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

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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Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau

10.21203/rs.3.rs-101153/v2 ◽

2021 ◽

Author(s):

Niklas Mattsson-Carlgren ◽

Shorena Janelidze ◽

Randall Bateman ◽

Ruben Smith ◽

Erik Stomrud ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Medial Temporal Lobe ◽

Amyloid Plaques ◽

Amyloid Plaque ◽

Amyloid Pet ◽

Tau Pathology ◽

Β Amyloid ◽

Tau Pet ◽

Disease Stages

Abstract Alzheimer’s disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N=88), both plaque and tangle density contributed independently to higher P-tau217. Several findings were replicated in a cohort with PET imaging (“BioFINDER-2”, N=426), where β-amyloid and tau PET were independently associated to P-tau217. P-tau217 correlated with β-amyloid PET (but not tau PET) in early disease stages, and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles.

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Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease

Science Advances ◽

10.1126/sciadv.aaz2387 ◽

2020 ◽

Vol 6 (16) ◽

pp. eaaz2387 ◽

Cited By ~ 18

Author(s):

Niklas Mattsson-Carlgren ◽

Emelie Andersson ◽

Shorena Janelidze ◽

Rik Ossenkoppele ◽

Philip Insel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Pet ◽

Phosphorylated Tau ◽

Positron Emission ◽

Aβ Aggregation ◽

Tau Pet ◽

5Xfad Mice ◽

Tau Aggregation ◽

T Tau

The links between β-amyloid (Aβ) and tau in Alzheimer’s disease are unclear. Cognitively unimpaired persons with signs of Aβ pathology had increased cerebrospinal fluid (CSF) phosphorylated tau (P-tau181 and P-tau217) and total-tau (T-tau), which increased over time, despite no detection of insoluble tau aggregates [normal Tau positron emission tomography (PET)]. CSF P-tau and T-tau started to increase before the threshold for Amyloid PET positivity, while Tau PET started to increase after Amyloid PET positivity. Effects of Amyloid PET on Tau PET were mediated by CSF P-tau, and high CSF P-tau predicted increased Tau PET rates. Individuals with MAPT mutations and signs of tau deposition (but without Aβ pathology) had normal CSF P-tau levels. In 5xFAD mice, CSF tau increased when Aβ aggregation started. These results show that Aβ pathology may induce changes in soluble tau release and phosphorylation, which is followed by tau aggregation several years later in humans.

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Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET

Science Translational Medicine ◽

10.1126/scitranslmed.aau5732 ◽

2020 ◽

Vol 12 (524) ◽

pp. eaau5732 ◽

Cited By ~ 49

Author(s):

Renaud La Joie ◽

Adrienne V. Visani ◽

Suzanne L. Baker ◽

Jesse A. Brown ◽

Viktoriya Bourakova ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Pet ◽

Specific Distribution ◽

Positron Emission ◽

Pet Radiotracers ◽

Β Amyloid ◽

Tau Pet ◽

Prospective Longitudinal

β-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer’s disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients’ diagnostic and prognostic evaluation. In a group of 32 patients at early symptomatic AD stages, we tested whether β-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not β-amyloid–PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients. These data support disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient’s progression and design future clinical trials.

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IC-P-156: Baseline amyloid PET imaging, longitudinal amyloid accumulation, and Tau PET imaging in preclinical Alzheimer's disease

Alzheimer s & Dementia ◽

10.1016/j.jalz.2015.06.179 ◽

2015 ◽

Vol 11 (7S_Part_2) ◽

pp. P105-P105

Author(s):

Aaron P. Schultz ◽

Elizabeth C. Mormino ◽

Jasmeer P. Chhatwal ◽

Molly LaPoint ◽

Alex S. Dagley ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pet Imaging ◽

Amyloid Pet ◽

Preclinical Alzheimer’S Disease ◽

Amyloid Accumulation ◽

Tau Pet ◽

Tau Pet Imaging ◽

Amyloid Pet Imaging

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Elevated Tau PET Signal Depends on Abnormal Amyloid Levels and Correlates with Cognitive Impairment in Elderly Persons without Dementia

Journal of Alzheimer s Disease ◽

10.3233/jad-200526 ◽

2020 ◽

Vol 78 (1) ◽

pp. 395-404 ◽

Cited By ~ 1

Author(s):

Rui-Qi Zhang ◽

Shi-Dong Chen ◽

Xue-Ning Shen ◽

Yu-Xiang Yang ◽

Jia-Ying Lu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Executive Function ◽

Amyloid Β ◽

Amyloid Pet ◽

Elderly Persons ◽

Cross Sectional ◽

Memory Decline ◽

Tau Pet

Background: The recent developed PET ligands for amyloid-β (Aβ) and tau allow these two neuropathological hallmarks of Alzheimer’s disease (AD) to be mapped and quantified in vivo and to be examined in relation to cognition. Objective: To assess the associations among Aβ, tau, and cognition in non-demented subjects. Methods: Three hundred eighty-nine elderly participants without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent tau and amyloid PET scans. Cross-sectional comparisons and longitudinal analyses were used to evaluate the relationship between Aβ and tau accumulation. The correlations between biomarkers of both pathologies and performance in memory and executive function were measured. Results: Increased amyloid-PET retention was associated with greater tau-PET retention in widespread cortices. We observed a significant tau increase in the temporal composite regions of interest over 24 months in Aβ+ but not Aβ– subjects. Finally, tau-PET retention but not amyloid-PET retention significantly explained the variance in memory and executive function. Higher level of tau was associated with greater longitudinal memory decline. Conclusion: These findings suggested PET-detectable Aβ plaque pathology may be a necessary antecedent for tau-PET signal elevation. Greater tau-PET retention may demonstrate poorer cognition and predict prospective memory decline in non-demented subjects.

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White matter hyperintensities: relationship to amyloid and tau burden

Brain ◽

10.1093/brain/awz162 ◽

2019 ◽

Vol 142 (8) ◽

pp. 2483-2491 ◽

Cited By ~ 23

Author(s):

Jonathan Graff-Radford ◽

Eider M Arenaza-Urquijo ◽

David S Knopman ◽

Christopher G Schwarz ◽

Robert D Brown ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

White Matter ◽

White Matter Hyperintensities ◽

Cerebral Microbleeds ◽

Amyloid Angiopathy ◽

Amyloid Pet ◽

Gradient Recall Echo ◽

Tau Pet ◽

Topographic Pattern

Abstract Although white matter hyperintensities have traditionally been viewed as a marker of vascular disease, recent pathology studies have found an association between white matter hyperintensities and Alzheimer’s disease pathologies. The objectives of this study were to investigate the topographic patterns of white matter hyperintensities associated with Alzheimer’s disease biomarkers measured using PET. From the population-based Mayo Clinic Study of Aging, 434 participants without dementia (55% male) with FLAIR and gradient recall echo MRI, tau-PET (AV-1451) and amyloid-PET scans were identified. A subset had cerebral microbleeds detected on T2* gradient recall echo scans. White matter hyperintensities were semi-automatically segmented using FLAIR MRI in participant space and normalized to a custom template. We used statistical parametric mapping 12-based, voxel-wise, multiple-regression analyses to detect white matter hyperintense regions associated with Alzheimer’s biomarkers (global amyloid from amyloid-PET and meta-regions of interest tau uptake from tau-PET) after adjusting for age, sex and hypertension. For amyloid associations, we additionally adjusted for tau and vice versa. Topographic patterns of amyloid-associated white matter hyperintensities included periventricular white matter hyperintensities (frontal and parietal lobes). White matter hyperintense volumes in the detected topographic pattern correlated strongly with lobar cerebral microbleeds (P < 0.001, age and sex adjusted Cohen’s d = 0.703). In contrast, there were no white matter hyperintense regions significantly associated with increased tau burden using voxel-based analysis or region-specific analysis. Among non-demented elderly, amyloid load correlated with a topographic pattern of white matter hyperintensities. Further, the amyloid-associated, white matter hyperintense regions strongly correlated with lobar cerebral microbleeds suggesting that cerebral amyloid angiopathy contributes to the relationship between amyloid and white matter hyperintensities. The study did not support an association between increased tau burden and white matter hyperintense burden.

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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

Molecular Neurodegeneration ◽

10.1186/s13024-021-00451-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Tim West ◽

Kristopher M. Kirmess ◽

Matthew R. Meyer ◽

Mary S. Holubasch ◽

Stephanie S. Knapik ◽

...

Keyword(s):

Mass Spectrometry ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Resolution Mass Spectrometry ◽

Clinical Performance ◽

Characteristic Curve ◽

Youden Index ◽

Amyloid Pet ◽

Drug Trials ◽

Site Specific

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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KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease

Nature Communications ◽

10.1038/s41467-021-23755-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Julia Neitzel ◽

Nicolai Franzmeier ◽

Anna Rubinski ◽

Martin Dichgans ◽

Matthias Brendel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Regions ◽

Protective Role ◽

Amyloid Pet ◽

Tau Pathology ◽

Cross Sectional ◽

Memory Impairments ◽

Amyloid A ◽

Tau Pet

AbstractKlotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer’s disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VShet and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VShet showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VShet on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VShet was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VShet carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia.

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The Clinical Use of Alzheimer’s Biomarkers in Patients With Mild Cognitive Impairment: A European Alzheimer’s Disease Consortium Survey

10.21203/rs.3.rs-559570/v1 ◽

2021 ◽

Author(s):

Camilla Caprioglio ◽

Valentina Garibotto ◽

Frank Jessen ◽

Lutz Frölich ◽

Gilles Allali ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Fdg Pet ◽

Diagnostic Process ◽

Amyloid Pet ◽

Clinical Use ◽

Tau Pet ◽

T Tau

Abstract Background. This study aims to investigate the clinical use of the main Alzheimer’s disease (AD) biomarkers in patients with mild cognitive impairment (MCI) by examining the beliefs and preferences of clinicians and biomarker experts of the European Alzheimer’s Disease Consortium (EADC).Methods. Out of 306 contacted EADC professionals, 150 (101 clinicians, 43 biomarker experts, and 6 falling into other categories) filled in an online survey from May to September 2020. The investigated biomarkers were: medial temporal lobe atrophy score (MTA) on structural MRI, typical AD (i.e. temporoparietal and posterior cingulate) hypometabolism on FDG-PET, CSF (Aβ42, p-tau, t-tau), amyloid-PET and tau-PET.Results. Despite the abnormal accumulation of amyloid rather than tau was deemed by the majority of responders as the initial cause of AD, responders did not show a clear preference for amyloid-PET. The most widely used biomarker is MTA (77% of responders reported to use it at least frequently), followed by Aβ42, p-tau, t-tau levels in CSF (45%), typical AD hypometabolism on FDG-PET (32%), amyloid-PET (8%), and tau-PET (2%). Imaging and CSF biomarkers were found to be widely used to support the etiological diagnostic process in MCI, while APOE genotyping was performed only in a minority of patients. CSF is considered the most valuable biomarker in terms of additional diagnostic value, followed by amyloid-PET, tau-PET, and typical AD hypometabolism on FDG-PET. The combination of amyloidosis and neuronal injury biomarkers is associated with the highest diagnostic confidence in an etiological diagnosis of AD in MCI, while MTA alone was perceived as the less reliable biomarker.Conclusions. Biomarkers are widely used across Europe for the diagnosis of MCI. Overall, we observed that CSF is currently considered as the most useful biomarker, followed by amyloid-PET. Moreover, the use of molecular imaging (i.e. amyloid-PET and tau-PET) in the diagnostic work-up of MCI patients is increasing over time.

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