Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231

Background: Phosphorylation of tau protein at threonine 231 (using full-length tau, 441 amino acids, for the numbering scheme) (p-tau₂₃₁) occurs specifically in postmortem brain tissue of patients with Alzheimer disease (AD) and can be sensitively detected in cerebrospinal fluid (CSF). Objectives: To determine to what extent CSF levels of p-tau₂₃₁ distinguish patients with AD from control subjects and from patients with other dementias, and to investigate whether p-tau₂₃₁ levels are a better diagnostic marker than levels of total tau protein (t-tau) in CSF. Design and Setting: Cross-sectional, multicenter, memory clinic-based studies. Participants: One hundred ninety-two patients with a clinical diagnosis of AD, frontotemporal dementia (FTD), vascular dementia, Lewy body dementia, or other neurological disorder and healthy controls. Main Outcome Measures: Levels of CSF tau proteins as measured with enzyme-linked immunosorbent assays. Results: Mean CSF levels of p-tau₂₃₁ were significantly elevated in the AD group compared with all other groups. Levels of p-tau₂₃₁ did not correlate with dementia severity in AD, and discriminated with a sensitivity of 90.2% and a specificity of 80.0% between AD and all non-AD disorders. Moreover, p-tau₂₃₁ levels improved diagnostic accuracy compared with t-tau levels when patients with AD were compared with healthy controls (P=.03) and demented subjects (P<.001), particularly those with FTD (P<.001), but not those with vascular and Lewy body dementias. Sensitivity levels between AD and FTD were raised by p-tau₂₃₁ compared with t-tau levels from 57.7% to 90.2% at a specificity level of 92.3% for both markers. Conclusion: Increased levels of CSF p-tau₂₃₁ may be a useful, clinically applicable biological marker for the differential diagnosis of AD, particularly for distinguishing AD from FTD.