Blood Aβ Research Articles

Biomarkers as Endpoints in Clinical Trials for Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease that imposes economic and societal burden. Biomarkers have played a crucial role in the recent approval of aducanumab and lecanemab as disease-modifying therapies which marked a significant milestone for the treatment of AD. The inclusion of biomarkers in AD trials facilitates precise diagnosis, monitors safety, demonstrates target engagement, and supports disease modification. This study analyzed the utilization state and trends of biomarkers as endpoints in AD trials. In this retrospective study, trials were collected by searching clinicaltrials.gov using the term "Alzheimer". Primary and secondary outcomes were analyzed separately for each phase. Among the 1,048 analyzed trials, 313 (29.87%) adopted biomarkers as primary endpoints and 364 (34.73%) as secondary endpoints, mainly in phases 1 and 2. The top three biomarkers adopted as primary endpoints in phases 1, 2, and 3 were amyloid-PET, tau-PET, and MRI. The top three biomarkers adopted as secondary endpoints, in phase 1, were cerebrospinal fluid (CSF) amyloid-β (Aβ), blood Aβ and amyloid-PET; in phase 2, they were MRI, CSF Aβ, and CSF phospho-tau; and in phase 3, they were amyloid PET, MRI, and blood Aβ. There was a statistically significant increase in the adoption of biomarkers as primary endpoints in phase 2 trials (p = 0.001) and secondary endpoints in phase 3 trials (p = 0.001). The growing recognition of the importance of biomarkers in AD trial' design and drug development is evident by the significant steady increase in biomarkers' utilization in phases 2 and 3.

Subsequent correlated changes in complement component 3 and amyloid beta oligomers in the blood of patients with Alzheimer's disease.

Alzheimer's disease (AD) involves the complement cascade, with complement component 3 (C3) playing a key role. However, the relationship between C3 and amyloid beta (Aβ) in blood is limited. Plasma C3 and Aβ oligomerization tendency (AβOt) were measured in 35 AD patients and 62 healthy controls. Correlations with cerebrospinal fluid (CSF) biomarkers, cognitive impairment, and amyloid positron emission tomography (PET) were analyzed. Differences between biomarkers were compared in groups classified by concordances of biomarkers. Plasma C3 and AβOt were elevated in AD patients and in CSF or amyloid PET-positive groups. Weak positive correlation was found between C3 and AβOt, while both had strong negative correlations with CSF Aβ42 and cognitive performance. Abnormalities were observed for AβOt and CSF Aβ42 followed by C3 changes. Increased plasma C3 in AD are associated with amyloid pathology, possibly reflecting a defense response for Aβ clearance. Further studies on Aβ-binding proteins will enhance understanding of Aβ mechanisms in blood.

Associations between Alzheimer's disease biomarkers and postoperative delirium or cognitive dysfunction: A meta-analysis and trial sequential analysis of prospective clinical trials.

The relationship between Alzheimer's disease biomarkers and postoperative complications, such as postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), remains a subject of ongoing debate. This meta-analysis aimed to determine whether there is an association between perioperative Alzheimer's disease biomarkers and postoperative complications. We conducted a meta-analysis of observational clinical studies that explored the correlation between Alzheimer's disease biomarkers and POD or POCD in patients who have undergone surgery, following PRISMA guidelines. The protocol was previously published (INPLASY: INPLASY202350001). A comprehensive search was conducted across PubMed, Embase, Web of Science, and Cochrane databases until March 2023. Surgical patients aged at least 18 years, studies focusing on POD or POCD, research involving Alzheimer's disease biomarkers, including Aβ or tau in blood or cerebrospinal fluid (CSF), and availability of the full text. Our meta-analysis included 15 studies: six focusing on POD and nine on POCD. The findings revealed a negative correlation between preoperative CSF β-amyloid 42 (Aβ42) levels and the onset of POD [mean difference -86.1, 95% confidence interval (CI), -114.15 to -58.05, I2 : 47%]; this association was strongly supported by trial sequential analysis (TSA). A similar negative correlation was discerned between preoperative CSF Aβ42 levels and the incidence of POCD (-165.01, 95% CI, -261.48 to -68.53, I2 : 95%). The TSA also provided robust evidence for this finding; however, the evidence remains insufficient to confirm a relationship between other Alzheimer's disease biomarkers [β-amyloid 40 (Aβ40), total tau (T-tau), phosphorylated tau (P-tau), and Aβ42/T-tau ratio] and POD or POCD. The study results indicate a negative correlation between preoperative CSF Aβ42 levels and the occurrence of both POD and POCD. Future investigations are warranted to identify the predictive cutoff value of preoperative CSF Aβ42 for POD and POCD.

Glymphatic function maintains sleep‐sensitive cognitive performance and predicts overnight changes in plasma amyloid β in humans

AbstractBackgroundDuring sleep, the glymphatic system facilitates rapid exchange of fluid through brain tissues, clearing solutes, including amyloid β (Aβ), tau, and α synuclein that accumulate through the course of waking activity. Glymphatic clearance is widely believed to underlie the restorative effects of sleep on cognition, and its impairment is proposed to reflect the biological basis for the corrosive effects of sleep disruption. We sought to determine if glymphatic function or sleep EEG predicted changes in cognitive performance and overnight differences in Aβ biomarker levels using a new non‐invasive investigational medical device (IMD) to measure glymphatic function by dynamic impedance spectro‐tomography.MethodEighteen healthy 50‐65 y/o participants were enrolled in a cross‐over randomized control clinical trial encompassing one night of sleep and one night of sleep deprivation. Participants were instrumented with the IMD and overnight change in brain parenchymal resistance to flow, R, was measured. Sleep EEG powerbands, slow (0.4‐1Hz), delta (1‐4Hz), beta (15‐30Hz), and time spent in N2, N3 and REM sleep were derived from the device EEG. In both sleep and sleep deprivation interventions, cognitive tests (symbol digit modality test, SDMT; psychomotor vigilance test, PVT) were administered at 7am and blood Aβ biomarkers (Aβ40; Aβ42) were taken at 10pm and 7am.ResultOvernight parenchymal resistance R predicted intraindividual paired differences (sleep – sleep deprivation) in cognitive test scores (A SDMT ρ = ‐0.65, p = 0.003; B PVT STD RT, ρ = 0.41, p = 0.095) and Aβ42 blood amyloid biomarker changes (C Aβ42 ρ = ‐0.53, p = 0.03; D Aβ40 ρ = ‐0.33, p = 0.21). Sleep EEG powerbands and time spent in N2, N3, and REM sleep were not predictive of sleep‐related changes in cognition or plasma Aβ biomarker levels.ConclusionGlymphatic function, measured continuously by dynamic impedance spectro‐tomography, predicted changes in the restorative effect of sleep on cognition and plasma Ab biomarker levels as hypothesized, but not previously demonstrated. In contrast, sleep EEG powerbands and time spent in N2, N3 and REM were not predictive. Detection of glymphatic impairment in real‐world settings may permit (i) early identification of individuals at‐risk for developing sleep‐related Alzheimer’s disease pathology, and (ii) enable precision targeted enhancement of glymphatic function to enhance glymphatic function and pathological protein clearance.

Allostatic load profiles of stress to predict Alzheimer’s disease: an accessible opportunity to identify risk at early stages

AbstractBackgroundAlzheimer’s disease (AD) can start decades before symptoms appear, yet detection at preclinical stages remains a challenge due to a lack of screening tools that are both accurate and accessible. The multi‐system Allostatic Load index (AL), a stress‐related marker of cumulative biological risk, is associated with β‐amyloid (Aβ), tau proteins, and hippocampal atrophy, potentially linking AL to AD. If this is correct, a low‐cost and readily accessible peripheral blood AL‐based screening tool can offer an opportunity to identify individuals at risk for AD in primary care facilities. Here, we determined the AL profiles that predict the conversion risk from mild cognitive impairment (MCI) to AD by 36 months before diagnosis and associated with hippocampus volume (HV) reduction.MethodsUsing the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, we analyzed longitudinal data from 385 older adults with MCI at baseline, 12, and 36 months. Blood neuroendocrine (cortisol, LH, prolactin, testosterone) and immunologic (C‐reactive protein,fibrinogen,IL‐13,IL‐16,IL‐18,IL‐3,IL‐6,MCP‐3,MCP4,TNF‐alpha,insulin‐like growth factor) stress‐related biomarkers obtained at baseline and 12 months were transformed into AL indexes to generate the following profiles: 1)Decreasing AL: high at baseline and decrease over 12‐months; 2)Increasing AL: low at baseline, increase; and 3)Sustained High AL: high at baseline, remain high or increase. The ADNI consensus diagnosis determined the AD conversion and brain MRI assessed HV. Models were adjusted for socioeconomic and APOE4 covariates.Results41.6% of participants with Sustained High AL converted to AD, while 27.9% with Decreasing profiles remained MCI (p = 0.01). Increasing AL showed higher conversion risk than Decreasing profile (OR: 3.96). Sustained High AL was associated with faster HV reduction (p = 0.04). AL and blood Aβ models were compared for prediction accuracy.ConclusionThe odds of converting to AD were almost four times higher among participants with Sustained High AL profiles with faster hippocampus reduction than Decreasing AL profiles, suggesting that elevated AL profiles might be a risk factor and a potential mechanism explaining MCI conversion to AD. These findings set the foundation for exploring accessible bio‐behavioral screening tools to sign risk in vulnerable individuals in primary care facilities and refer them to specialized clinics for timely intervention.

Antibody-Mediated Clearance of Brain Amyloid-β: Mechanisms of Action, Effects of Natural and Monoclonal Anti-Aβ Antibodies, and Downstream Effects.

Immunotherapeutic efforts to slow the clinical progression of Alzheimer's disease (AD) by lowering brain amyloid-β (Aβ) have included Aβ vaccination, intravenous immunoglobulin (IVIG) products, and anti-Aβ monoclonal antibodies. Neither Aβ vaccination nor IVIG slowed disease progression. Despite conflicting phase III results, the monoclonal antibody Aducanumab received Food and Drug Administration (FDA) approval for treatment of AD in June 2021. The only treatments unequivocally demonstrated to slow AD progression to date are the monoclonal antibodies Lecanemab and Donanemab. Lecanemab received FDA approval in January 2023 based on phase II results showing lowering of PET-detectable Aβ; phase III results released at that time indicated slowing of disease progression. Topline results released in May 2023 for Donanemab's phase III trial revealed that primary and secondary end points had been met. Antibody binding to Aβ facilitates its clearance from the brain via multiple mechanisms including promoting its microglial phagocytosis, activating complement, dissolving fibrillar Aβ, and binding of antibody-Aβ complexes to blood-brain barrier receptors. Antibody binding to Aβ in peripheral blood may also promote cerebral efflux of Aβ by a peripheral sink mechanism. According to the amyloid hypothesis, for Aβ targeting to slow AD progression, it must decrease downstream neuropathological processes including tau aggregation and phosphorylation and (possibly) inflammation and oxidative stress. This review discusses antibody-mediated mechanisms of Aβ clearance, findings in AD trials involving Aβ vaccination, IVIG, and anti-Aβ monoclonal antibodies, downstream effects reported in those trials, and approaches which might improve the Aβ-clearing ability of monoclonal antibodies.

Association of sleep disorders with clinical symptoms and age in Chinese older adult patients with and without cognitive decline.

To investigate correlation between cognitive function, age, and sleep disturbances. This retrospective clinical study enrolled 78 patients with sleep disorders who were divided into three groups: a group of 24 patients with sleep disorders accompanied by cognitive decline (SD-CD); 54 patients with sleep disorders and no cognitive decline (SD-nCD) was divided into two groups, one of 30 patients aged between 60 and 70 years and another of 24 patients aged >70 years. Polysomnography was used to record patients' sleep indicators throughout night; these included total sleep duration, sleep efficiency (SE), sleep latency, sleep structure and percentage of N1, N2, and N3 stages, rapid eye movement (REM) stage, as well as apnea hypopnea index (AHI), and oxygen saturation (OS). Analysis of variance (ANOVA) for continuous variables and chi-square test for categorical variables were used to analyze variables between different groups. Pearson's correlation was used to analyze correlation between sleep parameters and mini-mental state examination (MMSE). Blood samples were used to determine their Aβ, Aβ40, Aβ42, total tau, phosphorylated tau protein (ptau), ptau181, ptau217, the inflammatory factor IL-1β, vitamin B12 (VB12), and melatonin levels. In the SD-CD group, there was a significant decrease in SE and an increase in N1 stage sleep in older patients and a significant increase in AHI, REM stage AHI, and non-REM stage AHI. In patients with SD-nCD, the minimum OS, minimum OS in the REM period, and minimum OS in the non-REM period were significantly reduced. OS was significantly correlated with cognitive level, as evaluated by the MMSE. The addition of sleep parameters can significantly improve the accuracy of dementia diagnosis. Dementia biomarkers of Aβ and tau proteins in blood showed cognition-related differences, while ptau181 was associated with both cognition and age-related differences. Regression models revealed that age was related to higher levels of cognitive decline before (β = -0.43, P < 0.001) and after (β = -0.38, P < 0.001) adjustment of gender, BMI, and education level. There was a significant mediation effect of relationship between aging and cognitive function by sleep efficiency and N1 stage sleep. Sleep disorders and low OS are associated with a higher incidence of cognitive decline and dementia.

Physiological β-amyloid clearance by the liver and its therapeutic potential for Alzheimer’s disease

Cerebral amyloid-β (Aβ) accumulation due to impaired Aβ clearance is a pivotal event in the pathogenesis of Alzheimer's disease (AD). Considerable brain-derived Aβ is cleared via transporting to the periphery. The liver is the largest organ responsible for the clearance of metabolites in the periphery. Whether the liver physiologically clears circulating Aβ and its therapeutic potential for AD remains unclear. Here, we found that about 13.9% of Aβ42 and 8.9% of Aβ40 were removed from the blood when flowing through the liver, and this capacity was decreased with Aβ receptor LRP-1 expression down-regulated in hepatocytes in the aged animals. Partial blockage of hepatic blood flow increased Aβ levels in both blood and brain interstitial fluid. The chronic decline in hepatic Aβ clearance via LRP-1 knockdown specific in hepatocytes aggravated cerebral Aβ burden and cognitive deficits, while enhancing hepatic Aβ clearance via LRP-1 overexpression attenuated cerebral Aβ deposition and cognitive impairments in APP/PS1 mice. Our findings demonstrate that the liver physiologically clears blood Aβ and regulates brain Aβ levels, suggesting that a decline of hepatic Aβ clearance during aging could be involved in AD development, and hepatic Aβ clearance is a novel therapeutic approach for AD.

Senile plaques in Alzheimer's disease arise from Aβ- and Cathepsin D-enriched mixtures leaking out during intravascular haemolysis and microaneurysm rupture.

Senile plaques are a pathological hallmark of Alzheimer's disease (AD), yet the mechanism underlying their generation remains unknown. Beta-amyloid peptide (Aβ) is a major component of senile plaques. We analysed AD brain tissues with histochemistry, immunohistochemistry and fluorescence imaging to examine the neural, vascular or blood Aβ contribution to senile plaque development. We found little neural marker co-expression with plaque Aβ, while co-expression of blood markers, such as Haemin and ApoE, was abundant. The plaque cores were structured with vascular and glial proteins outside and blood metabolites inside, co-localizing with a characteristic of Hoechst staining-independent blue autofluorescence. Erythrocyte-interacting Aβ is linked to coagulation, elevated calcium and blue autofluorescence, and it is associated with intravascular haemolysis, atherosclerosis, cerebral amyloid angiopathy, microaneurysm, and often with Cathepsin D co-expression. We identified microaneurysms as major sites of amyloid formation. Our data suggest that senile plaques arise from Aβ- and Cathepsin D-enriched mixtures leaking out during intravascular haemolysis and microaneurysm rupture.

Plasma amyloid-beta oligomer is related to subjective cognitive decline and brain amyloid status

BackgroundSubjective cognitive decline (SCD) is a target for Alzheimer’s disease prediction. Plasma amyloid-beta oligomer (AβO), the pathogenic form of Aβ in blood, has recently been proposed as a novel blood-based biomarker of AD prediction by representing brain Aβ deposition. The relationship between plasma AβO, brain Aβ deposition, and SCD in individuals with normal objective cognition has not been investigated.MethodsIn this cross-sectional study, we analyzed 126 participants with normal objective cognition. More SCD symptoms were expressed as higher scores of the Subjective Cognitive Decline Questionnaire (SCDQ) and Memory Age-associated Complaint Questionnaire (MACQ). The plasma AβO level of each participant was measured twice for validation and expressed as a concentration (ng/mL) and a ratio relative to the mean value of two internal standards. Brain Aβ deposition was assessed by [18F] flutemetamol positron emission tomography (PET) and expressed as standard uptake value ratio (SUVR). Associations of SCDQ and MACQ with plasma AβO levels or SUVR were analyzed in multiple linear regression models. The association between plasma AβO level and flutemetamol PET positivity was assessed in logistic regression and receiver operative characteristic analyses.ResultsOverall, participants were 73.3 years old with female predominance (69.0%). After adjustment for confounders, high SCDQ and MACQ scores were associated with the high plasma AβO levels as both concentrations and ratios (ratios: standardized coefficient = 0.246 and p = 0.023 for SCDQ, standardized coefficient = 0.209 and p = 0.029 for MACQ; concentrations: standardized coefficient = 0.257 and p = 0.015 for SCDQ, standardized coefficient = 0.217 and p = 0.021 for MACQ). In contrast, SCDQ and MACQ were not significantly associated with SUVRs (p = 0.134 for SCDQ, p = 0.079 for MACQ). High plasma AβO levels were associated with flutemetamol PET (+) with an area under the curve of 0.694 (ratio) or 0.662 (concentration). Combined with APOE e4, plasma AβO presented area under the curves of 0.789 (ratio) and 0.783 (concentration).ConclusionsOur findings indicate that the high plasma AβO level could serve as a potential surrogate biomarker of severe SCD and the presence of brain Aβ deposition in individuals with normal objective cognition.

Testing the link between isoaspartate and Alzheimer's disease etiology.

Isoaspartate (isoAsp) is a damaging amino acid residue formed in proteins as a result of spontaneous deamidation. IsoAsp disrupts protein structures, making them prone to aggregation. Here we strengthened the link between isoAsp and Alzheimer's disease (AD) by novel approaches to isoAsp analysis in human serum albumin (HSA), the most abundant blood protein and a major carrier of amyloid beta (Aβ) and phosphorylated tau (p-tau) in blood. We discovered a reduced amount of anti-isoAsp antibodies (P < 0.0001), an elevated isoAsp level in HSA (P < 0.001), more HSA aggregates (P < 0.0001), and increased levels of free Aβ (P < 0.01) in AD blood compared to controls. We also found that deamidation significantly reduces HSA capacity to bind with Aβ and p-tau (P < 0.05). These suggest the presence in AD of a bottleneck in clearance of Aβ and p-tau, leading to their increased concentrations in the brain and facilitating their aggregations there.

Endothelial expression of human amyloid precursor protein leads to amyloid β in the blood and induces cerebral amyloid angiopathy in knock-in mice

The deposition of amyloid β (Aβ) in blood vessels of the brain, known as cerebral amyloid angiopathy (CAA), is observed in most patients with Alzheimer’s disease (AD). Compared with the pathology of CAA in humans, the pathology in most mouse models of AD is not as evident, making it difficult to examine the contribution of CAA to the pathogenesis of AD. On the basis of biochemical analyses that showed blood levels of soluble amyloid precursor protein (APP) in rats and mice were markedly lower than those measured in human samples, we hypothesized that endothelial APP expression would be markedly lower in rodents and subsequently generated mice that specifically express human WT APP (APP770) in endothelial cells (ECs). The resulting EC-APP770+ mice exhibited increased levels of serum Aβ and soluble APP, indicating that endothelial APP makes a critical contribution to blood Aβ levels. Even though aged EC-APP770+ mice did not exhibit Aβ deposition in the cortical blood vessels, crossing these animals with APP knock-in mice (AppNL-F/NL-F) led to an expanded CAA pathology, as evidenced by increased amounts of amyloid accumulated in the cortical blood vessels. These results highlight an overlooked interplay between neuronal and endothelial APP in brain vascular Aβ deposition. We propose that these EC-APP770+:AppNL-F/NL-F mice may be useful to study the basic molecular mechanisms behind the possible breakdown of the blood–brain barrier upon administration of anti-Aβ antibodies.

First-in-human study of blood amyloid β removal from early Alzheimer's disease patients with normal kidney function.

Amyloid β (Aβ) is a brain protein that causes Alzheimer's disease (AD). This study aimed to verify whether hemadsorption using a hexadecyl-alkylated cellulose bead (HexDC) column removes blood Aβ and brain Aβ accumulation in mild cognitive impairment/mild AD cases with normal kidney function. Two patients with positive Aβ on brain imaging underwent HexDC hemadsorption weekly for 6 months. The Aβ removal efficiency of HexDC was 87-99%. Aβ1-40 /Aβ1-42 influx into the blood in one session was 596/56 and 489/48 ng for Case A and Case B, respectively. Although brain Aβ accumulation did not clearly change after 6 months of hemadsorption, cognitive functions measured by the two tests were maintained or slightly improved. Blood Aβ removal was performed in two early AD patients with normal kidney function without adverse events, and it slightly improved or maintained cognitive function.

Chemical-Driven Outflow of Dissociated Amyloid Burden from Brain to Blood.

Amyloid‐β (Aβ) deposition in the brain is a primary biomarker of Alzheimer's disease (AD) and Aβ measurement for AD diagnosis mostly depends on brain imaging and cerebrospinal fluid analyses. Blood Aβ can become a reliable surrogate biomarker if issues of low concentration for conventional laboratory instruments and uncertain correlation with brain Aβ are solved. Here, brain‐to‐blood efflux of Aβ is stimulated in AD transgenic mice by orally administrating a chemical that dissociates amyloid plaques and observing the subsequent increase of blood Aβ concentration. 5XFAD transgenic and wild‐type mice of varying ages and genders are prepared, and blood samples of each mouse are collected six times for 12 weeks; three weeks of no treatment and additional nine weeks of daily oral administration, ad libitum, of Aβ plaque‐dissociating chemical agent. By the dissociation of Aβ aggregates, the altered levels of plasma Aβ distinguish between transgenic and wild‐type mice, displaying potential as an amyloid burden marker of AD brains.

Time dependent expression profiling of PTK2B and its relationship with Aβ, Tau and LRP-1 in hippocampus and blood of APPswe/PS1dE9 double-transgenic mouse

Objective: To uncover the time-dependent expression pattern of ptk2b gene and ptk2b-encoded protein, protein tyrosine kinase 2 beta(PTK2B), in the brain tissues of transgenic animal models of Alzheimer's disease (AD) and its relationship with the levels of Aβ1-42, phosphorylation of Tau (p-Tau) and low density lipoprotein receptor-related protein-1(LRP-1) in blood and brain tissues. Methods: In this study, 5-, 10- and 15-month-old APPswe/PS1dE9 double-transgenic mice harboring the genotype of AD confirmed by the gene test were divided into the 5-, 10- and 15-month-old experiment groups, and simultaneously, age-matched C57BL/6J mice were placed into the corresponding control groups, with 8 mice in each group. All mice were subjected to the Morris Water Maze for test of cognitive and behavioral ability. Expression profiles of PTK2B, Aβ1-42, p-Tau/Tau and LRP-1 in the hippocampus or blood of mice were quantified by using the immunohistochemistry staining, Western blot or enzyme-linked immunosorbent assay (ELISA), while the mRNA expression of ptk2b in the hippocampus was quantified by using the real-time quantitative polymerase chain reaction (qRT-PCR). Results: Results of experiment groups demonstrated that as mice aged, the expression levels of PTK2B, ptk2b mRNA, Aβ1-42 and p-Tau/Tau in the hippocampus were increased, and the expression of LRP-1 was decreased gradually. While in the blood, the level of Aβ1-42 was decreased, and the cognitive and behavioral ability was decreased in an age-dependent manner (all P＜ 0.05). However, comparisons among the control groups, only the age-dependent downregulation of LRP-1 were observed in hippocampus(P＜0.05), but other indicators had no significant differences (P＞0.05). Conclusion: In the hippocampus of APP/PS1 double-transgenic mice, the expressions of PTK2B, Aβ1-42 and p-Tau/Tau are upregulated, LRP-1 is downregulated, while cognitive and behavioral ability is decreased, and such changes are presented in a time-dependent manner.

Recent advances in blood and gut microbiota biomarkers for Alzheimer&amp;rsquo;s disease

<p indent="0mm">Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases, with a high prevalence among the elderly. However, the mechanism of its occurrence is not clear, and there is a lack of convenient means of early diagnosis, which makes it difficult to intervene in and treat the disease in its early stage. In recent years, with the development of mass spectrometry, immunological methods and other new technologies, potential biomarkers for early diagnosis and disease monitoring of Alzheimer’s disease have been identified, including peripheral blood Aβ, p-tau, exosomes, miRNA, and intestinal bacteria. In this article, we reviewed the current research status of AD peripheral blood biomarkers and AD-related intestinal microbiota biomarkers, in order to provide a reference for the early diagnosis and prediction of the disease progression.

Efficient ratiometric fluorescence probe based on dual-emission luminescent lanthanide coordination polymer for amyloid β-peptide detection

As an important biomarker for early Alzheimer’s disease (AD) diagnostics and a valuable therapeutic target, amyloid β peptide (Aβ) in blood has attracted extensive attention concerning its detection and monitoring. The tough challenges for monitoring subtle changes of Aβ in blood are low expression and high interference from environmental factors. Here, we constructed a ratiometric sensor based on dual-emission luminescent lanthanide metal–organic coordination polymer (DE-LMOCP) as fluorescence probe for simple, sensitive and accurate detection of Aβ. The DE-LMOCP (luminol-Tb-GMP-Cu) fluorescent probe was composed of terbium ion(Tb3+) as the center metal ions, cupric ion(Cu2+) as a cofactor for Tb3+ fluorescence silence, guanine monophosphate (GMP) as a bridging ligand can strengthen the fluorescence of Tb3+, and luminol as an auxiliary ligand. In the DE-LMOCP fluorescent probe, the fluorescence of the GMP-Tb is quite weak because the existing cofactor Cu2+ prevents the energy transfer of intramolecular between GMP and Tb3+ and results in the quench of GMP-Tb fluorescence. The fluorescence of luminol acts as inner reference. In the presence of Aβ, the high binding affinity of Aβ for Cu2+ causes a remarkable emission enhancement of GMP-Tb and suppresses the quenching effect. However, the fluorescence emission of luminol remains constant as inner reference. Hence, sensitive and accurate determination of Aβ were performed by the ratio of the fluorescence of luminol (F430) to the Tb3+(F547). With this ratiometric probe, Aβ was determined with sensitivity down to 20 pM. Moreover, the ratiometric probe was successfully used to the detection of Aβ in human plasma with satisfactory results due to its capability to eliminate auto-fluorescence. Significantly, it exhibited sound specificity and selectivity to recognize Aβ1−40, and successfully applied to visual detection of Aβ, which validates the potential on-site application. Given the analytical characteristics with high sensitivity, specificity, and accuracy, the ratiometric fluorescence sensor may have great potential in applications of Aβ1−40 detection and the early diagnosis of Alzheimer’s disease, as well as point-of-care tests.

A dual-screening electrochemiluminescent aptasensor based on a mesoporous silica nano-sieve for specific detection of amyloid-β monomer

Amyloid β-protein (Aβ) aggregation in the brain is a closely related symptom of Alzheimer’s disease (AD), while Aβ in blood might be a more accessible peripheral biomarker to predict AD much earlier due to its abnormal fluctuation. However, when developing an aptasensor for Aβ detection, the specificity of the sensor will be impaired by Aβ aggregates such as Aβ oligomers or fibers because they have the same unit of recognition. Herein, a novel dual-screening sensing strategy based on specific recognition by aptamers and nano-sieving by a mesoporous silica membrane (MSM) with electrochemiluminescence (ECL) as the output signal is reported, in which the MSM achieves a size-screening effect to eliminate the influence of those macromolecules, assisting the specificity screening of the aptamer. The ECL signal is determined by the steric hindrance of the specifically captured Aβ on the aptamer in the nanochannels of the MSM towards the probe (luminol), affording a highly sensitive and specific detection ability for Aβ in complex matrices. In general, this work develops an ECL sensor that integrates aptamer recognition with size-selective separation for blood Aβ detection, which positively helps to monitor the occurrence and development of AD.

Blood Triglyceride and High-Density Lipoprotein Levels Are Associated with Plasma Amyloid-β Transport: A Population-Based Cross-Sectional Study.

Studies have found that blood lipids are associated with plasma amyloid-β (Aβ) levels, but the underlying mechanism is still unclear. Two Aβ transporters, soluble form of low-density lipoprotein receptor related protein-1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE), are crucial in peripheral Aβ transport. The aim was to investigate the effects of lipids on the relationships between plasma Aβ and transporter levels. This study included 1,436 adults aged 40 to 88 years old. Blood Aβ, sLRP1, sRAGE, and lipid levels were measured. Univariate and multivariate analyses were used to analyze the relationships between lipids and plasma Aβ, sLRP1, and sRAGE. After adjusting for all possible covariates, high-density lipoprotein (HDL-c) was positively associated with plasma Aβ42 and sRAGE (β= 6.158, p = 0.049; β= 121.156, p < 0.001, respectively), while triglyceride (TG) was negatively associated with plasma Aβ40, Aβ42, and sRAGE (β= -48.389, p = 0.017; β= -11.142, p = 0.020; β= -147.937, p = 0.003, respectively). Additionally, positive correlations were found between plasma Aβ and sRAGE in the normal TG (Aβ40: β= 0.034, p = 0.005; Aβ42: β= 0.010, p = 0.001) and HDL-c groups (Aβ40: β= 0.023, p = 0.033; Aβ42: β= 0.008, p = 0.002) but not in the high TG and low HDL-c groups. Abnormal levels of TG and HDL-c are associated with decreased Aβ and sRAGE levels. Positive correlations between plasma Aβ and sRAGE were only found in the normal TG and HDL-c groups but not in the high TG and low HDL-c groups. These results indicated that dyslipidemia contributing to plasma Aβ levels might also be involved in peripheral Aβ clearance.

Aβ Influx into the Blood Evoked by Different Blood Aβ Removal Systems: A Potential Therapy for Alzheimer's Disease.

PurposeAmyloid-β (Aβ) is a brain protein that causes Alzheimer’s disease. We have revealed that extracorporeal blood Aβ-removal systems evoked a large Aβ influx into the blood. This study investigated the system that is more effective in evoking Aβ influx.MethodsAβ removal activities were compared between hexadecyl-alkylated cellulose beads (HexDC) and fragments of polysulfone hollow fibers (PSf-HFs) in mini-columns to eliminate the filtration effect. Then, adsorptive filtration systems were adapted for PSf hemodialyzers to enhance Aβ adsorption on micropores in the wall of hollow fibers. Plasma Aβ concentrations of patients with renal failure were analyzed during treatment with PSf hemodialyzers alone for 8 h or tandemly connected HexDC and PSf hemodialyzers for 4 h.ResultsIn the in vitro study, Aβ removal efficiency for HexDC was approximately 100% during the 60 min treatment, whereas the removal efficiency for PSf-HF fragments gradually decreased. However, PSf hemodialyzer in adsorptive filtration systems removed Aβs comparably or more than HexDC. Aβ influx into the blood increases time-dependently. Concomitant use of HexDC and PSf hemodialyzer evoked a larger Aβ1–40 influx than that of PSf hemodialyzer alone. However, Aβ1–42 influx by PSf hemodialyzer alone was similar to or a little larger than influx by the combined system. Both systems evoked almost doubled Aβ influx than estimated Aβs existing in the normal brain during the 4 h treatment.ConclusionPSf hemodialyzer alone for a longer period and concomitant use of HexDC and PSf hemodialyzer for a shorter time effectively evoked a larger Aβ influx. To evoke Aβ1–42 influx, PSf hemodialyzer alone was effective enough. These findings of devices and treatment time may lead to optimal clinical settings for therapy and prevention of Alzheimer’s disease.