Alzheimer's disease (AD) has long been characterized primarily by extracellular deposition of Aβ protein. It is a genetically intricate neurodegenerative disorder. Presenilins (PSs) (presenilin 1 [ PS1] and presenilin 2 [PS2]) and apolipoprotein E (APOE) ε4 allele have been found to be potentially linked to Aβ accumulation and accrual in turn contributing for the AD pathology, despite their significant role in processing of amyloid precursor protein (APP) and lipid metabolism. In this review, the role of PSs and APOE in general physiology and AD pathology due to the mutations occurring in them has been discussed. In addition, a few animal models employed to study these mutations and a few therapeutic avenues studied were summarized.