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Background: Reliable blood biomarkers are crucial for early detection and treatment evaluation of cognitive impairment, including Alzheimer's disease and other dementias., Objective: To examine whether plasma biomarkers and their combination are different between older people with mild cognitive impairment (MCI) and cognitively normal individuals, and to explore their relations with cognitive performance., Methods: This cross-sectional study included 250 older adults, including 124 participants with MCI, and 126 cognitively normal participants. Plasma brain-derived neurotrophic factor (BDNF), irisin and clusterin were measured, and BDNF/irisin ratio was calculated. Global cognition was evaluated by the Montreal Cognitive Assessment., Results: Plasma irisin levels, but not BDNF, were significantly different between MCI group and cognitively normal group. Higher irisin concentration was associated with an increased probability for MCI both before and after controlling covariates. By contrast, plasma BDNF concentration, but not irisin, was linearly correlated with cognitive performance after adjusting for covariates. Higher BDNF/irisin ratios were not only correlated with better cognitive performance, but also associated with lower risks of MCI, no matter whether we adjusted for covariates. Plasma BDNF and irisin concentrations increased with aging, whereas BDNF/irisin ratios remained stable. No significant results of clusterin were observed., Conclusions: Plasma BDNF/irisin ratio may be a reliable indicator which not only reflects the odds of the presence of MCI but also directly associates with cognitive performance.

Background: Apolipoprotein J (ApoJ) is present in both plasma and tissues, including brain. Growing evidence suggest that this protein may play an early role on the development of the two most common forms of dementia, Alzheimer's disease (AD) and vascular dementia (VD)., Objective: To evaluate whether serum ApoJ levels might be able to predict the progression to AD, VD, or mixed dementia (AD&VD) in individuals with mild cognitive impairment (MCI)., Methods: Serum ApoJ was measured in 196 MCI subjects (aged ≥60 years) with a median follow up of 2.9 years., Results: One hundred thirty-two of the enrolled MCI subjects converted to dementia. Among these, 45% developed AD, 33% mixed dementia, 13% VD (VD), and 9% other forms of dementia. A significant trend toward a progressive reduction in the incidence of dementia, regardless of the type, from tertile I (83.1%), to tertile II (63.1%), to tertile III (56.1%) was observed (p = 0.003). After adjustment for potential confounders, a twofold increase in the risk of conversion to dementia was found in subjects belonging to tertile I of Apo J compared with tertile III; the risk increased after two years of follow up, while no differences emerged within the first 2 years., Conclusions: Our results suggest that in MCI subjects, low APOJ levels may be associated with increased risk of developing dementia., (Copyright © 2021 Elsevier B.V. All rights reserved.)

To explore plasma protein panels as potential biomarkers to screen for mild cognitive impairment (MCI) among elderly Chinese individuals with different educational backgrounds. Forty-four illiterate, 36 lower education (1-6 years), and 55 higher education (7 years or more) elderly individuals were included in the present study. Among all subjects, 67 were healthy individuals and 68 were diagnosed with MCI. Fifty plasma proteins in blood samples collected from these subjects were analyzed via the Luminex assay. Binary logistic regression was utilized to explore diagnostic models for MCI among the three educational subgroups. Then, receiver operating characteristic (ROC) curves were conducted for the clinical validity of the MCI models. Among the analyzed proteins, clusterin was used in the model of MCI among the total sample with a sensitivity (se) of 67.6%, a specificity (sp) of 59.7%, and a classification rate of 63.68%. The MCI model for the illiterate group included cystatin C, plasminogen activator inhibitor-1, and apolipoprotein A-I (se: 71.4%, sp.: 82.6%, accuracy: 77.25%). The sensitivity, specificity, and classification rate of the diagnostic model of MCI in elderly adults with lower education (human serum albumin) were each 75.0%. Additionally, the sensitivity, specificity, and accuracy rate of the diagnostic model for MCI elderly individuals with higher education (alpha-acid glycoprotein + soluble intercellular adhesion molecule-1 + pancreatic polypeptide) were 77.8%, 89.3%, and 83.60%, respectively. The performance of diagnostic models for MCI based on different educational levels is superior to that of diagnostic models for MCI without grouping by educational level.

Oxidative stress plays a pivotal and early role in the pathophysiology of Alzheimer's disease (AD). There is convincing evidence that oxidative alterations in AD and in mild cognitive impairment (MCI) patients are not limited to the brain but are extended to the blood compartment. However, the oxidative pattern in plasma is still inconclusive. Moreover, their potential association with the clinical scores MMSE (Mini-Mental State Examination) and MoCA (Montreal Cognitive Assessment) is poorly investigated. The aim of our study was to establish a pattern of blood-based redox alterations in prodromal AD and their evolution during the progression of the disease. Our results showed a reduction in the total antioxidant capacity (TAC) and an increase of the stress-response proteins apolipoprotein J (ApoJ) and Klotho in MCI subjects. For the first time, we evidenced circulating-proteasome activity. We found that the alteration of the circulating-proteasome activity is associated with the accumulation of oxidized proteins in plasma form early AD. Interestingly, the TAC, the levels of vitamin D and the activity of proteasome were positively associated to the clinical scores MMSE and MoCA. The levels of protein carbonyls and of ApoJ were negatively associated to the MMSE and MoCA scores. The levels of apolipoprotein D (ApoD) were not different between groups. Interestingly, the receiver operating characteristic (ROC) curves analysis indicated that these redox markers provide a fair classification of different groups with high accuracy. Overall, our results strengthen the notion that some specific oxidative markers could be considered as non-invasive blood-based biomarkers for an early MCI diagnosis and AD progression., (Copyright © 2018. Published by Elsevier Inc.)

There is a critical unmet need for reliable markers of disease and disease course in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). The growing appreciation of the importance of inflammation in early AD has focused attention on inflammatory biomarkers in cerebrospinal fluid or plasma; however, non-specific inflammation markers have disappointed to date. We have adopted a targeted approach, centered on an inflammatory pathway already implicated in the disease. Complement, a core system in innate immune defense and potent driver of inflammation, has been implicated in pathogenesis of AD based on a confluence of genetic, histochemical, and model data. Numerous studies have suggested that measurement of individual complement proteins or activation products in cerebrospinal fluid or plasma is useful in diagnosis, prediction, or stratification, but few have been replicated. Here we apply a novel multiplex assay to measure five complement proteins and four activation products in plasma from donors with MCI, AD, and controls. Only one complement analyte, clusterin, differed significantly between control and AD plasma (controls, 295 mg/l; AD, 388 mg/l: p < 10- 5). A model combining clusterin with relevant co-variables was highly predictive of disease. Three analytes (clusterin, factor I, terminal complement complex) were significantly different between MCI individuals who had converted to dementia one year later compared to non-converters; a model combining these three analytes with informative co-variables was highly predictive of conversion. The data confirm the relevance of complement biomarkers in MCI and AD and build the case for using multi-parameter models for disease prediction and stratification.

Amnestic mild cognitive impairment (aMCI) is a sub-clinical condition characterized by memory deficits that are not severe enough to affect daily functioning. Here we investigated two potential biomarkers found in the cerebrospinal fluid of AD patients, APLP1-derived Aβ-like peptides 28 (APL1β28) and clusterin plasma levels, in terms of their relationship to cognitive function, as reflected in the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA) and the Cognitive Assessment Screening Instrument (CASI) in aMCI patients. Forty-seven aMCI patients and thirty-five age- and gender-matched healthy adult controls were recruited for this study. Using the ELISA method, we found that the mean concentrations of both APL1β28 and clusterin were not significantly different between the control and aMCI groups. The APL1β28 levels were positively correlated with clusterin and that both were negatively correlated with the MMSE scores of the aMCI patients. Clusterin levels were negatively correlated with the MoCA and CASI scores of the aMCI patients. Using multivariate analysis, the correlation between clusterin and MMSE/MoCA/CASI was independent of other AD risk factors including age, education, sex, body mass index and ApoE genotype. The data presented here demonstrate that plasma clusterin levels reflect cognitive function in aMCI patients.

Aim: Substantial evidence links atherosclerosis and Alzheimer's disease (AD). Apolipoproteins, such as apolipoprotein E, have a causal relationship with both diseases. The rs11136000 SNP within the CLU gene, which encodes clusterin (apolipoprotein J), is also associated with increased AD risk. The aim of this study was to investigate the relationship between plasma clusterin and the rs11136000 genotype in mild cognitive impairment (MCI) and AD., Methods: Plasma and DNA samples were collected from control, MCI and AD subjects (n=142, 111, 154, respectively). Plasma clusterin was determined by ELISA and DNA samples were genotyped for rs11136000 by TaqMan assay., Results: Plasma clusterin levels were higher in MCI and AD subjects vs. controls (222.3 ± 61.3 and 193.6 ± 58.2 vs. 178.6 ± 52.3 μg/ml, respectively; p<0.001 for both comparisons), and in MCI vs. AD (p<0.05). Plasma clusterin was not influenced by genotype in the MCI and AD subjects, although in control subjects plasma clusterin was lower in the TT vs. TC genotypes (157.6 ± 53.4 vs. 188.6 ± 30.5 μg/ml; p<0.05)., Conclusion: This study examined control, MCI and AD subjects, identifying for the first time that plasma clusterin levels were influenced, not only by the presence of AD, but also the transitional stage of MCI, while rs11136000 genotype only influenced plasma clusterin levels in the control group. The increase in plasma clusterin in MCI and AD subjects may occur in response to the disease process and would be predicted to increase binding capacity for amyloid-beta peptides in plasma, enhancing their removal from the brain.

Cognitive impairment is frequent in patients with Parkinson's disease (PD), and can range from mild deterioration to dementia. Recently a contribution of Alzheimer's disease for the cognitive dysfunction in PD has been proposed, whereas the presence of tau protein and amyloid was recognized. Clusterin/ApoJ is a protein involved in the deposition of beta-amyloid and in its neurotoxicity. In this study we aimed to investigate the clusterin/ApoJ's plasma levels in patients with PD to assess its potential role in fisiopathogenetic cognitive impairment.

Recent genetic and proteomic studies demonstrate that clusterin/apolipoprotein-J is associated with risk, pathology, and progression of Alzheimer's disease (AD). Our main aim was to examine associations between plasma clusterin concentration and longitudinal changes in brain volume in normal aging and mild cognitive impairment (MCI). A secondary objective was to examine associations between peripheral concentration of clusterin and its concentration in the brain within regions that undergo neuropathological changes in AD. Non-demented individuals (N=139; mean baseline age 70.5 years) received annual volumetric MRI (912 MRI scans in total) over a mean six-year interval. Sixteen participants (92 MRI scans in total) were diagnosed during the course of the study with amnestic MCI. Clusterin concentration was assayed by ELISA in plasma samples collected within a year of the baseline MRI. Mixed effects regression models investigated whether plasma clusterin concentration was associated with rates of brain atrophy for control and MCI groups and whether these associations differed between groups. In a separate autopsy sample of individuals with AD (N=17) and healthy controls (N=4), we examined the association between antemortem clusterin concentration in plasma and postmortem levels in the superior temporal gyrus, hippocampus and cerebellum. The associations of plasma clusterin concentration with rates of change in brain volume were significantly different between MCI and control groups in several volumes including whole brain, ventricular CSF, temporal gray matter as well as parahippocampal, superior temporal and cingulate gyri. Within the MCI but not control group, higher baseline concentration of plasma clusterin was associated with slower rates of brain atrophy in these regions. In the combined autopsy sample of AD and control cases, representing a range of severity in AD pathology, we observed a significant association between clusterin concentration in the plasma and that in the superior temporal gyrus. Our findings suggest that clusterin, a plasma protein with roles in amyloid clearance, complement inhibition and apoptosis, is associated with rate of brain atrophy in MCI. Furthermore, peripheral concentration of clusterin also appears to reflect its concentration within brain regions vulnerable to AD pathology. These findings in combination suggest an influence of this multi-functional protein on early stages of progression in AD pathology., (Published by Elsevier Inc.)