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4(2), 172-185,2011
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Cerebrospinal fluid biomarkers for the diagnosis of Alzheimer’s disease
Kaori Morimoto1) and Yoshihiro Konishi1)*1) Department of Clinical Research, National Tottori Medical Center, Tottori 689-0203, Japan*Correspondence: ykonishi@tottori-iryo.hosp.go.jp

Abstract
The histopathological changes in the Alzheimer’s disease (AD) brain begin years before the first clinicalsymptoms become apparent. Hence, reliable biomarkers have long been sought for the early diagnosis of AD,
prediction of conversion to AD from mild cognitive impairment (MCI), identification of AD at the preclinicalstage of AD, differentiation among AD, MCI and other types of dementia, and assessment of clinical trials for
AD therapies; however, biomarkers of AD at various stages of development and clinical evaluation have so far
not been established in clinical routine. Recently, revised diagnostic criteria have been proposed for AD
dementia, MCI and preclinical AD from the National Institute on Aging (NIA)-Alzheimer’s Association (AA)workgroups on diagnostic guidelines for AD. In each phase, the revisions are related to the incorporation ofdiagnostic biomarkers into the diagnostic criteria. Only the five most widely studied biomarkers of AD havebeen formally incorporated into the diagnostic criteria. The five biomarkers include: (i) abnormal tracer
retention on amyloid imaging, (ii) decreased levels of the 42 amino acid form of β-amyloid (Aβ1-42) peptide in
cerebrospinal fluid (CSF), (iii) elevated levels of both total and phosphorylated tau (t-tau and p-tau,
respectively) in CSF, (iv) decreased fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET),and (v) atrophy on structural magnetic resonance imaging (MRI). The former and latter two are biomarkers forAβ accumulation and for neuronal degeneration or injury, respectively; however, the role of biomarkers differs
in each of these stages. In the preclinical AD stage, biomarkers are used to identify the presence of thepathophysiology of AD in research subjects with no or very subtle overt dementia symptoms, while, in both theMCI and AD dementia stages, clinical diagnoses are paramount and biomarkers are complementary.
There is a reduction of Aβ1-42 in CSF by approximately 50% in AD patients, compared to age-matched
non-demented controls, with diagnostic sensitivity and specificity levels ranging between 80 and 90%. CSF
Aβ1-42 levels are now considered to be the most sensitive single analyte for the detection of AD compared withcognitively normal elderly. Low levels of CSF Aβ1-42 are already observed in subjects with MCI who are later
converted to AD, and furthermore may predict a cognitive decline in healthy elderly individuals in whom AD
dementia develops later. An increase in CSF t-tau in AD compared to elderly controls is consistently observed,
with a sensitivity of 77% and a specificity of 91%. Similar increases in CSF t-tau are shown in patients withMCI who are at increased risk of AD. CSF levels of p-tau181 and p-tau231 proteins are also increased in AD andyield a sensitivity of 64 and 93% and a specificity of 86 and 94%, respectively, in discriminating AD fromhealthy controls. CSF p-tau yields a higher specificity than t-tau in diagnosing AD compared to other types ofdementia. High CSF levels of p-tau significantly predict cognitive decline and subsequent conversion to AD in
MCI subjects.
It should be noted that the ability of CSF biomarkers to discriminate AD from other types of dementia,
especially vascular dementia (VAD), is still unsatisfactory. A combination of two CSF biomarkers, Aβ1-42 andtau, seems to give significantly higher diagnostic accuracy than any biomarker alone; however, further studies
are likely to be necessary to confirm whether a panel of biomarkers rather than single analytes has more ability