We established the pluripotent interleukin-1β (IL-1 β) cytokine as a significant player in the pathogenesis of Alzheimer’s disease as it sets in motion a self-amplifying positive-feedback cycle in which neuronal stress induces synthesis of the neuron's acute phase protein β APP and release of its fragments sAPPa and Aβ. Both these proteins activate microglia and a progressive elevation of IL-1 β, which drives chronically enhanced formation of the hallmark aggregates of AD: A β plaques and, via IL-1 β -induced synthesis and activation of specific kinases, hyperphosphorylation of tau in neurofibrillary tangles in neurons and glial fibrillary acidic protein (GFAP) in astrocytes. Interestingly, both events are dramatically enhanced in AD patients who inherit the Alzheimer gene from both parents (genotype ApoE4,4). Although these IL-1 β and ApoE genotype driven events favor negative outcomes, our progress in drug-development initiatives shows that they are amenable to treatment. Specifically, GFAP-binding chemical agents were shown to inhibit protein aggregation. Further, we discovered a novel function of the APOE£4 gene, which is a toxic gain-of- function exhibited by its protein product, ApoE4. We have demonstrated that ApoE4 competes with Transcriptional Factor EB (TFEB) for binding to the CLEAR DNA motifs, thus, hindering the transcription of three proteins crucial for lysosomal autophagy. We show this to be the case in brain tissues from AD 4,4, but not AD 3,3 patients. Now, importantly, we have identified a lead compound that binds to ApoE4 protein, obviating its interactions with CLEAR DNA and restoring the expression of three autophagy genes, that encode for production of p62, LC3B, and LAMP2 proteins. Now, we are prepared to further elucidate the role of IL-1 β in cellular pathophysiology, establishing its effects on kinases and kinase targets that manifest the modifications which drive predominant aggregate nucleation or propagation events. Our advanced molecular and histological approaches will be applied to confirm predictions of protein-protein interactions derived from proteomics approaches, particularly those involving GFAP. Moreover, these interactions can now be evaluated across brain regions and disease states to test their concordance with known AD parameters. Finally, we will elucidate the mechanisms of action of our identified novel small-molecule drugs targeted to ApoE4 in inhibiting all its pathognomonic interactions with other ApoE4 targeted DNA sequences. Successful completion of our proposed work promises a preventive strategy for foiling the known dramatic role that ApoE4 plays in Alzheimer neuropathogenesis. RELEVANCE: Successful completion of this proposed work will obviate the many pathognomonic aspects of inheritance of the Alzheimer gene (APOEE4) in the 1 in 4 individuals in the US, i.e., 80 million, who inherit one or both copies of this gene. Through the action of our specific drug candidates to inhibit the ApoE4 protein we will, therefore, restore the lysosomal autophagy necessary for efficient clearance of large aggregates, which, as we reported, is repressed in the brains of those who inherit one or both APOE4 genes.