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

Article type: Systematic Review

Authors: Krance, Saffire H.^{a; b; c; 1} | Wu, Che-Yuan^{b; c; d; 1} | Chan, Alison C.Y.^{b; c; d} | Kwong, Stephanie^{b; c; d} | Song, Bing Xin^{c; d} | Xiong, Lisa Y.^{b; c; d} | Ouk, Michael^{b; c; d} | Chen, Ming Hui^d | Zhang, Jane^d | Yung, Adrian^d | Stanley, Meagan^e | Herrmann, Nathan^{c; f; g} | Lanctôt, Krista L.^{c; d; f; g; h; i} | Swardfager, Walter^{b; c; d; h; *}

Affiliations: [a] Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada | [b] Sandra Black Centre for Brain Resilience and Recovery, Sunnybrook Research Institute, Toronto, ON, Canada | [c] Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada | [d] Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada | [e] Western Libraries, University of Western Ontario, London, ON, Canada | [f] Department of Psychiatry, University of Toronto, Toronto, ON, Canada | [g] Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada | [h] University Health Network KITE Toronto Rehabilitation Institute, Toronto, ON, Canada | [i] Toronto Dementia Research Alliance, Toronto, ON, Canada

Correspondence: [*] Correspondence to: Walter Swardfager, PhD, Department of Pharmacology & Toxicology, Room 4207, Medical Sciences Building, University of Toronto, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada. Tel.: +1 416 480 6100; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: 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: NAD/NHC = 348/381, SMD [95% CI] = 0.599 [0.268, 0.930], I2 = 72.8%; LAMP-2: NAD/NHC = 401/510, SMD [95% CI] = 0.480 [0.134, 0.826], I2 = 78.7%) and intra-lysosomal proteins (GM2A: NAD/NHC = 390/420, SMD [95% CI] = 0.496 [0.039, 0.954], I2 = 87.7%; CTSB: NAD/NHC = 485/443, SMD [95% CI] = 0.201 [0.029, 0.374], I2 = 28.5%; CTSZ: NAD/NHC = 535/820, SMD [95% CI] = –0.160 [–0.305, –0.015], I2 = 24.0%) and in proteins involved in endocytosis (AP2B1:NAD/NHC = 171/205, SMD [95% CI] = 0.513 [0.259, 0.768], I2 = 27.4%; FLOT1: NAD/NHC = 41/45, SMD [95% CI] = –0.489 [–0.919, –0.058], I2 <0.01). LC3B, an autophagy marker, also showed a difference (NAD/NHC = 70/59, SMD [95% CI] = 0.648 [0.180, 1.116], I2 = 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.

Keywords: Alzheimer’s disease, autophagy, biomarkers, dementia, endosomes, lysosomes, meta-analysis, proteins, systematic review

DOI: 10.3233/JAD-220360

Journal: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1279-1292, 2022