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

Objective: The apolipoprotein E (APOE) epsilon 4 allele may accelerate the progression of HIV disease, and increase the risk for developing HIV-associated neurocognitive disorder (HAND). Whether APOE epsilon 4 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 APOE epsilon 4- subjects, SN controls with APOE epsilon 4 had better memory and larger global brain volumes (cerebral white matter and cortex) while HIV subjects with the APOE epsilon 4 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) APOE epsilon 4 + SN subjects had larger putamen and cerebral white matter, while younger APOE epsilon 4 + HIV subjects had poorer performance on verbal fluency and smaller brain volumes [3-way (HIV-status x APOE epsilon 4 x Age) interaction-p-values = 0.005 to 0.03]. Interpretation: These findings suggest that APOE epsilon 4 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 neuroinflammation or greater amyloid deposition in younger HIV subjects with APOE epsilon 4 allele(s). Early screening for the APOE epsilon 4 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. (C) 2011 Elsevier Inc. All rights reserved.