Background: Blood-based biomarkers can be very useful in formulating new diagnostic and treatment proposals in the field of dementia, especially in Alzheimer’s disease (AD). However, due to the influence of several factors on the reproducibility and reliability of these markers, their clinical use is still very uncertain. Thus, up-to-date knowledge about the main blood biomarkers that are currently being studied is extremely important in order to discover clinically useful and applicable tools, which could also be used as novel pharmacological strategies for the AD treatment. Objective: The aim of this paper was to carry out a literature review on the major blood-based biomarkers for AD, connecting them with the pathophysiology of the disease. Methods: A narrative review was performed based on the current candidates of blood-based biomarkers for AD to show the main results from different studies, focusing on their clinical applicability and association with AD pathogenesis. Results: Recent advances in the search of blood-based AD biomarkers were summarized in this review. The biomarkers were classified according to the topics related to the main hallmarks of the disease such as inflammation, amyloid, and tau deposition, synaptic degeneration and oxidative stress. Moreover, molecules involved in the regulation of proteins related to these hallmarks were described, such as non-coding RNAs, neurotrophins, growth factors and metabolites. Cells or cellular components with the potential to be considered as blood-based AD biomarkers were described in a separate topic. Conclusion: A series of limitations undermine new discoveries on blood-based AD biomarkers. The lack of reproducibility of findings due to the small size and heterogeneity of the study population, different analytical methods and other assay conditions make longitudinal studies necessary in this field to validate these structures, especially when considering a clinical evaluation that includes a broad panel of these potential and promising blood-based biomarkers.

ADAM10 is the main α-secretase that participates in the non-amyloidogenic cleavage of amyloid precursor protein (APP) in neurons, inhibiting the production of β-amyloid peptide (Aβ) in Alzheimer’s disease (AD). Strong recent evidence indicates the importance of the localization of ADAM10 for its activity as a protease. In this study, we investigated ADAM10 activity in plasma and CSF samples of patients with amnestic mild cognitive impairment (aMCI) and mild AD compared with cognitively healthy controls. Our results indicated that plasma levels of soluble ADAM10 were significantly increased in the mild AD group, and that in these samples the protease was inactive, as determined by activity assays. The same results were observed in CSF samples, indicating that the increased plasma ADAM10 levels reflect the levels found in the central nervous system. In SH-SY5Y neuroblastoma cells, ADAM10 achieves its major protease activity in the fraction obtained from plasma membrane lysis, where the mature form of the enzyme is detected, confirming the importance of ADAM10 localization for its activity. Taken together, our results demonstrate the potential of plasma ADAM10 to act as a biomarker for AD, highlighting its advantages as a less invasive, easier, faster, and lower-cost processing procedure, compared to existing biomarkers.

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Biomarkers capable of identifying and distinguishing types of dementia such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) have been become increasingly relentless. Studies of possible biomarker proteins in the blood that can help formulate new diagnostic proposals and therapeutic visions of different types of dementia are needed. However, due to several limitations of these biomarkers, especially in discerning dementia, their clinical applications are still undetermined. Thus, the updating of biomarker blood proteins that can help in the diagnosis and discrimination of these main dementia conditions is essential to enable new pharmacological and clinical management strategies, with specificities for each type of dementia. To review the literature concerning protein blood-based AD and non-AD biomarkers as new pharmacological targets and/or therapeutic strategies. Recent findings for protein-based AD, PDD, LBD, and FTD biomarkers are focused on in this review. Protein biomarkers were classified according to the pathophysiology of the dementia types. The diagnosis and distinction of dementia through protein biomarkers is still a challenge. The lack of exclusive biomarkers for each type of dementia highlights the need for further studies in this field. Only after this, blood biomarkers may have a valid use in clinical practice as they are promising to help in diagnosis and in the differentiation of diseases.

Background: Alterations in the insulin pathway proteins have been associated with brain disorders, including Alzheimer’s disease (AD). Objectives: To investigate the peripheral levels of the insulin pathway proteins between cognitively and metabolically preserved participants, patients with DM2, AD and those with the concomitant presence of AD and DM2. Methods: The study was approved by the UFSCar’s ethics committee (CAAE: 31634720.9.0000.5504). Patients were diagnosed with AD using the criteria of the National Institute on Aging/Alzheimer’s Association (NIA/AA). DM2 was defined as self-report of taking oral antidiabetic medication. Plasma was collected by venipuncture from 36 participants. The levels of the of following proteins were analyzed by ELISA (Enzyme Enzyme-Linked Immunosorbent Assay): ISNR, IGF1R, IGF, IRS1, Akt1/PKB, PI3KCD/PI3Kdelta, MAPK1/ERK2, MAPK8/JNK1, PTP1B and IDE (Life-Span Biosciences). Results: Several proteins of the insulin pathway were altered in patients with AD, DM2 and AD+DM2, compared to healthy controls, reinforcing the strong correlation between DM2 and AD. Conclusions: This study shows peripheral alterations in the insulin signaling pathway proteins, confirming the relation between DM2 and AD and pointing out the importance of characterizing in detail the insulin signaling pathways, as they may play a key role in the pathogenesis of AD.

Background: Alzheimer's disease (AD) is a gradual and progressive neurodegenerative disease characterized by predominant cortical atrophy in the medial temporal lobe. Since the results of the Rotterdam study in 1992, it has been known that type 2 diabetes mellitus (T2DM) increases the risk of dementia. Persons with T2DM have structural brain changes and cognitive impairment, with a high risk of developing AD.These data suggest that insulin may play a key role in brain activity and memory formation. The objective of this study was to verify if there are alterations in the levels of proteins of the insulin pathway in cognitively healthy individuals, with AD, with T2DM and with the concomitant presence of AD and T2DM. Method:The study was approved by the UFSCar's ethics committee (CAAE: 31634720.9.0000.5504) and recruited participants aged 60 years or older. The AD diagnosis was obtained using the criteria of the National Institute Aging Alzheimer's Association (NIA/AA). T2DM was defined as self-reported use of oral antidiabetic drugs. Specific inclusion and exclusion criteria and cognitive assessment of the MMSE and CDR were applied to all participants. Plasma was collected by venepuncture and protein levels of ISNR, IRS1, Akt1, PI3KCD, MAPK1, MAPK8, PTP1B and IDE (Life-Span Biosciences) were analysed using ELISA (Enzyme Enzyme-Linked Immunosorbent Assay).Result: Several proteins of the insulin pathway were found to be significantly different among patients with AD, T2DM and AD+T2DM, compared with healthy controls (figure 1), reinforcing the strong correlation between T2DM and AD. Main alterations were found for INSR, IRS1, Akt1, PIK3, MAPK, PTP1b and IDE among healthy participants and those with AD+T2DM. Conclusion:The peripheral alterations found in the levels of insulin pathway proteins confirm the possible relationship between T2DM and AD and reinforce the importance of the insulin signalling pathways, as they can play a fundamental role in AD. The clinical impact of this study is related to a new approach that could be used in the treatment of this type of dementia, also observing the metabolic and inflammatory states of the patients, in addition to contributing to a better understanding of the biology of the disease itself.

Background: Active ADAM10 is a transmembrane protein with α-secretase function that inhibits β-amyloid (Aβ) peptide formation, an important neuropathological agent of Alzheimer's disease (AD). In addition, persons with cognitive decline, such as Mild Cognitive Impairment (MCI), have a high conversion rate to AD. Previous studies show that the levels of active platelet ADAM10 are reduced in persons with AD dementia, compared with cognitively healthy individuals. In blood plasma the inactive and soluble form of ADAM10 is found. In this study we investigated the levels of inactive ADAM10 in plasma in order to corroborate with previous results found in platelets. Method:This study was approved by the UFSCar's Research Ethics Committee (CAAE: 02763012.0.0000.5504). Altogether, samples from 88 participants (n = 28 MCI, n = 31 AD and n = 29 controls) were analysed in this study. Blood samples were collected, plasma was separated and total protein content (15µg) was run on gel electrophoresis