Cerebrospinal fluid biomarkers for Alzheimer's disease are associated with neuropathology in cortical brain biopsy

CSF biomarkers of AD correlate with neuropathology of autopsy samples and CSF Aβ42 reflects the amyloid accumulation in PIB PET imaging. However, the relationship of CSF biomarkers and brain biopsy has not been proven before. Thus, we evaluated the connection between ventricular and lumbar CSF biomarkers and AD-related neuropathological changes in frontal cortical brain biopsy of patients with presumed normal pressure hydrocephalus (NPH) and assessed the relationship of CSF biomarkers and cortical biopsy with the final clinical diagnosis of AD. Cortical brain biopsies and ventricular CSF samples of 182 patients with presumed NPH were obtained prior to the insertion of an intraventricular catheter for 24-hour ICP monitoring. Aβ plaques and tau in the biopsy sample were correlated with ventricular and lumbar CSF Aβ42, total tau and p-tau-181 levels measured by ELISA. Total of 51 patients were clinically diagnosed to have dementia of AD type after a median follow-up of 2.0 years. The APOE status was available for 152 patients. The APOE-ε4 positive patients exhibited significantly lower lumbar and ventricular CSF Aβ42 concentrations (P <0.001), and their amyloid load in cortical brain biopsy was higher as compared to APOE-ε4 negative patients (P <0.001). There was a dose-dependent effect with the number of ε4 alleles. When Aβ plaques were present in the biopsy, the CSF Aβ42 concentrations were lower than in patients with no Aβ plaques present (P = 0.009). The patients with tau in the cortical biopsy had lower Aβ42 (P = 0.014) but higher p-tau-181 (P = 0.015) in CSF as compared to those with no tau in the cortical biopsy. The patients with both amyloid-positive and tau-positive biopsies had the lowest CSF Aβ42 concentration with highest tau and p-tau-181 levels. The CSF Aβ42 correlated inversely to the semi-quantitation of the Aβ plaques (r = -0.213, P = 0.004).