Impact of apolipoprotein E ε4 and HIV on cognition and brain atrophy: Antagonistic pleiotropy and premature brain aging

Abstract

Objective The apolipoprotein E (APOE) ε4 allele may accelerate the progression of HIV disease, and increase the risk for developing HIV-associated neurocognitive disorder (HAND). Whether APOEε4 allele(s) and age may influence brain atrophy in HIV patients is unknown and was evaluated. Methods Automated morphometry on magnetic resonance images, using FreeSurfer analyses, neuropsychological testing and APOE genotyping were performed in 139 subjects [70 seronegative controls (SN); 69 clinically-stable HIV subjects]. Results Compared to SN, HIV subjects had smaller volumes throughout the brain regardless of their HAND status. Compared to APOEε4− subjects, SN controls with APOEε4 had better memory and larger global brain volumes (cerebral white matter and cortex) while HIV subjects with the APOEε4 allele(s) had poorer cognition (verbal fluency, learning, executive function and memory) and smaller cerebral and cerebellar white matter and subcortical structures. Further stratification of age showed that younger (<50 years) APOEε4+SN subjects had larger putamen and cerebral white matter, while younger APOEε4+HIV subjects had poorer performance on verbal fluency and smaller brain volumes [3-way (HIV-status × APOEε4 × Age) interaction-p-values=0.005 to 0.03]. Interpretation These findings suggest that APOEε4 allele(s) may show antagonistic pleiotropy on cognition and brain atrophy in SN controls, but may lead to premature aging with neurodegeneration in younger HIV patients prior to the development of HAND. Potential mechanisms for such interactions may include stronger neuro-inflammation or greater amyloid deposition in younger HIV subjects with APOEε4 allele(s). Early screening for the APOEε4 allele and brain atrophy with morphometry may guide neuroprotective intervention of cognitively normal HIV subjects prior to the development of HAND. Longitudinal follow-up studies and larger sample sizes are needed to validate these cross-sectional results.

Effects of APOE ε4, age, and HIV on glial metabolites and cognitive deficits

“…However, in some HIV-positive individuals, the negative effect of APOE e4 may emerge earlier because younger HIV1 APOE e4 carriers already showed brain atrophy and cognitive deficits. 5 In the current study, APOE e41 exacerbated the cognitive deficits in our HIV subjects across all ages, except for the performance on Trail B, which was slower only in older e41 HIV1 subjects. The poorer performance on some of the cognitive tasks in older HIV APOE e41 patients likely resulted from the lower cognitive reserve in the aging HIV-infected brain, especially those with HAND.…”

“…APOE e41 negatively affects cognition in AD 28 and in other brain injuries, such as traumatic brain injury, 29 and younger individuals with MS. 30 However, the effects of APOE e4 allele on HAND were inconsistent among studies. [4][5][6][7][8][9][10] Several studies found that HIV1 APOE e4 carriers had increased risk of HAND, [5][6][7][8] while others found increased risk only in older individuals ($50 years) 4 or no increased risk of HAND. 9,10 These conflicting findings may in part be attributable to the antagonistic pleiotropy effect of the APOE e4 allele(s), 11 which negatively affects older individuals but may enhance cognitive function in younger individuals.…”

“…However, APOE e41 HIV1 subjects showed greater atrophy in subcortical gray matter structures and white matter. 5 In addition, in postmortem HIV-infected brains, both APOE e4 and older age increased the likelihood of cerebral b-amyloid (Ab) plaque deposition (as diffuse plaques and mild to moderate amyloid angiopathy, but sparse phospho-tau neurofibrillary tangles), and only APOE e4 carriers with the Ab plaques had greater probability of HAND. 33 Furthermore, CSF ApoE protein was elevated only in HIV1 APOE e41 subjects, and the levels correlated with the severity of cognitive deficits, 8 suggesting that the aberrant ApoE e4 protein could not clear the Ab and contributed to HAND.…”

“…pleiotropy, because the APOE e4 allele(s) 5,11 has a negative effect on cognition only in older individuals.…”

Adaptive working memory training improved brain function in human immunodeficiency virus–seropositive patients

“…Nonetheless, the decreased activation on the 2‐back task 1 month after WMT indicates that both groups became more efficient. However, changes in activation were regionally different for the two groups and likely reflect the abnormal baseline neural networks in HIV participants, who typically show hyperactivation in the contralateral (left) caudate and frontal regions,42 lesser striatal‐frontal connectivity,43 reduced dopamine transporters,26, 27 and greater atrophy in subcortical structures 44. The greater decreased activation predominantly in the cortical regions in our HIV participants also indicate lesser requirement of the “top‐down” attention network 24.…”