Effects of APOE epsilon 4, age, and HIV on glial metabolites and cognitive deficits

Objective: We aimed to evaluate the combined effects of HIV and APOE epsilon 4 allele(s) on glial metabolite levels, and on known cognitive deficits associated with either condition, across the ages. Methods: One hundred seventy-seven participants, primarily of white and mixed race (97 seronegative subjects: aged 44.7 + or - 1.3 years, 85 [87.6%] men, 28 [28.9%] APOE epsilon 4+; 80 HIV+ subjects: aged 47.3 + or - 1.1 years, 73 [91.3%] men, 23 [28.8%] APOE epsilon 4+), were assessed cross-sectionally for metabolite concentrations using proton magnetic resonance spectroscopy in 4 brain regions and for neuropsychological performance. Results: Frontal white matter myo-inositol was elevated in subjects with HIV across the age span but showed age-dependent increase in seronegative subjects, especially in APOE epsilon 4+ carriers. In contrast, only seronegative APOE epsilon 4 subjects showed elevated myo-inositol in parietal cortex. All APOE epsilon 4+ subjects had lower total creatine in basal ganglia. While all HIV subjects showed greater cognitive deficits, HIV+ APOE epsilon 4+ subjects had the poorest executive function, fluency memory, and attention/working memory. Higher myo-inositol levels were associated with poorer fine motor function across all subjects, slower speed of information processing in APOE epsilon 4+ subjects, and worse fluency in HIV+ APOE epsilon 4+ subjects. Conclusions: In frontal white matter of subjects with HIV, the persistent elevation and lack of normal age-dependent increase in myo-inositol suggest that persistent glial activation attenuated the typical antagonistic pleiotropic effects of APOE epsilon 4 on neuroinflammation. APOE epsilon 4 negatively affects energy metabolism in brain regions rich in dopaminergic synapses. The combined effects of HIV infection and APOE epsilon 4 may lead to greater cognitive deficits, especially in those with greater neuroinflammation. APOE epsilon 4 allele(s) may be a useful genetic marker to identify white and mixed-race HIV subjects at risks for cognitive decline.