Differential Diagnosis of Alzheimer Disease With Cerebrospinal Fluid Levels of Tau Protein Phosphorylated at Threonine 231

Abstract

ABNORMAL hyperphosphorylation of the microtubule-associated tau protein and its incorporation into neurofibrillary tangles are major hallmarks of Alzheimer disease (AD). Until recently, only total tau protein (t-tau) as a marker of neuronal damage was detectable in cerebrospinal fluid (CSF). Elevated levels of CSF t-tau have been observed in patients with AD,¹ even in those with mild dementia,² compared with healthy elderly controls. However, CSF t-tau levels are of limited value in the differential diagnosis of AD, because they can be increased in other dementia disorders.^3-8 Therefore, it appears likely that t-tau levels reflect neuronal degeneration rather than AD-specific pathophysiology. The use of antibodies to sites of tau that are specifically phosphorylated in AD may help to increase diagnostic accuracy, because the marker would be linked to a neuropathological hallmark of the disease. Detection of phosphorylated tau protein in the CSF therefore may provide a useful biomarker as outlined by the consensus report of the Working Group on Molecular and Biochemical Markers of Alzheimer's Disease.⁹