Predictive Accuracy of Blood-Derived Biomarkers for Amyloid-β Brain Deposition Along with the Alzheimer’s Disease Continuum: A Systematic Review

Background: An amyloid-β (Aβ) positron emission tomography (Aβ-PET) scan of the human brain could lead to an early diagnosis of Alzheimer’s disease (AD) and estimate disease progression. However, Aβ-PET imaging is expensive, invasive, and rarely applicable to cognitively normal subjects at risk for dementia. The identification of blood biomarkers predictive of Aβ brain deposition could help the identification of subjects at risk for dementia and could be helpful for the prognosis of AD progression. Objective: This study aimed to analyze the prognostic accuracy of blood biomarkers in predicting Aβ-PET status along with progression toward AD. Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched bibliographic databases from 2010 to 2020. The quality of the included studies was assessed by the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Results: A total of 8 studies were retrieved. The prognostic accuracy of Aβ-PET status was calculated by obtaining ROCs for the following biomarkers: free, total, and bound Aβ 42 and Aβ 40; Aβ 42/40 ratio; neurofilaments (NFL); total tau (T-tau); and phosphorylated-Tau181 (P-tau181). Higher and lower plasma baseline levels of P-tau181 and the Aβ 42/40 ratio, respectively, showed consistently good prognostication of Aβ-PET brain accumulation. Only P-tau181 was shown to predict AD progression. Conclusion: In conclusion, the Aβ 42/40 ratio and plasma P-tau181 were shown to predict Aβ-PET status. Plasma P-tau181 could also be a preclinical biomarker for AD progression.

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Blood Biomarkers for Alzheimer’s Disease in Down Syndrome

Journal of Clinical Medicine ◽

10.3390/jcm10163639 ◽

2021 ◽

Vol 10 (16) ◽

pp. 3639

Author(s):

Laia Montoliu-Gaya ◽

Andre Strydom ◽

Kaj Blennow ◽

Henrik Zetterberg ◽

Nicholas James Ashton

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Down Syndrome ◽

Amyloid Β ◽

Detection Methods ◽

Blood Biomarkers ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Positron Emission ◽

Diagnosis Of Dementia

Epidemiological evidence suggests that by the age of 40 years, all individuals with Down syndrome (DS) have Alzheimer’s disease (AD) neuropathology. Clinical diagnosis of dementia by cognitive assessment is complex in these patients due to the pre-existing and varying intellectual disability, which may mask subtle declines in cognitive functioning. Cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers, although accurate, are expensive, invasive, and particularly challenging in such a vulnerable population. The advances in ultra-sensitive detection methods have highlighted blood biomarkers as a valuable and realistic tool for AD diagnosis. Studies with DS patients have proven the potential blood-based biomarkers for sporadic AD (amyloid-β, tau, phosphorylated tau, and neurofilament light chain) to be useful in this population. In addition, biomarkers related to other pathologies that could aggravate dementia progression—such as inflammatory dysregulation, energetic imbalance, or oxidative stress—have been explored. This review serves to provide a brief overview of the main findings from the limited neuroimaging and CSF studies, outline the current state of blood biomarkers to diagnose AD in patients with DS, discuss possible past limitations of the research, and suggest considerations for developing and validating blood-based biomarkers in the future.

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Comparison of Amyloid β and Tau Spread Models in Alzheimer’s Disease

Cerebral Cortex ◽

10.1093/cercor/bhy311 ◽

2018 ◽

Vol 29 (10) ◽

pp. 4291-4302 ◽

Cited By ~ 1

Author(s):

Hang-Rai Kim ◽

Peter Lee ◽

Sang Won Seo ◽

Jee Hoon Roh ◽

Minyoung Oh ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Large Scale ◽

Amyloid Β ◽

Brain Network ◽

Amyloid Positron Emission Tomography ◽

Local Spread ◽

Positron Emission ◽

Spread Model ◽

Graph Theoretical Approach

Abstract Tau and amyloid β (Aβ), 2 key pathogenic proteins in Alzheimer’s disease (AD), reportedly spread throughout the brain as the disease progresses. Models of how these pathogenic proteins spread from affected to unaffected areas had been proposed based on the observation that these proteins could transmit to other regions either through neural fibers (transneuronal spread model) or through extracellular space (local spread model). In this study, we modeled the spread of tau and Aβ using a graph theoretical approach based on resting-state functional magnetic resonance imaging. We tested whether these models predict the distribution of tau and Aβ in the brains of AD spectrum patients. To assess the models’ performance, we calculated spatial correlation between the model-predicted map and the actual map from tau and amyloid positron emission tomography. The transneuronal spread model predicted the distribution of tau and Aβ deposition with significantly higher accuracy than the local spread model. Compared with tau, the local spread model also predicted a comparable portion of Aβ deposition. These findings provide evidence of transneuronal spread of AD pathogenic proteins in a large-scale brain network and furthermore suggest different contributions of spread models for tau and Aβ in AD.

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Trait mindfulness is associated with less amyloid, tau, and cognitive decline in individuals at risk for Alzheimer's disease

10.1101/2021.05.17.21257320 ◽

2021 ◽

Author(s):

Cherie Strikwerda-Brown ◽

Hazal Ozlen ◽

Alexa Pichet Binette ◽

Marianne Chapleau ◽

Natalie Marchant ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

At Risk ◽

Cognitive Decline ◽

Protective Factor ◽

Present Moment ◽

Trait Mindfulness ◽

Cognitive Assessments ◽

Positron Emission

Mindfulness, defined as the ability to engage in non-judgmental awareness of the present moment, has been associated with an array of health benefits. Mindfulness may also represent a protective factor for Alzheimer's disease (AD). Here, we tested the potential protective effect of trait mindfulness on cognitive decline and AD pathology in older adults at risk of AD dementia. Measures of trait mindfulness, longitudinal cognitive assessments, and AB- and tau- positron emission tomography (PET) scans were collected in 261 nondemented older adults with a family history of AD dementia from the PREVENT-AD observational cohort study. Multivariate partial least squares analyses were used to examine relationships between combinations of different facets of trait mindfulness and (1) cognitive decline, (2) AB, and (3) tau. Higher levels of trait mindfulness, particularly mindful nonjudgment, were associated with less cognitive decline, AB, and tau. Trait mindfulness may represent a psychological protective factor for AD dementia.

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Positron Emission Tomography in at Risk Patients and in the Progression of Mild Cognitive Impairment to Alzheimer's Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-2010-1224 ◽

2010 ◽

Vol 19 (1) ◽

pp. 291-300 ◽

Cited By ~ 12

Author(s):

Juha O. Rinne ◽

Kjell Någren

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Positron Emission Tomography ◽

At Risk ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Emission Tomography ◽

Positron Emission ◽

Risk Patients

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Patterns of Compensation and Vulnerability in Normal Subjects at Risk of Alzheimer's Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-2012-129015 ◽

2012 ◽

Vol 33 (s1) ◽

pp. S427-S438 ◽

Cited By ~ 3

Author(s):

Oscar L. Lopez ◽

James T. Becker ◽

Lewis H. Kuller

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

At Risk ◽

Normal Subjects

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The Trajectory of Cerebrospinal Fluid Growth-Associated Protein 43 in the Alzheimer’s Disease Continuum: A Longitudinal Study

Journal of Alzheimer s Disease ◽

10.3233/jad-215456 ◽

2021 ◽

pp. 1-12

Author(s):

Heng Zhang ◽

Diyang Lyu ◽

Jianping Jia ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Amyloid Β ◽

Dementia Patients ◽

Positron Emission ◽

Potential Biomarker ◽

Synaptic Degeneration ◽

Over Time

Background: Synaptic degeneration has been suggested as an early pathological event that strongly correlates with severity of dementia in Alzheimer’s disease (AD). However, changes in longitudinal cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) as a synaptic biomarker in the AD continuum remain unclear. Objective: To assess the trajectory of CSF GAP-43 with AD progression and its association with other AD hallmarks. Methods: CSF GAP-43 was analyzed in 788 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 246 cognitively normal (CN) individuals, 415 individuals with mild cognitive impairment (MCI), and 127 with AD dementia based on cognitive assessments. The associations between a multimodal classification scheme with amyloid-β (Aβ), tau, and neurodegeneration, and changes in CSF GAP-43 over time were also analyzed. Results: CSF GAP-43 levels were increased at baseline in MCI and dementia patients, and increased significantly over time in the preclinical (Aβ-positive CN), prodromal (Aβ-positive MCI), and dementia (Aβ-positive dementia) stages of AD. Higher levels of CSF GAP-43 were also associated with higher CSF phosphorylated tau (p-tau) and total tau (t-tau), cerebral amyloid deposition and hypometabolism on positron emission tomography, the hippocampus and middle temporal atrophy, and cognitive performance deterioration at baseline and follow-up. Furthermore, CSF GAP-43 may assist in effectively predicting the probability of dementia onset at 2- or 4-year follow-up. Conclusion: CSF GAP-43 can be used as a potential biomarker associated with synaptic degeneration in subjects with AD; it may also be useful for tracking the disease progression and for monitoring the effects of clinical trials.

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Neurophysiological signatures in Alzheimer’s disease are distinctly associated with TAU, amyloid-β accumulation, and cognitive decline

Science Translational Medicine ◽

10.1126/scitranslmed.aaz4069 ◽

2020 ◽

Vol 12 (534) ◽

pp. eaaz4069 ◽

Cited By ~ 5

Author(s):

Kamalini G. Ranasinghe ◽

Jungho Cha ◽

Leonardo Iaccarino ◽

Leighton B. Hinkley ◽

Alexander J. Beagle ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Amyloid Β ◽

Tracer Uptake ◽

Therapeutic Approaches ◽

Regional Patterns ◽

Positron Emission ◽

Network Synchrony ◽

Network Disruptions

Neural synchrony is intricately balanced in the normal resting brain but becomes altered in Alzheimer’s disease (AD). To determine the neurophysiological manifestations associated with molecular biomarkers of AD neuropathology, in patients with AD, we used magnetoencephalographic imaging (MEGI) and positron emission tomography with amyloid-beta (Aβ) and TAU tracers. We found that alpha oscillations (8 to 12 Hz) were hyposynchronous in occipital and posterior temporoparietal cortices, whereas delta-theta oscillations (2 to 8 Hz) were hypersynchronous in frontal and anterior temporoparietal cortices, in patients with AD compared to age-matched controls. Regional patterns of alpha hyposynchrony were unique in each neurobehavioral phenotype of AD, whereas the regional patterns of delta-theta hypersynchrony were similar across the phenotypes. Alpha hyposynchrony strongly colocalized with TAU deposition and was modulated by the degree of TAU tracer uptake. In contrast, delta-theta hypersynchrony colocalized with both TAU and Aβ depositions and was modulated by both TAU and Aβ tracer uptake. Furthermore, alpha hyposynchrony but not delta-theta hypersynchrony was correlated with the degree of global cognitive dysfunction in patients with AD. The current study demonstrates frequency-specific neurophysiological signatures of AD pathophysiology and suggests that neurophysiological measures from MEGI are sensitive indices of network disruptions mediated by TAU and Aβ and associated cognitive decline. These findings facilitate the pursuit of novel therapeutic approaches toward normalizing network synchrony in AD.

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Associations of Neprilysin Activity in CSF with Biomarkers for Alzheimer’s Disease

Neurodegenerative Diseases ◽

10.1159/000500811 ◽

2019 ◽

Vol 19 (1) ◽

pp. 43-50 ◽

Cited By ~ 1

Author(s):

Timo Grimmer ◽

Oliver Goldhardt ◽

Igor Yakushev ◽

Marion Ortner ◽

Christian Sorg ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fdg Pet ◽

Amyloid Β ◽

Neuronal Injury ◽

Pittsburgh Compound B ◽

Positron Emission ◽

Amyloid Load ◽

Alzheimer’S Pathology

Background: Neprilysin (NEP) cleaves amyloid-β 1–42 (Aβ42) in the brain. Hence, we aimed to elucidate the effect of NEP on Aβ42 in cerebrospinal fluid (CSF) and on in vivo brain amyloid load using amyloid positron emission tomography (PET) with [11C]PiB (Pittsburgh compound B). In addition, associations with the biomarkers for neuronal injury, CSF-tau and FDG-PET, were investigated. Methods: Associations were calculated using global and voxel-based (SPM8) linear regression analyses in the same cohort of 23 highly characterized Alzheimer’s disease patients. Results: CSF-NEP was significantly inversely associated with CSF-Aβ42 and positively with the extent of neuronal injury as measured by CSF-tau and FDG-PET. Conclusions: Our results on CSF-NEP are compatible with the assumption that local degradation, amongst other mechanisms of amyloid clearance, plays a role in the development of Alzheimer’s pathology. In addition, CSF-NEP is associated with the extent and the rate of neurodegeneration.

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Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease

Nature Communications ◽

10.1038/s41467-020-15436-0 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 30

Author(s):

Shorena Janelidze ◽

Erik Stomrud ◽

Ruben Smith ◽

Sebastian Palmqvist ◽

Niklas Mattsson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Amyloid Β ◽

Pet Tracer ◽

Positron Emission ◽

Diagnostic Work ◽

Work Up ◽

The Brain ◽

Better Than

AbstractCerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [18F]flortaucipir, and more accurately identifies individuals with abnormally increased [18F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with [18F]flortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-β burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [18F]flortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.

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