Endosomal-Lysosomal and Autophagy Pathway in Alzheimer's Disease: A Systematic Review and Meta-Analysis

Background: The endosomal-lysosomal and autophagy (ELA) pathway may be implicated in the progression of Alzheimer's disease (AD); however, findings thus far have been inconsistent. Objective: To systematically summarize differences in endosomal-lysosomal and autophagy proteins in the cerebrospinal fluid (CSF) of people with AD and healthy controls (HC). Methods: Studies measuring CSF concentrations of relevant proteins in the ELA pathway in AD and healthy controls were included. Standardized mean differences (SMD) with 95% confidence intervals (CI) between AD and healthy controls in CSF concentrations of relevant proteins were meta-analyzed using random-effects models. Results: Of 2,471 unique studies, 43 studies were included in the systematic review and meta-analysis. Differences in ELA protein levels in the CSF between AD and healthy controls were observed, particularly in lysosomal membrane (LAMP-1: N-AD/N-HC = 348/381, SMD [95% CI] = 0.599 [0.268, 0.930], I-2 = 72.8%; LAMP-2: N-AD/N-HC = 401/510, SMD [95% CI] = 0.480 [0.134, 0.826], I-2 = 78.7%) and intra-lysosomal proteins (GM2A: N-AD/N-HC = 390/420, SMD [95% CI] = 0.496 [0.039, 0.954], I-2 = 87.7%; CTSB: N-AD/N-HC = 485/443, SMD [95% CI] = 0.201 [0.029, 0.374], I-2 = 28.5%; CTSZ: N-AD/N-HC = 535/820, SMD [95% CI] = -0.160 [-0.305, -0.015], I-2 = 24.0%) and in proteins involved in endocytosis (AP2B1: N-AD/N-HC = 171/205, SMD [95% CI] = 0.513 [0.259, 0.768], I-2 = 27.4%; FLOT1: N-AD/N-HC = 41/45, SMD [95% CI] = -0.489 [-0.919, -0.058], I-2 <0.01). LC3B, an autophagy marker, also showed a difference (N-AD/N-HC = 70/59, SMD [95% CI] = 0.648 [0.180, 1.116], I-2 = 38.3%)), but overall there was limited evidence suggesting differences in proteins involved in endosomal function and autophagy. Conclusion: Dysregulation of proteins in the ELA pathway may play an important role in AD pathogenesis. Some proteins within this pathway may be potential biomarkers for AD.