EDITORIAL: Diagnostic biomarker for early stage of Alzheimer's disease: Current state and view in the future

Field: Medicine (Health Sciences)

Dementia is regarded as a common disease, because it is found in 1 in 10 people aged 65 years or more.1, 2 As an initial symptom is forgetfulness, it tends to be overlooked and earlier detection is very difficult, with people saying that 'It cannot be helped because of old age'. It is Alzheimer's disease (AD) that is the leading cause of dementia. AD can be treated with donepezil hydrochloride (the brand name Aricept). In addition, advances have been made and there have been rapid developments in the curative treatment of AD. The development of diagnostic biomarkers for the early stage of AD is expected in such a situation. A general physician who is leading the way in dementia diagnosis and treatment believes the biomarker to be an easy-to-use tool, because the data are obtained by numerical value. In the present Editorial, the current state and the view of diagnostic biomarker research at the early stage of AD are described. Biomarkers have two roles; useful screening and definite diagnosis. The Reagan Institute, which was established to research AD, demands high rates of specificity and sensitivity (both over 80%, respectively) at which AD is detected and a condition of a biomarker of AD is that the accuracy of diagnosis reflects the pathophysiology of AD, thus reducing the invasiveness to the patient and distinguishing AD from other dementia disorders. Expression named AD index and AD unit by combining with the amyloid β protein and the total tau protein in the cerebrospinal fluid considerably fills the above-mentioned standard sensitivity and the specificity. It is a major problem that total tau protein shows an extremely high value in meningoencephalitis and Creutzfeldt–Jakob disease. Therefore, we examined phosphorylated tau protein in cerebrospinal fluid. Tau protein of neurofibrillary tangles in the AD patient's brain is highly phosphorylated. Therefore, if phosphorylated tau protein can be selectively measured, better results can be expected than in total tau proteins. Then, our group developed a sandwich ELISA that focused on the phosphorylated site of serine 199 and measured phosphorylated N-terminal fragment of tau protein. The results showed that phosphorylated tau protein is better than total tau protein. In particular, meningoencephalitis and Creutzfeldt–Jakob disease showed high values with total tau protein and low values were shown with phosphorylated tau protein. Therefore, these results show an improvement, and both sensitivity and specificity showed 85% or more with receiver operating characteristic curve (ROC) analysis.5 The method of phosphorylation of threonine 181 and threonine 231 has been reported, as well as the method of phosphorylation of serine 199 that our group is reporting for phosphorylated tau protein, and it is now thought that phosphorylated tau protein measurement is the best biomarker in cerebrospinal fluid. Furthermore, an improvement of reliability would be necessary to discriminate between tauopathies; for example, it is necessary to improve the diagnostic accuracy of corticobasal degeneration and progressive supranuclear palsy.6, 7 It is necessary to include a simple screening study with this method, because the test using cerebrospinal fluid cannot be easily carried out, though it has been found that the biomarker is reliable and can put phosphorylated tau protein in the cerebrospinal fluid as aforementioned. To our regret, a powerful marker has not yet been established, though the method of the measurement with urine and blood samples has been examined. Our group has reported the development and utility of simple screening for dementia using a touch panel type computer. This method can discriminate between AD and healthy controls with a sensitivity of 96% and a specificity of 97% in ROC analysis. It is possible to carry this out easily and anywhere, and an extremely useful result is obtained (Fig. 1).8 The method of simple screening for dementia using a touch panel type computer is now marketed as a forgetfulness consultation program (made by a Japanese photoelectron company) (Fig. 2). Furthermore, this equipment has been used as a tool to examine dementia in rural communities, and we obtained data that can be used as an acceptable screening method, even in a multicenter study. Results of screening tests using touch-panel type computer. Screening tools using touch-panel type computer. It will be expected that a biomarker that uses samples obtained from blood and/or urine and so on will be established. Diagnostic biomarker in serum does not seem to be useful as a diagnostic biomarker for AD, because amyloid β protein in blood does not have a significant difference in cross-sectional analysis compared with controls. However, amyloid β protein in blood exists in uptrend, and there is a possibility of showing a significant change if it pursues the target in the time course. The possibility that there is a correlation between amyloid accumulation in the brain and the level of amyloid β protein in blood is assumed, and examining the correlation of the amyloid β protein level in amyloid imaging and blood has been carried out. The measurement of amyloid β protein in urine has also been carried out. It has been reported that attempts have been made to analyze protein in blood in order to find candidate proteins and feature patterns in dementia with Lewy bodies and AD, respectively, and to examine whether it might be useful for differential diagnosis.9, 10 However, the result may not show the cause though it might be high and a more detailed analysis of the pattern analysis on the protein will be necessary in the future. It is well known that wheat germ agglutinin (WGA)-binding protein binds with sialic acid, and O type and N type glucose, to detect a high mannose type, the mixed type, and the combined type. Furthermore, it exists in a high density in the cerebral cortex, and a decrease in the temporal and parietal cortex is reported in AD. A previous study examined the WGA-binding protein and it showed a significant difference (P < 0.001) between the AD group (44 samples) and control group (32 samples), and suggested the possibility that a significant difference could also be shown between the AD group (40 samples) and tauopathies group (13 samples; Fig. 3).11 Next, this sugar protein was identified as a transferrin. When WGA-binding transferrin was measured in blood, we found a significant difference between AD and controls (Fig. 4). It is expected that WGA-binding protein will be one of the biomarkers used in blood in the future. CSF wheat germ agglutinin binding transferrin. CBD, cerebro spinal fluid; DLB, dementia with lewy body; PSP, progressive supranuclear palsy. Serum wheat germ agglutinin binding transferrin. AD, Alzheimer's disease; NDC, non-demented controls. It is now expected that the diagnosis and treatment of dementia can be made by general physicians, and the existence of a biomarker that can easily diagnose dementia is also expected. It is hoped that a biomarker that can appreciate from the numerical value by using samples that can be easily taken, such as blood and urine, develops hereafter.