Cerebrospinal fluid ß-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain

Abstract

The proposed research criteria of prodromal Alzheimer's disease (AD) emphasize the use of biomarkers in addition to the presence of impairment of episodic memory. Atrophy of the medial temporal lobe structures and changes in the levels of CSF tau protein and beta-amyloid 42 (Aß42) peptide in patients with AD are well documented in single center and multicenter studies, and these biomarkers also predict AD in amnestic MCI. However, the relationship between e.g. CSF biomarkers and neuropathologic changes in the brain is not well established. Objective: To study the relationship between antemortem CSF biomarker levels and AD-type neuropathologic changes in the brain. Methods: We studied correlations between levels of CSF Ab42, total tau, and phosphorylated tau (ptau) with neuropathologic changes in the postmortem brain in 123 patients (79 clinically diagnosed AD, 29 other dementia, and 15 other neurologic disease). All study subjects underwent clinical evaluation and provided antemortem lumbar CSF samples. CSF markers were measured using standard commercial immunoassays. Neuropathologic evaluations included the classic silver impregnation method and immunohistochemistry for Aß, hyperphosphorylated tau, and alpha-synuclein. Also vascular pathology was assessed. Results: CSF Aß42, tau and ptau levels were significantly related to amyloid load and the presence of neurofibrillary tangles (NFT) in the brain. CSF Aß42 level correlated inversely with total Aß load in the brain, and CSF tau level correlated with results of immunohistochemistry for tau and with neocortical NFTs. Alpha-synuclein or vascular pathology did not influence CSF biomarker concentrations. In multivariate logistic regression analysis, the number of neuritic plaques in the brain remained a significant predictor of decreased CSF Aß42 level and of increased CSF tau level. Based on the ratio of ptau level to Aß42 level, sensitivity was 91.6%, and specificity was 85.7%, with an overall accuracy of 90.2% for the presence of AD-type brain pathology. Conclusions: CSF Aß42 and tau proteins are associated with amyloid and tau pathology but not with alpha-synuclein or vascular pathology. The combination of low Aß42 and high tau levels in CSF predicted AD pathologic features with high accuracy and may be helpful in diagnosing the presence of AD pathologic changes in the brain.