Apolipoprotein L1 is Increased in Frontotemporal Lobar Degeneration Post-mortem Brain but Not in Ante-mortem Cerebrospinal Fluid

Abstract Background: Frontotemporal Dementia (FTD) is a spectrum of heterogeneous disorders caused by frontal-temporal lobar degeneration (FTLD). FTLD is mainly characterized by brain protein aggregates of tau (FTLD-Tau) or TDP-43 (FTLD-TDP), however, the clinicopathological heterogeneity across the FTLD spectrum makes ante-mortem diagnosis of these pathological subtypes challenging. Our unbiased proteomics study showed increased Apolipoprotein L1 (APOL1) levels, a protein involved in lipid metabolism and transport, in CSF of FTD patients, which was more prominent in FTLD-Tau. We aimed to understand APOL1 expression in FTLD post-mortem brain tissue with defined pathology and to validate its potential as a CSF biomarker for FTD and its pathological subtypes.Methods: APOL1 levels were analyzed in the frontal cortex of FTLD (n = 62, including 23 FTLD-Tau and 29 FTLD-TDP) and non-demented controls (n = 18) by immunohistochemistry, western blot (WB), and a novel prototype ELISA. The association of APOL1 immunoreactivity with phosphorylated Tau (pTau) and TDP-43 (pTDP43) immunoreactivity was assessed. CSF APOL1 was analyzed in confirmed FTD patients (n = 27, including 12 FTLD-Tau and 15 FTLD-TDP) and controls (n = 15) using the same ELISA.Results: APOL1 levels were significantly increased in FTLD compared to controls as measured by immunohistochemistry (p < 0.001), WB (p < 0.001), and ELISA (p < 0.05), but no differences between the pathological subtypes were observed. APOL1 immunoreactivity was present in neuronal and glial cells. APOL1 immunoreactivity did not specifically co-localize with any of the main FTLD proteinopathies (pTau or pTDP43). CSF APOL1 levels were comparable between FTD patients and controls and between FTLD pathological subtypes. Conclusion: We show an upregulation of APOL1 in FTLD pathology irrespective of the subtypes, indicating a role of this novel protein in FTD pathophysiology. The APOL1 levels detected in brain tissue were not mirrored in the CSF, limiting its potential as a specific FTD biofluid-based biomarker using our current in-house immunoassay. Future research should explore the role of APOL1 downstream specific FTLD pathologies.