Generalizability of Alzheimer’s disease plasma biomarkers phospho‐Tau and beta amyloid in individuals of diverse genetic ancestries
Anthony J. GriswoldFarid RajabliTianjie GuJamie ArvizuC. GolightlyPatrice L. WhiteheadKara L. Hamilton‐NelsonLarry D. AdamsKatrina CelisKatrina CelisJosé Javier SánchezPedro MenaTakiyah D. StarksMaryenela Illanes‐ManriqueConcepcion Silva‐VergaraMichael L. CuccaroJeffery M. VanceBriseida E. Feliciano‐AstacioMario Cornejo‐OlivasGoldie S. ByrdGary W. BeechamJonathan L. HainesMargaret A Pericak‐Vance
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Abstract Background Plasma concentrations of phosphorylated threonine‐181 of Tau (pTau181) and the ratio of amyloid beta isoforms Aβ42/Aβ40 are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). However, assessment of the utility of these biomarkers has been in non‐Hispanic, European individuals. Given differences in AD risk across populations, generalizability of these findings is not assured in individuals of diverse ancestries. Here we evaluate the levels of plasma pTau181 and Aβ42/Aβ40 and assess their utility in discriminating clinically diagnosed AD from cognitively unimpaired (CU), age‐matched controls in ancestrally diverse, admixed cohorts. Method We measured pTau181 and Aβ42/Aβ40 with Simoa chemistry using the pTau181 AdvantageV2 and NEUROLOGY 3‐PLEX A assays, respectively. Our cohorts consisted of: 923 African Americans (319 AD, 604 CU), 149 Peruvians (49 AD, 100 CU), and 667 Caribbean Hispanics (613 Puerto Ricans (288 AD, 325 CU) and 54 Cubans (24 AD, 30 CI)). Linear mixed‐effect regression models adjusted for age, sex, population substructure and relatedness followed by Bonferroni correction was applied to identify biomarker differences. Diagnostic performance and receiver operator characteristic (ROC) curves were created from logistic regression models. Result Plasma pTau181 concentrations did not differ across any of the cohorts within AD or CU. There was a clear elevation of pTau181 concentration in AD compared to CU (p < 1.7x10 ‐13 ) taking into account all individuals and in each cohort separately (African Americans, p =1.9x10 ‐8 ; Caribbean Hispanics, p=3.1x10 ‐7 ; Peruvians, p=0.05). There was no significant difference in the plasma Aβ42/Aβ40 ratio, however there was a trend towards a decreasing ratio in AD. Using the area under the ROC, pTau181 was more accurate at predicting status than the Aβ42/Aβ40 ratio, but the classification improved when both biomarkers were combined. Conclusion These results suggest AD biomarkers are generalizable across ancestries, with baseline values being consistent across diverse populations. Ultimately, combining genomic, biomarker, and social and environmental data from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses in individuals of diverse ancestries.Keywords:
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Adults with Down syndrome (DS) are predisposed to Alzheimer's disease (AD) and reveal early amyloid beta (Aβ) pathology in the brain. Positron emission tomography (PET) provides an in vivo measure of Aβ throughout the AD continuum. Due to the high prevalence of AD in DS, there is need for longitudinal imaging studies of Aβ to better characterize the natural history of Aβ accumulation, which will aid in the staging of this population for clinical trials aimed at AD treatment and prevention.Adults with DS (N = 79; Mean age (SD) = 42.7 (7.28) years) underwent longitudinal [C-11]Pittsburgh compound B (PiB) PET. Global Aβ burden was quantified using the amyloid load metric (AβL). Modeled PiB images were generated from the longitudinal AβL data to visualize which regions are most susceptible to Aβ accumulation in DS. AβL change was evaluated across Aβ(-), Aβ-converter, and Aβ(+) groups to assess longitudinal Aβ trajectories during different stages of AD-pathology progression. AβL change values were used to identify Aβ-accumulators within the Aβ(-) group prior to reaching the Aβ(+) threshold (previously reported as 20 AβL) which would have resulted in an Aβ-converter classification. With knowledge of trajectories of Aβ(-) accumulators, a new cutoff of Aβ(+) was derived to better identify subthreshold Aβ accumulation in DS. Estimated sample sizes necessary to detect a 25% reduction in annual Aβ change with 80% power (alpha 0.01) were determined for different groups of Aβ-status.Modeled PiB images revealed the striatum, parietal cortex and precuneus as the regions with earliest detected Aβ accumulation in DS. The Aβ(-) group had a mean AβL change of 0.38 (0.58) AβL/year, while the Aβ-converter and Aβ(+) groups had change of 2.26 (0.66) and 3.16 (1.34) AβL/year, respectively. Within the Aβ(-) group, Aβ-accumulators showed no significant difference in AβL change values when compared to Aβ-converter and Aβ(+) groups. An Aβ(+) cutoff for subthreshold Aβ accumulation was derived as 13.3 AβL. The estimated sample size necessary to detect a 25% reduction in Aβ was 79 for Aβ(-) accumulators and 59 for the Aβ-converter/Aβ(+) group in DS.Longitudinal AβL changes were capable of distinguishing Aβ accumulators from non-accumulators in DS. Longitudinal imaging allowed for identification of subthreshold Aβ accumulation in DS during the earliest stages of AD-pathology progression. Detection of active Aβ deposition evidenced by subthreshold accumulation with longitudinal imaging can identify DS individuals at risk for AD development at an earlier stage.
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Injection of amyloid-beta peptide (Aβ 1-42) into hippocampal and cortical regions of brain may have utility as an animal model of Alzheimers disease (AD) emphasizing the inflammatory component of disease pathology. This review summarizes recent evidence supporting the relevance of the peptide injection model to describe inflammatory conditions in AD brain. A wide spectrum of responses are considered from effects of Aβ 1-42 on animal behavior and cognitive performance to peptide actions at the cellular and molecular levels. In the latter case a particular focus is placed on inflammatory responses mediated by activated microglia. Specific pharmacological modulations of microglial signaling pathways and factors and how they shape patterns of inflammatory reactivity in peptide-injected brain are included. Overall, the considerations for the validity and limitations of Aβ 1-42 injection as an animal model for AD pathology are also discussed. Keywords: Alzheimer's disease, amyloid-β peptide (Aβ1 - 4 2 ), Aβ1, –, 4 2 injection animal model, inflammatory reactivity, pharmacological modulations
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The Alzheimer A beta amyloid peptide (A beta) is the principal proteinaceous component of amyloid associated with Alzheimer disease (AD). We have determined the relative abundance of A beta structural variants present in amyloid from brains of 10 individuals with sporadic AD, 2 individuals with familial AD carrying specific mutations in the Alzheimer amyloid precursor protein gene, and 5 nondemented elderly controls. A procedure of isolation based on the extreme insolubility of A beta amyloid was used. The purified, nondigested A beta was analyzed by N-terminal sequencing and electrospray-ionization mass spectrometry. Three principal A beta variants were detected--A beta-(1-40), A beta-(1-42), and A beta-(11-42)--in all brains analyzed. The predominant variant in sporadic AD was A beta-(1-40), whereas the principal A beta variant in nondemented elderly controls was A beta-(1-42). The ratio A beta-(1-40)/A beta-(1-42) differed by 10-fold between brains from nondemented controls and those with sporadic AD.
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As a well-known common neurodegenerative disease in aging, Alzheimers disease will cause the loss of the ability to talk, cognization and memorize. Amyloid beta is considered to be a major cause of Alzheimers disease. It will form many different types and accumulate in human brain and cause Alzheimers disease. However, a recent report about the plagiarism of the fundamental paper of this theory makes many people think that our research direction on Alzheimers disease is wrong. The author agrees that the plagiarism of the paper is terrible and should be punished, but the author does not think that this will waste everything we have done about amyloid beta. Amyloid beta is still a major reason that causes Alzheimers disease and find a way to stop the accumulation of amyloid beta in brain is a feasible way to cure Alzheimers disease. Research on the role of amyloid beta in Alzheimers disease, whether it is a major cause is the major purpose of the essay. Whats more a new method that aim to reduce amyloid beta in brain to cure and relief Alzheimers disease will be introduced in this article. This method aims to stop the signal transduction of amyloid beta to neuron cells, thus, stop amyloid beta from damaging our brain and cause Alzheimers disease. The reason this article is written is to confirm the importance of amyloid beta for Alzheimers disease. In addition, introduce a new cure method. Since this method is new, conclude the advantages and disadvantages of this method could inspire other researchers, and improve the performance of the drugs developed based on this method to reach the final goal, which is cure the Alzheimers disease.
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Article abstract-We measured plasma levels of amyloid beta protein (A beta) ending at positions 40 (A beta 40) and 42(43) [A beta 42(43)] in six carriers of beta APP717 (Val to Ile) mutation linked to familial Alzheimer9s disease (FAD) as well as in patients with sporadic AD (sAD) and controls. The percentage and the level of A beta 42(43) were significantly higher in carriers of beta APP717 mutation relative to sAD, whereas A beta 40 levels were decreased. In contrast, A beta levels and ratios were at similar levels in sAD, regardless of the stage of the disease, compared with non-AD neurologic disease controls and nondemented control individuals. These results suggest that the reported increase in the percentage of A beta 42(43) secretion in transfected cells with beta APP717 mutant genes actually takes place in the bodies of carriers of beta APP717 mutation, and that plasma A beta could be used as an indicator of the alterations of beta APP/A beta metabolism in subtypes of AD. NEUROLOGY 1997;48: 741-745
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The deposition of beta-amyloid is inducible in the brains of susceptible hosts by seeds consisting of aggregated beta-amyloid. Current evidence favors the view that the corruptive templating of beta-amyloid is similar to the process by which prions convey their pathogenic structural features to naïve prion protein molecules. In Alzheimer's disease, the proteinaceous lesions appear to arise endogenously and then spread systematically to other brain areas. beta-amyloid seeds thus are a potential vector for the amplification of proteinaceous aggregates in vivo. The cellular mechanisms by which beta-amyloid seeds travel from one place to another remain poorly understood. Using an established exogenous seeding paradigm, beta-amyloid-rich brain extracts were infused into the hippocampal formation or neocortex of APP-transgenic rodents. The temporal and spatial disposition of the seeds and of the subsequently induced deposits were analyzed. The local pattern of exogenously seeded beta-amyloid deposition is governed to a considerable extent by simple diffusion of the injected brain extract. When beta-amyloid deposition is focally induced by beta-amyloid seeds in one brain region, other areas are subsequently beset by beta-amyloid aggregates. The secondarily affected areas contain extracellular deposits (which generally emerge systematically in axonally interconnected regions) and/or vascular deposits (cerebral amyloid angiopathy). Beta-amyloid deposition can be seeded in the brains of transgenic rodents by beta-amyloid-rich brain extracts. Once the seeding of beta-amyloid has been initiated, cellular (and possibly vascular) mechanisms promote the continued ramification of beta-amyloid aggregation at distal sites. Key Collaborators: Amarallys Cintron, Rebecca Rosen, Harry LeVine III, and Mathias Jucker and colleagues in Tübingen, Germany.
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