Rethinking APOE in Alzheimer’s Disease: ApoER2, Ferroptosis and Tau Pathology

Using genetic, cellular and biochemical approaches, we have identified apoER2 as a potential modifier of Alzheimer’s disease-related phenotypes. Human genetic analyses and experimental models suggest that variation in apoER2 can influence disease-relevant outcomes, while loss of apoER2 alters susceptibility to lipid peroxidation and ferroptotic stress and affects tau-associated pathology. These findings point to an unexpected connection between apoE receptor signalling, ferroptosis and tau biology.

In parallel, we are examining how APOE isoforms shape brain lipid composition and cellular proteostasis across ageing. Our data indicate that APOE genotype-dependent changes in lipid species are accompanied by differences in susceptibility to lipid peroxidation and in pathways controlling protein clearance. Ongoing studies implicate altered endosomal trafficking, autophagy and lysosomal processing as potential mechanisms linking apoE-dependent lipid biology to the age-dependent accumulation of proteins such as tau.

Together, these studies support a model in which apoE influences Alzheimer’s disease not only through lipid transport, but through coordinated effects on receptor signalling, lipid peroxidation and cellular protein-clearance pathways. Understanding these interconnected mechanisms may help identify new approaches to modify neurodegenerative disease progression.

Bio: Dr Abdel Ali Belaidi is Head of the Neurodegeneration Therapeutics Laboratory at The Florey Institute of Neuroscience and Mental Health and an Honorary Senior Research Fellow at the University of Melbourne. He completed his PhD in Biochemistry in Germany and undertook postdoctoral research at the University of Cologne, where he investigated the mechanisms of neuronal death in a rare metabolic disease named Molybdenum Cofactor Deficiency. His work identified excitotoxicity as a major disease mechanism and contributed to the development of the first curative treatment that received approval from the US Food and Drug Administration and the European Medicines Agency in 2021.

Dr Belaidi moved to Australia in 2014 after receiving a DFG International Fellowship and undertook further training in neuroscience under the guidance of Professor Ashley Bush. He subsequently established an independent research programme focused on apolipoprotein E (apoE), lipid biology and neurodegeneration. His research demonstrated that apoE can directly protect cells from ferroptosis, providing new insight into how apoE genotype may influence Alzheimer’s disease risk and progression.

His laboratory investigates the roles of apoE, apoE receptors, lipid metabolism, ferroptosis and protein homeostasis in Alzheimer’s disease, with particular interest in how these pathways influence tau pathology and age-related neurodegeneration. He is also developing mRNA-based therapeutic strategies for multiple indications, including dementia, neurodegenerative disorders and rare metabolic diseases.