β-Amyloid discordance of cerebrospinal fluid and positron emission tomography imaging shows distinct spatial tau patterns

Abstract Extracellular β-amyloid plaques and intracellular neurofibrillary tau tangles are the primary hallmarks of Alzheimer's disease. β-Amyloid pathology can be directly quantified by positron emission tomography imaging or indirectly by measuring the decrease of cerebrospinal fluid β-amyloid42/β-amyloid40 ratio. Although these two β-amyloid biomarkers may be considered interchangeable, they sometimes show discordance, particularly in early stage of Alzheimer's disease. Individuals with cerebrospinal fluid β-amyloid positive only or β-amyloid positron emission tomography positive only may be at early amyloidosis stage compared to those who are cerebrospinal fluid β-amyloid negative and β-amyloid positron emission tomography negative orcerebrospinal fluid β-amyloid positive and β-amyloid positron emission tomography positive. Besides, β-amyloid pathology may play an initiating role in Alzheimer's disease onset, leading to subsequent tau increases. However, it is still unclear whether individuals with different β-amyloid pathways have distinct spatial patterns of cortical tau tangles in early amyloidosis stage. In this study, we analyzed 238 cognitively unimpaired and 77 mild cognitive impairment individuals with concurrent (interval of acquisition <1 year) 18F-flortaucipir tau positron emission tomography, β-amyloid (18F-florbetapir or 18F-florbetaben) positron emission tomography and cerebrospinal fluid β-amyloid42 and β-amyloid40 and cerebrospinal fluid p-Tau181 and divided them into four different cerebrospinal fluid/positron emission tomography groups based on the abnormal status of cerebrospinal fluid β-amyloid42/β-amyloid40 (cerebrospinal fluid±) and β-amyloid positron emission tomography (±). We determined the cortical regions with significant tau elevations of different cerebrospinal fluid/positron emission tomography groups and investigated the region-wise and voxel-wise associations of tau positron emission tomography images with cerebrospinal fluid β-amyloid42/β-amyloid40, β-amyloid positron emission tomography and cerebrospinal fluid p-Tau/β-amyloid40 in early (cerebrospinal fluid positive/positron emission tomography negative and cerebrospinal fluid negative/positron emission tomography positive) and late (cerebrospinal fluid positive/positron emission tomography positive) amyloidosis stages. By compared to the cerebrospinal fluid negative/positron emission tomography negative individuals (Ref) without evidence of tau increase measured by cerebrospinal fluid or positron emission tomography, cerebrospinal fluid positive/positron emission tomography negative individuals showed higher tau in entorhinal but not in BraakIII/IV and BraakV/VI, whereas cerebrospinal fluid negative/positron emission tomography positive individuals had significant tau elevations in BraakV/VI but not in entorhinal and BraakIII/IV. In contrast, cerebrospinal fluid positive/positron emission tomography positive individuals showed significant tau increases in all the cortical regions than the Ref group. The voxel-wise analyses provided further evidence that lower cerebrospinal fluid β-amyloid42/β-amyloid40 was associated with higher tau in entorhinal, whilst higher β-amyloid positron emission tomography was related to higher tau in BraakV/VI regions in early amyloidosis stage. Both lower cerebrospinal fluid β-amyloid42/β-amyloid40 and higher β-amyloid positron emission tomography were correlated with tau aggregation in all the Braak stages regions in late amyloidosis stage. These findings provide novel insights into the spatial patterns of cortical tau tangles in different amyloidosis stages of Alzheimer's disease, suggesting cerebrospinal fluid β-amyloid and β-amyloid positron emission tomography discordant groups may have distinct characteristics of cortical tau tangles in early amyloidosis stage.