**2. CSF markers**

Diagnostic markers are anticipated to be present in secreted proteins followed by a result of cell damage in pathological states. Although CSF sampling by lumbar puncture definitely is known to be an invasive procedure, at present CSF is probably the most informative fluid in biomarker detection for neurodegenerative disease prognosis [7]. CSF has direct contact with the brain, and it does not easily escape from the brain owing to the fact that the blood-brain barrier (BBB) is tightly regulated. In general, if a biomarker candidate is identified in CSF, its possibility as a true biomarker for brain-specific activities, as well as disease pathology, would be considered to be more promising compared with any other body fluid biomarker candidate. It has been demonstrated that senile plaque formation and neuronal loss precede clinical onset of Alzheimer's disease [8]. Senile plaques are polymorphous and comprise Amyloid β peptide (Aβ), a proteolytic product of amyloid precursor protein (APP) that accumulates in the brains of AD patients. Several species of Aβ peptide depending on the cleavage sites on APP have been identified in the body fluid. APP processing consists of initially proteolysis by β-secretase and then by β-secretase, which leads to the formation of Aβ peptides with 38–43 residues [9]. Of these, Aβ42 with 42 amino acid residues is the most remarkably focused due to its toxic effect. Aβ42 is highly hydrophobic and forms oligomers and fibrils that accumulate as extrac‐ ellular plaques, which correlates inversely with plaque pathology [1, 10]. Attenuated activity of Aβ-degrading catabolic enzymes including neprilysin and insulin-degrading enzymes with age or abnormal production of Aβ due to gene mutation(s) of related proteins such as on APP have been identified, which in turn leads to the accumulation of Aβ42 in the brain tissue [11].

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

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

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

Diagnostic markers are anticipated to be present in secreted proteins followed by a result of cell damage in pathological states. Although CSF sampling by lumbar puncture definitely is known to be an invasive procedure, at present CSF is probably the most informative fluid in biomarker detection for neurodegenerative disease prognosis [7]. CSF has direct contact with the brain, and it does not easily escape from the brain owing to the fact that the blood-brain barrier (BBB) is tightly regulated. In general, if a biomarker candidate is identified in CSF, its possibility as a true biomarker for brain-specific activities, as well as disease pathology, would be considered to be more promising compared with any other body fluid biomarker candidate.

reported that dementia is often overlooked in community care settings [4].

observed in AD patients in several of studies [6].

on results of a specific blood plasma candidate.

**2. CSF markers**

68 Update on Dementia

On the other hand, TAU that is an intracellular protein, is believed to be involved in filament stabilization, and has been shown to aggregate to form filaments in neurons. In normal individuals, only a low concentration of TAU is present in CSF. The function of TAU is tightly regulated by a number of posttranslational modifications possibly due to phosphorylation at serine and threonine residues. Several studies have suggested that hyperphosphorylation and formation of neurofibrillary tangles (NFTs) is the pathophysiological phenomenon of the development of AD [12]. It is remarkable that functional loss of TAU following hyperphos‐ phorylation, the dissociation of TAU from microtubule and subsequent polymerization into insoluble paired helical filaments (PHF) could result in the loss of axonal integrity in the neuronal cells [13, 14]. NFT formation and neuronal degradation is an essential part of AD pathology.

Due to significant disruption of the neuronal architecture, the TAU and its hyperphosphory‐ lated form (P-TAU) could appear in CSF [15]. Therefore, the phenomenon of increased levels of TAU and P-TAU in CSF represents well with the onset of neurodegeneration in AD. The total TAU (t-TAU) concentration in CSF has been measured by the method of ELISA using monoclonal antibodies against all TAU isoforms. Several groups have indicated that t-TAU concentration in CSF of AD patients is significantly higher than control [15, 16]. On the other hand, the attenuation of the amount of Aβ42 in CSF has been noted due to accumulation in the brain [17]. Thus, decrease in level of Aβ42, increase in t-TAU and P-TAU have been utilized as CSF biomarkers contributing to the diagnosis of AD [18]. In addition, the development of imaging biomarkers has provided evidence of an ongoing AD pathophysiological process.

The Aβ ratio (Aβ40 to Aβ42) in the AD group was significantly increased compared with that in the normal control group, the non-AD type dementia group, and the other neuronal disease group [19]. For the enhancement of the diagnostic relevance of AD, AD index that is calculated by multiplying TAU level by the Aβ ratio was shown to be useful for discrimination of AD patients from healthy controls with good sensitivity and specificity [19].

It was reported that low CSF level of Aβ42 appeared to predict conversion of mild cognitive impairment (MCI) to AD, while a decrease in Aβ42 level has also been observed in other neurodegenerative disorders [20]. Furthermore, it was shown that levels of TAU and P-TAU at Ser181 (P-TAU181) in CSF, but not Aβ42, correlated oppositely with whole brain volume in the early stage of AD, whereas levels of CSF Aβ42, but not TAU or P-TAU181, was positively correlated with whole brain volume in nondemented controls [17].

It is thought that the production and accumulation of unfavorable Aβ species proceeds over time as the disease progresses. Abnormal activity by the Aβ species is initiated before patho‐ logical change and reaches a plateau before the clinical symptoms appear. Thereafter, elevation of TAU and P-TAU that are the biomarkers for neuronal injury, dysfunction, and degeneration, become apparent in the later stage of the disease and correlate with clinical symptom severity [8]. On the other hand, MRI imaging is valuable as it is the last biomarker to show abnormality. As such, MRI retains a closer relationship with cognitive performance later on in the disease compared with other biomarkers. Moreover, none of the biomarkers is stable; that is, the rate of change for each biomarker is not linear over time [8].

The revised guideline for AD diagnosis was released by a working group from the National Institute of Aging in 2011, in which both CSF and imaging biomarkers have been implemented. The new guideline provides evidence of an ongoing AD pathophysiological process, and it is also possible to make a preclinical diagnosis of MCI due to AD [21–23]. AD is classified into three separate stages: preclinical AD, MCI due to AD, and AD with dementia.

Since fluid biomarkers of either CSF or blood plasma can serve as objective criteria for dementia diagnosis, this guideline is aiming at early and reliable diagnosis. However, it is clear that at present no single biomarker plays a sufficient discriminatory role in screening for future development of late-onset AD or dementia.
