Regarding impaired lipid metabolism, AMD in humans has been shown to be associated with mutations in several cholesterol-related genes, including ApoE, hepatic lipase, cholesteryl ester transfer protein, lipoprotein lipase, and ATP-binding cassette transporter A1.
27,28 ApoE is primarily expressed in retinal ganglion cells, Müller cells, and the RPE.
29,30 It is a glycoprotein and part of lipoprotein particles, which are essentially involved in regulation of cholesterol metabolism and lipid transport in neural tissues.
31 Furthermore, it is suggested to play an important role in subretinal inflammation possibly through interleukin-6.
26 Human APOE exists in three isoforms, form E2, E3 and E4. Dysfunction of ApoE, especially ApoE e4 allele, has been shown to play an important role in the pathogenesis of Alzheimer's disease.
32 Contrarily, ApoE e4 allele might have a protective effect in AMD development.
33 ApoE2 has been noted to potentially increase the risk of AMD, which is still controversially discussed.
34,35 Moreover, ApoE is one of the major components of drusen.
31 For these reasons, manipulation of the ApoE gene was proposed as a fruitful approach to producing drusen with high esterified cholesterol in laboratory animals.
36 ApoE
−/− mice did, in fact, exhibit similar ultrastructure to basal linear deposit in Bruch's membrane.
15