Apolipoprotein-E genotype and human immunodeficiency virus-associated neurocognitive disorder: the modulating effects of older age and disease severity

Abstract

Background The apolipoprotein-E (APOE) ε4 allele is a risk factor for vascular dementia and Alzheimer’s disease. Recent studies are equivocal with regards to whether or not the ε4 allele confers increased risk for the development of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND), but suggest that age and/or disease severity may be modulating factors. The aim of this study was to assess the interactions and contributions of APOE genotype, age, and HIV disease severity as risk factors for HAND in HIV-infected adults. Methods Participants were 259 HIV-positive individuals who underwent APOE genotyping, a standardized neurological evaluation, a comprehensive neuropsychological evaluation, and laboratory testing. Results Older ε4 carriers showed a higher frequency of HAND compared with age-matched non-ε4 carriers. Analysis by discrete neurocognitive domain revealed that advanced age modulated the effect of the ε4 allele, such that older ε4 allele carriers showed reduced executive functioning and information processing speed. Exploratory analyses assessing the relationship between ε4 and disease severity in the overall sample revealed that disease severity modulated the effect of the ε4 allele on cognition. Lower absolute CD4+ cell count among ε4 allele carriers was associated with poorer working memory ability. Conclusion Advancing age and degree of immunosuppression may influence the association between APOE ε4 allele status and HAND. These two factors need to be taken into account in future research.

No association between Apoε4 alleles, HIV infection, age, neuropsychological outcome, or death

“…Our failure to find an association between ApoE genotype, age, and cognitive impairment is at odds with some reports (Spector, Singh et al 2010, Hoare, Westgarth-Taylor et al 2012, Soontornniyomkij, Moore et al 2012, Panos, Hinkin et al 2013). However, the discrepancy may be, in part, due to the fact that these other reports have detailed cross-sectional analyses which may be affected by selective survival (i.e., the older infected men may be more likely to have had a longer history of uncontrolled HIV replication and thus entered any study with greater degree of CNS involvement).…”

“…(Valcour, Shiramizu et al 2008, Panos, Hinkin et al 2013)]; we found no such associations here. Again, this may be due, in part, to the fact that we adjusted our estimates for race as well as for cohort of entry, which adjusts for survivor bias.…”

“…Reports from cross-sectional studies found no association between the presence of an ε4 allele and cognitive impairment in HIV disease (Andres, Feger et al 2010, Joska, Combrinck et al 2010, Sun, Abadjian et al 2010, Morgan, Woods et al 2013), although this is not a consistent finding (Spector, Singh et al 2010, Chang, Andres et al 2011, Hoare, Westgarth-Taylor et al 2012, Soontornniyomkij, Moore et al 2012). However, it should be noted that studies that did find an association between HIV disease and ε4 include chronological age in their models (Panos, Hinkin et al 2013). The purpose of this study is to replicate and extend these previous findings in a larger sample, and specifically to examine incident cognitive impairment (i.e.…”

ApoE ε4 Is Associated With Cognition, Brain Integrity, and Atrophy in HIV Over Age 60

“…Studies of ApoE ε4 in HIV-infected populations suggest this genotype plays a role in HIV neuropathology; a more complete review of these studies was recently published by Panos et al 14 Before cART use became widespread, HIV-infected individuals with at least one ApoE ε4 allele were twice as likely to have dementia compared to those without. 15 In a more recent cohort study, HIV-infected individuals who are homozygous for ApoE ε4 have accelerated disease progression compared to those with the E3/e3 or E3/E4 genotype, although reported rates of dementia are reported to be similar by ApoE ε4 carrier status.…”

Apolipoprotein E ε4 genotype status is not associated with neuroimaging outcomes in a large cohort of HIV+ individuals

“…Several investigations report no significant effect of ApoE ε4 on cognitive function in HIV+ individuals (Burt et al, 2008; Joska et al, 2010; Sun et al, 2010; Morgan et al, 2013; Becker et al, 2014), while others identified significant relationships between ApoE ε4 and cognitive impairment or increased prevalence of HIV-associated neurocognitive disorders (HAND; Valcour et al, 2004; Spector et al, 2010; Chang et al, 2011; Hoare et al, 2013; Panos et al, 2013). The strongest relationships were observed in older (≥50 years old) ApoE ε4+ HIV+ individuals with older HIV+ APOE4+ individuals demonstrating the worst cognition (Valcour et al, 2004; Panos et al, 2013). The association between ApoE ε4 genotype in HIV+ individuals using neuroimaging methods is less well-studied.…”