Interactions between betaine, insulin resistance, and cognitive impairment in people with and without HIV

Metabolic dysfunction and neurocognitive decline share inflammatory pathways that may be amplified in people with HIV (PWH). Prior studies suggest insulin resistance correlates with cognitive decline, while gut-related metabolites, such as betaine, may be protective through metabolic regulation and anti-inflammatory effects. We investigated whether metabolic markers differentially associate with cognitive performance in PWH versus people without HIV (PWoH).

We enrolled 200 participants, equally stratified by HIV and diabetes mellitus status, into four groups of 50. All completed neuropsychological testing yielded demographically corrected global T-scores (higher indicates better performance). Biomarkers included GlycA, Diabetes Risk Index (DRI), Lipoprotein Insulin Resistance Index (LP-IR), branched-chain amino acids, and betaine. Multiple linear regression examined associations between metabolic markers and T-scores, adjusting for covariates.

Participants had a mean age of 55.7 years (71.0% male). GlycA levels were higher in individuals with diabetes (p = 0.001). Higher DRI levels were associated with worse global T-scores (standardized β = -0.27, p = 0.009). Higher LP-IR was associated with worse cognitive performance in PWH, but not in PWoH (interaction p = 0.007). HIV moderated the association between betaine and global T-scores (interaction p = 0.01); higher betaine was associated with better cognitive performance (standardized β = 0.24, p = 0.02). Higher betaine correlated with lower LP-IR in PWH (standardized β = -0.47, p < 0.01) and lower DRI in all participants (ps < 0.05).

Insulin resistance might play a prominent role in cognitive health in PWH than PWoH, suggesting HIV-related metabolic vulnerability is affecting brain health. Associations between betaine, which has immunomodulatory effects, and improved metabolic profiles suggest potential therapeutic targets to preserve cognitive function in PWH. These observational findings may reflect metabolic, dietary, or lifestyle-related factors and require confirmation in studies with detailed nutritional assessment.