**1. Introduction**

The augmented number of dementia patients has been dramatic due to the aging of society in advanced countries. Alzheimer's disease (AD) is the most common type of dementia and accounts for more than half (50–70% depending on the reports) of all dementia. AD is charac‐ terized by a gradual onset by developing neuronal damage and continuing cognitive decline related to stress-induced cell damage in the patient's brain [1], which ultimately causes significant

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impairment to social and occupational functions. The mean duration from the onset of clinical symptoms to the death of the patient has been reported to be approximately 8.5 years [2].

AD is defined by the presence of plaques and tangles in the brain, thus the gold standard for the diagnosis of Alzheimer's disease (AD) is set by means of the histological examination of brain tissue at autopsy, which is usually done after a patient has died, or, rarely, following brain biopsy. On the other hand, clinical diagnosis of AD during life has been performed with a sensitivity ranging from 70.9% to 87.3% and specificity from 44.3% to 70.8% [3]. It was also reported that dementia is often overlooked in community care settings [4].

For objective diagnostic analysis, several biomarkers are available. The reliable biomarker candidates for AD include brain imaging studies using magnetic resonance imaging (MRI) or positron emission tomography (PET), and proteins in cerebrospinal fluid (CSF). MRI is utilized for structural imaging, PET for molecular imaging of amyloid deposition and fluoro-deoxy-D-glucose (FDG)-PET for metabolic imaging, while measurements of amyloid peptide (Aβ) and TAU protein in cerebrospinal fluid (CSF) are used for quantitative analysis. However, structural changes measured by MRI only become apparent in the late stage of AD. Moreover, structural MRI and FDG-PET images are not direct measures of the core pathological hallmarks of AD. PET imaging is relatively expensive and limited in availability. CSF Aβ and TAU might be nonspecific for AD depending on each case [5]. At present, it can be stated that the most well-characterized and validated biomarkers are Aβ and TAU in CSF: the decrease in Aβ with 42 amino acid residues (Aβ42) and increase in TAU and phosphorylated TAU (P-TAU) has been observed in AD patients in several of studies [6].

An alternative method to the invasive CSF collection and expensive specialized facilities for diagnostic imaging is most desirable. Thus, plasma biomarkers have raised expectations because blood sampling is a much less invasive procedure. Blood-based biomarkers have the potential to overcome access and cost barriers and greatly facilitate advanced neuroimaging and cerebrospinal fluid biomarker approaches. Due to the fact that preanalytical processing shows the largest variation in laboratory testing, there are currently no available standardized preanalytical guidelines. In this review, the primary focus is on the fluid biomarkers, especially blood plasma protein biomarkers, as indicators of AD development together with our study on results of a specific blood plasma candidate.
