Objective: To assess whether high levels of cerebrospinal fluid neurogranin are found in atypical as well as typical Alzheimer's disease. Methods: Immunoassays were used to measure cerebrospinal fluid neurogranin in 114 participants including healthy controls (n=27), biomarker-proven amnestic Alzheimer's disease (n=68), and the atypical visual variant of Alzheimer's (n=19) according to international criteria. CSF total-tau, A beta 42, and neurofilament light concentrations were investigated using commercially available assays. All affected individuals had T1-weighted volumetric MR images available for analysis of whole and regional brain volumes. Associations between neurogranin, brain volumes, total-tau, A beta 42, and neurofilament light were assessed. Results: Median cerebrospinal fluid neurogranin concentrations were higher in typical and atypical Alzheimer's compared to controls (P<0.001 and P=0.005). Both neurogranin and total-tau concentrations, but not neurofilament light and A beta 42, were higher in typical Alzheimer's compared to atypical patients (P=0.004 and P=0.03). There were significant differences in the left hippocampus and right and left superior parietal lobules in atypical patients, which were larger (P=0.03) and smaller (P=0.001 and P<0.001), respectively, compared to typical patients. We found no evidence of associations between neurogranin and brain volumes but a strong association with total-tau (P<0.001) and a weaker association with neurofilament light (P=0.005). Interpretation: These results show significant differences in neurogranin and total-tau between typical and atypical patients, which may relate to factors other than disease topography. The differential relationships between neurogranin, total-tau and neurofilament light in the Alzheimer's variants, provide evidence for mechanistically distinct and coupled markers of neurodegeneration.
