Alzheimer’s disease (AD) is the leading cause of dementia and poses an escalating public health crisis in our aging population. Recent progress in anti-Aβ monoclonal antibody treatments, such as Lecanemab and Donanemab, has shown promise in slowing disease progression by promoting the clearance of aggregated Aβ. However, these therapies are frequently associated with adverse effects, notably amyloid-related imaging abnormalities (ARIA), highlighting the urgent need for alternative or complementary therapeutic strategies beyond Aβ.
Apolipoprotein E (APOE) ε4 is the most significant genetic risk factor for AD, implicated in over 70% of cases. Consequently, targeting APOE represents a compelling therapeutic avenue. Emerging anti-apoE therapies have demonstrated the potential to modulate AD pathology with significant reduced incidence of ARIA in both preclinical and early clinical studies. Nonetheless, the efficacy of current apoE-targeted approaches remains limited and warrants further optimisation.
In this project, we aim to identify and develop novel protective apoE variants that can be delivered via viral vector-mediated expression to mitigate AD pathology. Specifically, we will characterise the biophysical and biochemical properties of both naturally occurring protective apoE variants and synthetic variants generated in-house. With a series of biochemical assays and in vitro cellular models, we will systematically compare these variants to understand their structure-function relationships and neuroprotective potential of these variants in AD. This knowledge will guide the nomination and development of optimised apoE variants, laying the foundation for personalised gene therapies targeting APOE in AD.