While genetic studies have identified more than 75 genetic loci implicated in Alzheimer’s disease (AD) risk, the underlying causal genes and biological mechanisms involved in disease development remain unclear. This proposal aims to understand how two candidate AD risk genes, EED and PICALM, work together within the endolysosomal system to disrupt the ability of brain immune cells to clear cellular waste, a key function that helps maintain brain health. The first aim will investigate the role of EED and PICALM in modulating microglial responses to AD-relevant substrates, including disease-associated microglia (DAM) states, their signaling pathways, and phagocytic uptake involving TREM2, a key microglial receptor linked to AD. The second aim will focus on how EED and PICALM influence the subsequent digestion and degradation of substrates once they are taken up. This project will translate findings of genomic studies from statistical associations to biological function and enhance our understanding of the contribution of EED and PICALM to AD pathogenesis.
