In the brain, apolipoprotein E (ApoE) is mainly produced by astrocytes, and it transports cholesterol to neurons via ApoE receptors on the neuronal membrane, which are members of the low density lipoprotein receptor gene family. The ApoE gene is localized on chromosome 19. The gene consists of three introns and four exons. There are three major isoforms: ApoE2 (cys112, cys158), ApoE3 (cys112, arg158) and ApoE4 (arg112, arg158). These single-point mutations have significant effects on the structure and function of these proteins. E2 is present in about 7% of the population [3]. Individuals with an E2/E2 combination clear dietary fat slowly and are at greater risk for early atherosclerotic disease [4]. E2 has also been implicated in Parkinson’s disease [5]. E3 is found in about 80% of the population [3]. It is considered the ‘neutral’ Apo E genotype. E4 is found in approximately 13% of the population [3] and has been implicated in atherosclerosis, Alzheimer’s disease [6], impaired cognitive function [7], reduced hippocampal volume [8], unfavourable outcome after traumatic brain injury [9] and ischemic cerebrovascular disease [10]. Carriers of E4/E4 allele have an increased risk for Alzheimer’s disease by 10–30 times by age 75 years when compared to individuals with other ApoE alleles.

Multiple studies have investigated the role of ApoE alleles in the context of HAND. A recent cross-sectional study from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort compared 144 HIV-infected individuals with ApoE4 allele with 322 HIV-infected individuals without ApoE4 and did not find any difference with regard to the number of individuals in either of these two groups who had normal cognition and asymptomatic or symptomatic neurocognitive dysfunction (Morgan et al., 2013). A previous study from the pre-HAART (highly active antiretroviral therapy) era in a smaller sample size also did not find differences in the neurocognitive function as baseline when they compared the groups with (n = 11) and without (n = 33) ApoE4 allele. However, on longitudinal follow-up, they found that the group with ApoE4 allele failed to show a practice effect when retested at 6-month intervals for 3 years [11]. Subsequent studies have shown that older individuals with ApoE4 allele and HIV infection show more severe neurocognitive deficits when compared to those who did not have the ApoE4 allele. These differences were not apparent in the younger populations [12]. Autopsy studies show that HIV-infected individuals with ApoE4 allele compared to those with ApoE3 allele have a much higher level of oxidative stress in the brain as determined by measuring hydroxynonenal levels in lipid extracts from multiple regions from the brain. Whilst the differences were apparent in all regions tested, they were most pronounced in the frontal cortex [13]. When human neurons were treated with HIV proteins, gp120 and Tat, it was found that those that were homozygous for ApoE4, that is, ApoE4/4 showed the most neurotoxicity, whilst ApoE2/2, 2/4, 3/3 and 3/4 showed similar amounts of neurotoxicity. In another large clinical study, it was found that the rate of survival of HIV-infected individuals was significantly lower in the group with ApoE4/4 allele. This group also had a higher steady-state viral load [14].