Project Summary / Abstract Alzheimer's disease (AD) is a devastating dementia that occurs either in rare, familial forms or in common, sporadic forms. Current understanding of AD pathogenic mechanisms is incomplete, and amyloidocentric clinical trials have failed to show therapeutic efficacy, highlighting the need for a better understanding of AD pathogenic mechanisms to find new strategies of intervention. Dysregulated endosomal trafficking is increasingly recognized as a pathological hub in AD pathogenesis, but the molecular basis of endosomal dysfunction in AD remains unclear. Recent discovery of endosomal trafficking regulator SORL1 (sortilin- related receptor 1, also known as SORLA or LR11) as a major risk factor for both early-onset and late- onset AD opens up a new avenue for studying the pathogenic mechanisms that trigger endosomal dysfunction and neurodegeneration in AD. SORL1 has emerged as the fourth gene for autosomal- dominant familial AD, with loss-of-function SORL1 truncation mutations conferring high pathogenicity to a similar extent as that caused by mutations in the three well-known familial AD genes: amyloid precursor protein (APP) and presenilins 1 and 2. Furthermore, missense variants in the coding region of SORL1 gene have been identified as a genetic risk factor for development of sporadic AD. SORL1 is a sorting receptor in the control of cargo trafficking between endosome, trans-Golgi network (TGN), and plasma membrane. Increasing evidence indicates that SORL1 plays a key neuroprotective role against A accumulation and neurodegeneration by promoting APP trafficking from endosome to TGN and to cell surface, facilitating A trafficking to lysosome for degradation, and maintaining the integrity of the endo-lysosomal system. Despite strong evidence linking SORL1 dysfunction to AD pathogenesis, the molecular mechanisms that regulate SORL1 function remain poorly understood. The proposed project aims to address this knowledge gap and perform innovative research to elucidate SORL1 regulation mechanisms and their alterations in AD. The findings and novel insights generated from this project will advance our understanding of SORL1 dysfunction and endosomal trafficking dysregulation in AD and may point to new therapeutic strategies for AD treatment.