Relationship between amyloid and tau levels and its impact on tau spreading

Doré, Vincent; Krishnadas, Natasha; Bourgeat, Pierrick; Huang, Kun; Li, Shenpeng; Burnham, Samantha; Masters, Colin L.; Fripp, Jürgen; Villemagne, Victor L.; Rowe, Christopher C.

doi:10.1007/s00259-021-05191-9

Cited by 50 publications

(45 citation statements)

References 37 publications

(23 reference statements)

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“…We found that a non-linear fit best explains the data, showing that a rise in detectable Aβ precedes a detectable increase in tau. We have previously shown that Aβ levels above ~50 CL are required to show significant cognitive and clinical change in cognitively normal older persons followed for 8 years (van der Kall, Truong et al 2020 point where a significant rise in the prevalence of T+ cases in CU as well as MCI and AD patients occurs (Dore, Krishnadas et al 2021).…”

Section: Discussionmentioning

confidence: 99%

Tau Imaging with ¹⁸F-MK6240 across the Alzheimer’s Disease spectrum

Rowe

Doré

Krishnadas

et al. 2022

Preprint

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Tau deposition plays a critical role over cognition and neurodegeneration in Alzheimers disease (AD). Recent generation tracers have high target to background ratios giving a wide dynamic range that may improve sensitivity for detection of low levels of tau (Pascoal, Shin et al. 2018). Building on previous evidence, this study aims to characterize the effects of tau deposition as assessed by 18F-MK6240, in a large cohort of patients across the AD disease spectrum. A total of 464 participants, enrolled in the AIBL-ADNeT study, underwent 18F-MK6240 tau PET, 18F-NAV4964 Aβ PET, 3D structural MRI (hippocampal and whole-brain cortical volumes) and extensive neuropsychological evaluation. Participants included 266 cognitively unimpaired controls (CU), 112 patients with mild cognitive impairment (MCI), and 86 patients with probable AD dementia. Evaluation included the characterization of the pattern and degree of 18F-MK6240 tracer retention in each clinical group as well as assessment of the relationship between 18F-MK6240 and age, Aβ imaging, brain volumetrics and cognition in each of the clinical groups. Standard uptake value ratios (SUVR) were estimated in four predefined composite regions of interest (ROIs), reflecting the stereotypical progression of tau pathology in the brain: 1. Mesial-temporal (Me), 2. Temporoparietal (Te), 3. Remainder of neocortex (R), 4. A temporal meta-region termed metaT+. 18F-MK6240 retention was higher in AD patients compared with all other diagnostic groups, with 18F-MK6240 distinguishing patients with AD from CU individuals, with the highest effect size obtained in the amygdala (Cohen d: 2.07), and Me (Cohen d: 1.99). When considering Aβ status, 18F-MK6240 not only was able to distinguish between Aβ+ AD patients and Aβ- CU (Cohen d: 2.23), but also between Aβ+ and Aβ- CU (Cohen d: 1.32). In Aβ- CU, 18F-MK6240 retention in Me showed a slow age-related increase, while 18F-MK6240 retention was higher in younger elderly Aβ+ AD patients compared to their older counterparts. There was a sigmoidal relationship between subthreshold tau and Aβ, providing evidence for a very slow but steady increase in subthreshold tau prior to a fast increase in cortical Aβ. Moreover, a non-linear relationship between Aβ and tau suggest that detectable cortical Aβ precedes detectable cortical tau. While age was the main predictor of cognitive decline in CU, and Aβ and hippocampal volume in MCI, the main predictor of cognitive decline in the AD group was tau. High tau was associated with faster cognitive decline and clinical progression in the CU and MCI groups. This large study provides further evidence that 18F-MK6240 discriminates CU from AD and, most importantly, Aβ+ from Aβ- CU individuals with high effect sizes, suggesting that 18F-MK6240 can detect lower tau levels than earlier tau tracers, crucial for early detection of tau deposition as well as tracking small tau changes over time. In conclusion, identification of regional cortical tau deposition has critical diagnostic and prognostic implications and should become a standard tool to identify individuals at risk, as well as outcome measure, in both anti-Aβ and anti-tau trials.

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Section: Discussionmentioning

confidence: 99%

Tau Imaging with ¹⁸F-MK6240 across the Alzheimer’s Disease spectrum

Rowe

Doré

Krishnadas

et al. 2022

Preprint

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“…All image processing was done locally. Images were realigned, averaged, resliced to 1.5mm 3 , and smoothed to a resolution of 8mm 3 FWHM. Each PET image was registered to the closest structural T1-weighted MRI image.…”

Section: Image Acquisition and Processing -Adnimentioning

confidence: 99%

“…Alzheimer’s disease (AD) is characterized by a cascade of molecular and neurodegenerative brain changes, in which Aβ plaques start to accumulate ∼20 years before symptom onset followed by the accumulation and spreading of neurofibrillary tau aggregates with ensuing neurodegeneration and AD dementia 1,2 . Multiple imaging studies of in vivo pathological processes with positron emission tomography (PET) in AD showed that cortical Aβ deposition precedes neocortical tau aggregation by several years 1,3 , and Aβ has been shown to amplify tau spreading in preclinical studies 4,5 . In contrast, age-related tau pathology typically occurring in the medial temporal lobe rarely spreads widely into the neocortex in the absence of cortical Aβ 6,7 , suggesting that the progression of tau aggregates is modified by Aβ 1,5 .…”

Section: Introductionmentioning

confidence: 99%

Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer

Binette

Franzmeier

Spotorno

et al. 2022

Preprint

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For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, it is important to understand how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. In early stages of AD, increased concentration of soluble CSF p-tau was the main driver of accumulation of insoluble tau aggregates across the brain, and mediated the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations were mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations were associated with cognitive decline, which was mediated by faster increase of tau aggregates. In AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline was driven by the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD.

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“…A recent study on the histopathological interactions between global amyloid and medial temporal neuroinflammation (48) reported that, in relation to tau spread, amyloid appeared to interact with transentorhinal neuroinflammation which, in turn, triggered the spread of tau across the neocortex (Braak stages II-III), followed by a subsequent spread of tau across Braak stages III-IV and the associated brain regions. A sentiment that was supported a year later, among a group of researchers who concluded that a "moderate" Aβ level is required for tau within the neocortex to be detectable, and that >40 centiloid of global Aβ burden is required to induce an accelerated spread of tau (49).…”

Section: Positron Emission Tomography (Pet)mentioning

confidence: 99%

At a Glance: An Update on Neuroimaging and Retinal Imaging in Alzheimer’s Disease and Related Research

et al. 2022

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Neuroimaging serves a variety of purposes in Alzheimer’s disease (AD) and related dementias (ADRD) research - from measuring microscale neural activity at the subcellular level, to broad topological patterns seen across macroscale-brain networks, and everything in between. In vivo imaging provides insight into the brain’s structure, function, and molecular architecture across numerous scales of resolution; allowing examination of the morphological, functional, and pathological changes that occurs in patients across different AD stages (1). AD is a complex and potentially heterogenous disease, with no proven cure and no single risk factor to isolate and measure, whilst known risk factors do not fully account for the risk of developing this disease (2). Since the 1990’s, technological advancements in neuroimaging have allowed us to visualise the wide organisational structure of the brain (3) and later developments led to capturing information of brain ‘functionality’, as well as the visualisation and measurement of the aggregation and accumulation of AD-related pathology. Thus, in vivo brain imaging has and will continue to be an instrumental tool in clinical research, mainly in the pre-clinical disease stages, aimed at elucidating the biological complex processes and interactions underpinning the onset and progression of cognitive decline and dementia. The growing societal burden of AD/ADRD means that there has never been a greater need, nor a better time, to use such powerful and sensitive tools to aid our understanding of this undoubtedly complex disease. It is by consolidating and reflecting on these imaging advancements and developing long-term strategies across different disciplines, that we can move closer to our goal of dementia prevention. This short commentary will outline recent developments in neuroimaging in the field of AD and dementia by first describing the historical context of AD classification and the introduction of AD imaging biomarkers, followed by some examples of significant recent developments in neuroimaging methods and technologies.

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Relationship between amyloid and tau levels and its impact on tau spreading

Cited by 50 publications

References 37 publications

Tau Imaging with ¹⁸F-MK6240 across the Alzheimer’s Disease spectrum

Tau Imaging with ¹⁸F-MK6240 across the Alzheimer’s Disease spectrum

Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer

At a Glance: An Update on Neuroimaging and Retinal Imaging in Alzheimer’s Disease and Related Research

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Relationship between amyloid and tau levels and its impact on tau spreading

Cited by 50 publications

References 37 publications

Tau Imaging with 18F-MK6240 across the Alzheimer’s Disease spectrum

Tau Imaging with 18F-MK6240 across the Alzheimer’s Disease spectrum

Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer

At a Glance: An Update on Neuroimaging and Retinal Imaging in Alzheimer’s Disease and Related Research

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Product

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Tau Imaging with ¹⁸F-MK6240 across the Alzheimer’s Disease spectrum

Tau Imaging with ¹⁸F-MK6240 across the Alzheimer’s Disease spectrum