma Aβ, tau and P‐tau isoforms’ relationship to amyloid PET, tau PET, and clinical stage of Alzheimer’s disease

Alzheimer s & Dementia ◽

10.1002/alz.037518 ◽

2020 ◽

Vol 16 (S5) ◽

Author(s):

Randall J. Bateman ◽

Nicolas R. Barthelemy ◽

Tammie L.S. Benzinger ◽

James G. Bollinger ◽

Anne M. Fagan ◽

...

Keyword(s):

Mass Spectrometry ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Stage ◽

Amyloid Pet ◽

Tau Isoforms ◽

Tau Pet

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Comparison of amyloid PET measured in Centiloid units with neuropathological findings in Alzheimer’s Disease

10.21203/rs.2.17082/v2 ◽

2020 ◽

Author(s):

Sanka Amadoru ◽

Vincent Doré ◽

Catriona A McLean ◽

Fairlie Hinton ◽

Claire E Shepherd ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Roc Curves ◽

Neuritic Plaque ◽

Youden Index ◽

Amyloid Pet ◽

Neuritic Plaques ◽

Time To Death ◽

Post Mortem Findings ◽

Amyloid Aβ

Abstract Background: The Centiloid scale was developed to standardise the results of beta-amyloid (Aβ) PET. We aimed to determine the Centiloid unit (CL) thresholds for CERAD sparse and moderate density neuritic plaques, Alzheimer’s disease neuropathologic change (ADNC) score of intermediate or high probability of Alzheimer’s Disease (AD), final clinicopathological diagnosis of AD and expert visual read of a positive Aβ PET scan. Methods: Aβ PET results in CL for 49 subjects were compared with post-mortem findings, visual read, and final clinicopathological diagnosis. The Youden Index was used to determine the optimal CL thresholds from receiver operator characteristic (ROC) curves. Results: A threshold of 20.1 CL (21.3 CL when corrected for time to death, AUC 0.97) yielded highest accuracy in detecting moderate or frequent plaque density while <10 CL was optimal for excluding neuritic plaque. The threshold for ADNC intermediate or high likelihood AD was 49.4 CL (AUC 0.98). Those cases with a final clinicopathological diagnosis of AD yielded a median CL result of 87.7 (IQR ±42.2) with 94% > 45 CL. Positive visual read agreed highly with results >26 CL. Conclusions: Centiloid values <10 accurately reflected the absence of any neuritic plaque, >20 CL indicated the presence of at least moderate plaque density but approximately 50 CL or more best confirmed both neuropathological and clinicopathological diagnosis of Alzheimer’s disease.

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