Extracellular neuritic plaques composed of amyloid‑β (Aβ) protein and intracellular neurofibrillary tangles containing phosphorylated tau protein are the two hallmark proteins of Alzheimer's disease (AD), and the separate neurotoxicity of these proteins in AD has been extensively studied. However, interventions that target Aβ or tau individually have not yielded substantial breakthroughs. The interest in the interactions between Aβ and tau in AD is increasing, but related drug investigations are in their infancy. This review discusses how Aβ accelerates tau phosphorylation and the possible mechanisms and pathways by which tau mediates Aβ toxicity. This review also describes the possible synergistic effects between Aβ and tau on microglial cells and astrocytes. Studies suggest that the coexistence of Aβ plaques and phosphorylated tau is related to the mechanism by which Aβ facilitates the propagation of tau aggregation in neuritic plaques. The interactions between Aβ and tau mediate cognitive dysfunction in patients with AD. In summary, this review summarizes recent data on the interplay between Aβ and tau to promote a better understanding of the roles of these proteins in the pathological process of AD and provide new insights into interventions against AD.

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Interaction between Aβ and Tau in the Pathogenesis of Alzheimer's Disease.

Introduction Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a "Holy Grail" of AD research and intensively sought; however, there are no well-established plasma markers. Methods A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. Results Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOe4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). Discussion Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation.

/pdf/inflammatory-biomarkers-in-alzheimer-s-disease-plasma-3wiyh1tre0.pdf

Inflammatory biomarkers in Alzheimer's disease plasma

Introduction Blood-based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. Methods We investigated whether plasma concentrations of the Aβ 1–40 /Aβ 1–42 ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain Aβ positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-a-priori hypothesis study using machine learning. Results The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma Aβ 1–40 /Aβ 1–42 ratio. The accuracy is not affected by the apolipoprotein E ( APOE ) e4 allele, sex, or age. Discussion Our results encourage an independent validation cohort study to confirm the indication that the plasma Aβ 1–40 /Aβ 1–42 ratio, assessed via Simoa, may improve future standard of care and clinical trial design.

/pdf/plasma-amyloid-b-40-42-ratio-predicts-cerebral-amyloidosis-3kfu2pzz8e.pdf

Plasma amyloid β 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease.

Introduction Understanding the biological mechanism of subjective cognitive decline (SCD) in preclinical Alzheimer’s disease (AD) and identifying those who will soon convert to mild cognitive impairment (MCI) are critical for developing appropriate strategies for early diagnosis and intervention of AD. We present the study protocol of the Sino Longitudinal Study on Cognitive Decline (SILCODE), a longitudinal observational study focusing on SCD in the context of AD. Methods and analysis Within SILCODE, approximately 800 subjects with SCD who are between 50 and 79 years old will be recruited through standardised public advertisements or memory clinics. They will undergo extensive assessment, including clinical and neuropsychological assessments, blood sample collection for plasma beta-amyloid and ApoE genotype, urine samples collection for AD7c-NTP, and multimodal MRI scans (structural MRI, diffusion tensor imaging, resting-state functional MRI and optional task-based functional MRI) as well as optional glucose metabolism and amyloid positron emission tomography. Subjects will be contacted by telephone every 3 months and interviewed, on average, every 15 months for 5 years. The study endpoint is the development of mild cognitive impairment or dementia. Jak & Bondi’s actuarial neuropsychological method will be used for diagnosis of MCI. The least absolute shrinkage and selection operator logistic regression model followed by the sub-distribution hazard function model with death as a competing risk will be constructed to establish risk prediction models. Ethics and dissemination The ethics committee of the Xuanwu Hospital of Capital Medical University has approved this study protocol (ID: [2017]046). The results will be published in peer-reviewed journals and presented at national and international scientific conferences. Trial registration number NCT03370744; Pre-results.

pdf/sino-longitudinal-study-on-cognitive-decline-silcode-4plmiey5el.pdf

Sino Longitudinal Study on Cognitive Decline (SILCODE): protocol for a Chinese longitudinal observational study to develop risk prediction models of conversion to mild cognitive impairment in individuals with subjective cognitive decline.

Plasma amyloid beta levels are associated with cerebral amyloid and tau deposition

Introduction Diagnostic relevance of plasma amyloid β (Aβ) for Alzheimer's disease (AD) process yields conflicting results. The objective of the study was to assess plasma levels of Aβ 42 and Aβ 40 in amnestic mild cognitive impairment (MCI), nonamnestic MCI, and AD patients and to investigate relationships between peripheral and central biomarkers. Methods One thousand forty participants (417 amnestic MCI, 122 nonamnestic MCI, and 501 AD) from the Biomarker of AmyLoid pepTide and AlZheimer's diseAse Risk multicenter prospective study with cognition, plasma, cerebrospinal fluid (CSF), and magnetic resonance imaging assessments were included. Results Plasma Aβ 1–42 and Aβ 1–40 were lower in AD (36.9 [11.7] and 263 [80] pg/mL) than in amnestic MCI (38.2 [11.9] and 269 [68] pg/mL) than in nonamnestic MCI (39.7 [10.5] and 272 [52] pg/mL), respectively ( P  = .01 for overall difference between groups for Aβ 1–42 and P  = .04 for Aβ 1–40 ). Globally, plasma Aβ 1–42 correlated with age, Mini–Mental State Examination, and APOE  e4 allele. Plasma Aβ 1–42 correlated with all CSF biomarkers in MCI but only with CSF Aβ 42 in AD. Discussion Plasma Aβ was associated with cognitive status and CSF biomarkers, suggesting the interest of plasma amyloid biomarkers for diagnosis purpose.

Plasma amyloid levels within the Alzheimer's process and correlations with central biomarkers.

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Plasma amyloid levels within the Alzheimer's process and correlations with central biomarkers.