A single gene variant, APOE4, makes someone up to 15 times more likely to develop late-onset Alzheimer’s, yet no one knows exactly how it drives the disease. This project tackles that blind spot. Alzheimer’s affects millions, and over 95% of cases are late-onset. While amyloid plaques get the headlines, tangled tau protein inside brain cells correlates more closely with how severe the disease becomes. The APOE gene comes in three forms: APOE4 raises risk dramatically, APOE2 protects, and APOE3 sits in between. The researcher will use human-derived cell models and advanced imaging to watch how each APOE isoform affects tau aggregation, spread, and toxicity, and how they alter the behaviour of astrocytes and microglia—the brain’s support cells that can turn inflammatory. If successful, this work will reveal the molecular pathways that link APOE to tau-driven neurodegeneration. That knowledge could lead to isoform-specific treatments—for example, drugs that boost APOE2-like protection or block APOE4’s harmful effects. The human cell models developed here also provide a platform for drug screening. This is fundamental science with a clear translational path: understanding the mechanism is the necessary first step toward more precise diagnostics and therapies for a disease that strains healthcare systems worldwide.
View original technical description
Alzheimer’s disease (AD) is the most common cause of dementia, affecting millions of people worldwide and presenting a critical challenge to healthcare systems, societies, and global economies. AD is typically categorised into two types: early-onset, which occurs before the age of 65, and late-onset, which develops after 65 and accounts for over 95% of cases. With an ageing global population, the prevalence of AD is expected to rise sharply, placing an increasing burden on healthcare infrastructure and creating significant financial strain. Although the clinical presentation and pathological processes in AD can vary widely in severity and affected brain regions, nearly all patients share two defining pathological hallmarks: deposition of amyloid-beta (Aß) plaques and neurofibrillary tangles of tau in the affected brain. Among these, the accumulation of tau correlates more closely with disease severity than Aß, highlighting tau dysfunction as a critical target for understanding and treating AD. The exact causes of late-onset AD remain unclear, but genetic factors play a significant role. The apolipoprotein E (APOE) gene is the strongest known genetic determinant of late-onset AD risk. APOE has three isoforms: APOE2, APOE3, and APOE4. APOE4 increases the risk of developing AD by up to 15-fold, whereas APOE2 provides a neuroprotective effect. Despite these well-established correlation, the molecular mechanisms through which APOE influences tau pathology and contributes to neurodegeneration remain poorly understood. This proposal aims to uncover how APOE influences tau dysfunction to better understand its role AD progression. Using advanced imaging techniques and human-derived models, we will investigate the isoform-specific effects of APOE on tau aggregation, propagation, and associated toxicity at the molecular level. Additionally, we will explore how APOE isoforms modulate tau uptake and inflammatory responses in astrocytes and microglia - glial cells that are crucial for maintaining brain homeostasis but also known to contribute to neurodegeneration in AD. By studying the interactions between glia and neurons, we aim to determine how these processes may exacerbate or mitigate tau pathology in an isoform-specific manner. Finally, we will examine the indirect effects of APOE isoforms on tau pathology mediated by Aß, focusing on how ApoE-Aß interactions influence tau dysfunction in both neurons and glial cells. This research will provide critical insights into the molecular and cellular mechanisms by which APOE isoforms drive tau-mediated neurotoxicity and inflammation. By clarifying how these processes differ across isoforms, the study aims to elucidate the pathways linking APOE to AD risk and progression. The findings have the potential to inform the development of isoform-specific therapeutic strategies, such as modulating ApoE lipidation or targeting specific signalling pathways involved in tau and Aß interactions. The outcomes of this research have far-reaching implications. For basic science researchers, this proposed study will address significant gaps in understanding ApoE-tau interactions in human models system and determine their contribution to AD. For translational science, the human cell models developed in this work, which focus on tau dysfunction, can serve as platforms for drug discovery and screening targeted at tau pathology. Ultimately, for patients and healthcare providers, the long-term goal is to enable more precise diagnostics and effective treatments, contributing to alleviating the global burden of AD.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know