Late onset Alzheimer’s Disease (LOAD) is the most common type of Alzheimer’s accounting for >99% of cases, affecting over 55 million people worldwide with this set to reach 139 million by 2050. Our lack of understanding of the molecular mechanisms underlying LOAD continues to be a major bottleneck in developing widely effective therapies.

 

Both genetics and human postmortem studies demonstrate the importance of the endocytic pathway in the earliest stages of LOAD. This pathway is required for internalisation, trafficking and recycling of cellular components and is essential for normal neuronal and microglial function. Therefore, it is critical to investigate how changes in endocytic function impact the cells of the brain to broaden our understanding of the molecular mechanisms of LOAD. 

 

A challenge of studying LOAD is its genetic complexity. Although considered a sporadic disease there is a large genetic component, with heritability estimated at 60-80%. It is apparent that many genetic changes come together to increase an individual’s risk to developing the disease which makes understanding the underlying biological causes challenging to study using conventional models. To overcome this, my lab has developed an endocytic pathway specific polygenic risk score (PRS) which allows the stratification of patients, identifying individuals with a high burden of genetic changes in the endocytic pathway. Using this endocytic PRS we have already produced a unique resource of 20 patient derived induced pluripotent stem cell (iPSC) lines to study the underlying biological consequences of these endocytic alterations allowing the study of the combinatorial real-life genetics that occurs in LOAD. Initial phenotypic studies of these microglia demonstrate impacts across the endocytic pathway and more widely in regards to cellular function.