PROJECT SUMMARY / ABSTRACT As with many other diseases, Alzheimer’s disease (AD) is a multifactorial disorder consisting of multiple pathologies that are each known to be deleterious in their own right. Clinical trials assessing disease-modifying drugs for Alzheimer’s disease (AD) have largely been focused on amyloid beta (Aβ) pathology rather than other pathological components including tau pathology and gliosis. This is in part due to Aβ pathology being viewed as the initiating event responsible for all other pathologies. The interim result is Aducanumab (AduhelmTM; Biogen) recently approved by the Federal Drug Administration (FDA)l, likely to be effective at early stages of AD where it would be most effective in halting downstream pathologies. Treatments for later stages of diseases will require therapeutics not only for Aβ, but also tau pathology and gliosis namely combination therapy (CT). CT has recently been strongly encouraged by the European Union-North American Clinical Trials in Alzheimer’s disease Task Force (EU/US CTAD Task Force) and the FDA5. Aducanumab on its own is already dose-limited due to its potential for off-target toxicity and development of a CT including its use would result in additive toxicity that the other drugs may introduce plus possible unknown drug interactions. This makes CT extremely complex to research and to date unattractive for big pharma. To overcome these challenges, we have designed a smart cell-based drug delivery (SmACD) system to enable in vitro research highly translatable to in vivo validation that has the capability of support a large number of drugs currently being used in clinical trials and to deliver them in combination to the brain without the toxicity associated with systemic or other forms of bulk drug administration. We propose to use SmaCD to target the most afflicted brain regions in AD equipped with a CT based on Aducanumab and Zagotenemab to elicit microglia-mediated clearance of neurotoxic oligomeric Aβ and disease- spreading tau, respectively, accompanied by an immunomodulator to enhance the phagocytic activity of microglia whilst suppressing inflammation. We plan to test the technology initially in human cells and mouse cells followed by in vivo validation in a transgenic mouse model of AD that presents Aβ and tau pathology accompanied by gliosis at mid and late stages of disease development. Our results, if successful, would directly provide ‘proof-of-concept’ for the translatability of SmaCD-delivered CT drug therapy for use in the intervention of human disease.