APOE4 is a Risk Factor and Potential Therapeutic Target for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, the main pathological hallmark of which is the loss of neurons, resulting in cognitive and memory impairments. Sporadic late-onset AD is a prevalent form of the disease and the apolipoprotein E4 (APOE4) genotype is the strongest predictor of the disease development. The structural variations of APOE isoforms affect their roles in synaptic maintenance, lipid trafficking, energy metabolism, inflammatory response, and BBB integrity. In the context of AD, APOE isoforms variously control the key pathological elements of the disease, including Aβ plaque formation, tau aggregation, and neuroinflammation. Taking into consideration the limited number of therapy choices that can alleviate symptoms and have little impact on the AD etiology and progression to date, the precise research strategies guided by apolipoprotein E (APOE) polymorphisms are required to assess the potential risk of age-related cognitive decline in people carrying APOE4 genotype. In this review, we summarize the evidence implicating the significance of APOE isoforms on brain functions in health and pathology with the aim to identify the possible targets that should be addressed to prevent AD manifestation in individuals with the APOE4 genotype and to explore proper treatment strategies.