Increasing Precision of Clinical Diagnosis of Alzheimer's Disease Using a Combined Algorithm Incorporating Clinical and Novel Biomarker Data

Sabbagh, Marwan N.; Lue, Lih‐Fen; Fayard, Daniel; Shi, Jiong

doi:10.1007/s40120-017-0069-5

Cited by 85 publications

(51 citation statements)

References 54 publications

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“…This study has several limitations. First, our causal estimates may be affected by several factors; horizontal pleiotropy, which was not detected by the applied MR sensitivity analysis methods 71 , and the possibility of misclassified LOAD cases 72, 73 . Unlike the balanced or positive bias induced by horizontal pleiotropy, the misclassified cases in the outcome may lead our results toward null.…”

Section: Discussionmentioning

confidence: 99%

Causal relationship of cerebrospinal fluid biomarkers with the risk of Alzheimer’s disease: A two-sample Mendelian randomization study

Kim

Nho

et al. 2019

Preprint

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Whether the epidemiological association of amyloid beta (Aβ) and tau pathology with Alzheimer's disease (AD) is causal remains unclear. The recent failures to demonstrate the efficacy of several amyloid beta-modifying drugs may indicate the possibility that the observed association is not causal. These failures also led to efforts to develop tau-directed treatments whose efficacy is still tentative. Herein, we conducted a two-sample Mendelian randomization analysis to determine whether the relationship between the cerebrospinal fluid (CSF) biomarkers for amyloid and tau pathology and the risk of AD is causal. We used the summary statistics of a genome-wide association study (GWAS) for CSF biomarkers (Aβ 1-42 , phosphorylated tau 181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for late-onset AD (LOAD) in 21,982 LOAD cases and 41,944 cognitively normal controls. We tested the association between the change in the genetically predicted CSF biomarkers and LOAD risk.We found a modest decrease in the LOAD risk per one standard deviation (SD) increase in the genetically predicted CSF Aβ (odds ratio [OR], 0.63 for AD; 95% confidence interval[CI], 0.38-0.87; P = 0.02). In contrast, we observed a significant increase in the LOAD risk per one SD increase in the genetically predicted CSF p-tau (OR, 2.37; 95% CI, 1.46-3.28; P = 1.09×10 -5 ). However, no causal association was observed of the CSF t-tau with the LOAD risk (OR, 1.15; 95% CI, 0.85-1.45; P = 0.29). Our findings need to be validated in future studies with more genetic variants identified in larger GWASs for CSF biomarkers.Alzheimer's disease (AD), a leading cause of dementia, is the largest burden source of morbidity and mortality in older adults. One in every 85 individuals is expected to develop AD, which means that delaying the onset by one year can reduce the number of patients with AD worldwide up to 9 million by 2020 1 . Given that eightfold as many individuals have preclinical AD at risk of progression 2 , the development of disease-modifying therapies is urgently required. Amyloid beta (Aβ) peptides are transmembrane amyloid precursor proteins 3 and tau is a microtubule-associated protein 4 . Decades of research have accumulated the evidence on the pathophysiology of Aβ and tau proteins that independently form plaques and tangles and lead normal functional neurons into a disabled state, AD 5 . Understanding AD as the result of abnormal proteins, extracellular amyloid plaques, and intraneuronal neurofibrillary tau tangles, two-thirds of the novel treatment pipelines aim at diseasemodifying therapies, 90% of which are anti-amyloid and anti-tau protein agents 6 .However, numerous trials to develop novel therapies targeting the amyloid plaques to modify the disease progress recently turned out failures. These failures could bring a reasonable doubt about the role of Aβ in the pathophysiology of AD with delicate elaboration 7 . One possible explanation of the failure of clinical trials targeting the amyloid plaques is that the intervention is perfor...

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Section: Discussionmentioning

confidence: 99%

Causal relationship of cerebrospinal fluid biomarkers with the risk of Alzheimer’s disease: A two-sample Mendelian randomization study

Kim

Nho

et al. 2019

Preprint

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“…In this scenario, the most-common types of neuroimaging techniques used to diagnose AD are single photon emission computed tomography (SPECT), positron emission tomography (PET), 4 and magnetic resonance imaging (MRI). 5,6 Although the former two need the administration of a radioactive imaging agents into a patient, the latter, despite being noninvasive, is quite expensive and cannot detect early stages of the disease when development starts long before any noticeable decrease in hippocampal volume or deposition of plaques and tau tangles 7,8 ). Therefore, the search for new and reliable possible biomarkers in AD is still an open and widely investigated field.…”

Section: Alzheimer's Disease: Early Diagnosis and Cure Wantedmentioning

confidence: 99%

“…Unfortunately, if diagnosis is exclusively based on cognitive tests, then it cannot easily distinguish AD from mild cognitive impairment or normal aging, and thus the need for neuroimaging arises. In this scenario, the most‐common types of neuroimaging techniques used to diagnose AD are single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance imaging (MRI) . Although the former two need the administration of a radioactive imaging agents into a patient, the latter, despite being noninvasive, is quite expensive and cannot detect early stages of the disease when development starts long before any noticeable decrease in hippocampal volume or deposition of plaques and tau tangles).…”

Section: Introductionmentioning

confidence: 99%

Mass spectrometry is a multifaceted weapon to be used in the battle against Alzheimer's disease: Amyloid beta peptides and beyond

Grasso

2018

Mass Spectrometry Reviews

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Amyloid-β peptide (Aβ) accumulation and aggregation have been considered for many years the main cause of Alzheimer's disease (AD), and therefore have been the principal target of investigation as well as of the proposed therapeutic approaches (Grasso [2011] Mass Spectrom Rev. 30: 347-365). However, the amyloid cascade hypothesis, which considers Aβ accumulation the only causative agent of the disease, has proven to be incomplete if not wrong. In recent years, actors such as metal ions, oxidative stress, and other cofactors have been proposed as possible co-agents or, in some cases, main causative factors of AD. In this scenario, MS investigation has proven to be fundamental to design possible diagnostic strategies of this elusive disease, as well as to understand the biomolecular mechanisms involved, in the attempt to find a possible therapeutic solution. We review the current applications of MS in the search for possible Aβ biomarkers of AD to help the diagnosis of the disease. Recent examples of the important contributions that MS has given to prove or build theories on the molecular pathways involved with such terrible disease are also reviewed.

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“…More recently there has been a shift to look at pathologic tau in the progression of AD. It is the location and amount of tau found on autopsy in AD subjects that correlates best with stage and severity of symptomatology, not the amyloid plaque [14]. As far back as 1963, such tangles were noted to be composed of filaments with a diameter of approximately 10 nm that have come to be known as paired helical filaments (PHF) [15].…”

Section: Current Understanding Of Admentioning

confidence: 99%

Role of Tau Acetylation in Alzheimer’s Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment

et al. 2017

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Progressive neurodegenerative diseases plague millions of individuals both in the United States and across the world. The current pathology of progressive neurodegenerative tauopathies, such as Alzheimer's disease (AD), Pick's disease, frontotemporal dementia (FTD), and progressive supranuclear palsy, primarily revolves around phosphorylation and hyperphosphorylation of the tau protein. However, more recent evidence suggests acetylation of tau protein at lysine 280 may be a critical step in molecular pathology of these neurodegenerative diseases prior to the tau hyperphosphorylation. Secondary injury cascades such as oxidative stress, endoplasmic reticulum stress, and neuroinflammation contribute to lasting damage within the brain and can be induced by a number of different risk factors. These injury cascades funnel into a common pathway of early tau acetylation, which may serve as the catalyst for progressive degeneration. The post translational modification of tau can result in production of toxic oligomers, contributing to reduced solubility as well as aggregation and formation of neurofibrillary tangles, the hallmark of AD pathology. Chronic Traumatic Encephalopathy (CTE), caused by repetitive brain trauma is also associated with a hyperphosphorylation of tau. We postulated acetylation of tau at lysine 280 in CTE disease could be present prior to the hyperphosphorylation and tested this hypothesis in CTE pathologic specimens. We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first "triggering" event leading to neuronal loss. To the best of our knowledge, this is the first study to identify acetylation of the tau protein in CTE. Prevention of tau acetylation could possibly serve as a novel target for stopping neurodegeneration before it fully begins. In this study, we highlight what is known about tau acetylation and neurodegeneration.

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Increasing Precision of Clinical Diagnosis of Alzheimer's Disease Using a Combined Algorithm Incorporating Clinical and Novel Biomarker Data

Cited by 85 publications

References 54 publications

Causal relationship of cerebrospinal fluid biomarkers with the risk of Alzheimer’s disease: A two-sample Mendelian randomization study

Causal relationship of cerebrospinal fluid biomarkers with the risk of Alzheimer’s disease: A two-sample Mendelian randomization study

Mass spectrometry is a multifaceted weapon to be used in the battle against Alzheimer's disease: Amyloid beta peptides and beyond

Role of Tau Acetylation in Alzheimer’s Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment

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