Cerebrospinal Fluid Biomarkers for the Diagnosis of Alzheimer’s Disease

Abstract

The antemortem diagnosis of probable Alzheimer’s disease (AD) requires time-consuming and costly procedures. Therefore, biomarkers that can direct the physician rapidly to the correct diagnosis are highly desirable. According to the consensus report of the working group on “Molecular and Biochemical Markers of Alzheimer’s Disease,” the ideal biomarker for AD should have a sensitivity of >80% for detecting AD and a specificity of >80% for distinguishing other dementias. Candidate diagnostic markers were identified by quantitating proteins associated with the characteristic histopathological hallmarks of AD: β-amyloid plaques and neurofibrillary tangles (NFT). Cerebrospinal fluid (CSF) levels of amyloid β-peptide (Aβ42) and total tau protein, as well as combinations of the two, were shown to corroborate the clinical diagnosis of AD; however, they did so without fully meeting the working group guidelines. Combined CSF measurements of phosphorylated tau protein (phospho-tau) and Aβ42 and calculation of the phospho-tau/Aβ42 ratio resulted in a further, slight improvement of diagnostic accuracy (Maddalena et al. 2003). Thus, measurement of the CSF phospho-tau/Aβ42 ratio meets the working group guidelines for sensitivity and comes close to meeting the guidelines for specificity. It is currently unclear how both sensitivity and specificity values can be set at levels higher than 90%. It is unlikely that this goal can be achieved by measurement of Aβ peptides and tau proteins alone, because the AD neuropathology is characterized by a variety of other lesions, such as infarcts, gliosis, argyrophilic grains and Lewy bodies. Moreover, the neuropathology of other dementing conditions, such as frontotemporal lobe dementias, displays partially AD histopathological features.