Apolipoprotein E4 (ApoE) is a major genetic risk factor due to its increase incidence of developing Alzheimer's disease (AD). ApoE plays a major role in the brain to maintain a constant supply of neuronal lipids for rapid and dynamic membrane synthesis. Aggregation of beta amyloid plaques (Aβ) and neurofibrillary tangles in the brain has responsible for onset of AD. Clearance of Aβ aggregation is required and any defect in this clearance may cause AD. APOE with ε4 allele is the major genetic risk factor for Alzheimer's disease (AD). The study was designed to predict the compounds that may be helpful in drug designing to suppress the over activity of apoE4 protein. The study was composed of docking of 22 natural compounds (marine, microorganism and plant derivative) which were used as inhibitors with target protein apoE4. Six Synthetic compounds that are in different phases of clinical trials were docked with target protein in order to compare and analyze the docking results with natural compounds. Natural Compounds S-Allyl-L-Cysteine, Epicatechin Gallate and Fulvic Acid showed high binding affinity i.e. -7.1, - 7 and -7 respectively. Epicatechin Gallate showed hydrogen bonding with Gln156 and Asp35 while Fulvic Acid showed hydrogen bonding with Glu27. Among synthetic compound Tideglusib having high binding affinity with target protein but did not show hydrogen bonding with any amino acid residue. Same as of natural compound S-Allyl-L-Cysteine which showed high binding affinity but did not show hydrogen bonding with any amino acid residue. Protein-Protein interactions of apoE4 showed physical and functional interaction with related proteins while KEGG provided information about related networks for metabolism of this protein. Our study highlighted Epicatechin Gallate on the basis of binding affinity and hydrogen bonding with amino acid residue as a potential lead compound as an inhibitor of AD. Copyright© Bentham Science Publishers; For any queries, please email at [email protected]nthamscience.org.