PROJECT SUMMARY / ABSTRACT Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders among the aged population. Studies showed the critical impacts of apolipoprotein E (APOE) ε4 isoform on susceptibility and pathogenesis of late-onset AD (LOAD). APOE proteins modulate amyloid beta (Aβ) in extracellular plaque formation in an isoform dependent manner. Mitochondrial deficits were also shown associated with risk APOE ε4 and Aβ in AD. The interplay of APOE ε4 and Aβ likely modulates the inter-organelle crosstalk, which justifies the investigation into such crosstalk in AD pathogenesis. The pilot study found increased contacts formed between mitochondria and endolysosomal system in AD neurons compared to non-AD controls, both in human brain and the mouse model. Furthermore, many more contacts were observed among human AD APOE ε4 carriers than in AD APOE ε3 carriers. In vitro studies showed APOE AD risk isoform affected the mito- endolysosomal contacts and mitochondrial Aβ levels and identified STARD3 as an important mediator. These exciting data unveiled a novel abnormality in mito-endolysosomal contacts, which was associated with APOE ε4 regulated Aβ toxicity in AD. Therefore, we hypothesized that APOE ε4 caused abnormally increased mito-endolysosome interaction and mi- tochondrial translocation/accumulation of Aβ through enhanced interaction with STARD3 which led to mitochondrial dysfunction and neurodegeneration in sporadic LOAD. To test this hypothesis, the detailed examination of the mito- endolysosomal contact by in vivo and in vitro AD models is required. The long-term goal of this study is the pursuit of abnormal inter-organelle crosstalk that likely underlies mitochondrial dysfunction and neuronal degeneration in LOAD. In this regard, the efforts will strive to decipher these three specific aims: 1) whether and how the abnormal crosstalk be- tween mitochondria and endolysosomal system causes mitochondrial deficits, 2) what is the role of the interplay of APOE ε4 and its endosomal cargo Aβ in such inter-organelle crosstalk, 3) whether the underlying mechanism supports a thera- peutic potential for AD. The proposal will focus on the pathogenesis in general sporadic AD population associated with common AD risk APOE isoform. Importantly, the proposed novel mechanism will also pave the road for discovery of a yet uncharacterized therapeutic target for common AD population.