Objective: Nearly half of individuals living with HIV in the USA are now 50 or older. This rapidly ageing populace may be at an increasingly greater risk of Alzheimer's disease. However, the potential interaction between HIV-disease and Alzheimer's disease pathogenesis (i.e. Alzheimer's disease genetic risk factors) on brain function remains an open question. The present study aimed to investigate the impact of APOE e4 on brain function in middle-aged to older people with HIV (PWH), as well as the putative interaction between e4 and HIV disease severity.Methods: Ninety-nine PWH participated in a cross-sectional study (56.3 AE 6.5 years, range 41-70 years, 27 women, 26 e4 carriers and 73 noncarriers). Structural MRI and resting-state functional MRI were collected to assess alterations in brain structure and functional connectivity, respectively.Results: APOE e4 was associated with worse memory performance and reduced functional connectivity in the memory network. The functional connectivity reduction was centred at the caudate nucleus rather than hippocampus and correlated with worse memory performance. In e4 carriers, low CD4 þ cell count nadir was associated with reduced functional connectivity in the memory network, but this association was absent in noncarriers. Furthermore, there was an indirect detrimental impact of e4 on memory performance through memory network functional connectivity. However, this indirect effect was contingent on CD4 þ cell count nadir, that is the indirect effect of e4 on memory was only significant when CD4 þ cell count nadir was low.Interpretation: APOE e4 is associated with reduced memory and reduced functional connectivity within the memory network, and low CD4 þ cell count nadir -indicating a history of severe immunosuppression -may exacerbate the effects of e4.

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Background Neuronal dysfunction plays an important role in the high prevalence of HIV-associated neurocognitive disorders (HAND) in people with HIV (PWH). Transcranial direct current stimulation (tDCS)—with its capability to improve neuronal function—may have the potential to serve as an alternative therapeutic approach for HAND. Brain imaging and neurobehavioral studies provide converging evidence that injury to the anterior cingulate cortex (ACC) is highly prevalent and contributes to HAND in PWH, suggesting that ACC may serve as a potential neuromodulation target for HAND. Here we conducted a randomized, double-blind, placebo-controlled, partial crossover pilot study to test the safety, tolerability, and potential efficacy of anodal tDCS over cingulate cortex in adults with HIV, with a focus on the dorsal ACC (dACC). Methods Eleven PWH (47–69 years old, 2 females, 100% African Americans, disease duration 16–36 years) participated in the study, which had two phases, Phase 1 and Phase 2. During Phase 1, participants were randomized to receive ten sessions of sham (n = 4) or cingulate tDCS (n = 7) over the course of 2–3 weeks. Treatment assignments were unknown to the participants and the technicians. Neuropsychology and MRI data were collected from four additional study visits to assess treatment effects, including one baseline visit (BL, prior to treatment) and three follow-up visits (FU1, FU2, and FU3, approximately 1 week, 3 weeks, and 3 months after treatment, respectively). Treatment assignment was unblinded after FU3. Participants in the sham group repeated the study with open-label cingulate tDCS during Phase 2. Statistical analysis was limited to data from Phase 1. Results Compared to sham tDCS, cingulate tDCS led to a decrease in Perseverative Errors in Wisconsin Card Sorting Test (WCST), but not Non-Perseverative Errors, as well as a decrease in the ratio score of Trail Making Test—Part B (TMT-B) to TMT—Part A (TMT-A). Seed-to-voxel analysis with resting state functional MRI data revealed an increase in functional connectivity between the bilateral dACC and a cluster in the right dorsal striatum after cingulate tDCS. There were no differences in self-reported discomfort ratings between sham and cingulate tDCS. Conclusions Cingulate tDCS is safe and well-tolerated in PWH, and may have the potential to improve cognitive performance and brain function. A future study with a larger sample is warranted.

Depressive symptoms are more prevalent in persons with HIV (PWH) than HIVuninfected individuals. In HIV-uninfected individuals, depression has been associated with atrophy in the hippocampus and other brain regions. In the present study, we investigated the impact of depression on brain structure in PWH. One hundred PWH participated in a cross-sectional study (56.6 ± 6.4 yrs, range 41-70 yrs, 24 females, 63 African Americans). The Beck's Depression Inventory-II (BDI-II) was used to assess depressive symptoms. Structural MRI images were collected. Both the voxel-based morphometry (VBM) technique and a region of interest (ROI) based approach were used to examine the relationship between hippocampal gray matter volume (GMv) and depressive symptoms. The impact of HIV CD4 nadir and antidepressants was also investigated. Both VBM and ROI approaches revealed that higher BDI-II scores (implicating more severe depressive symptoms) were associated with loss of hippocampal GMv, especially in the right hippocampus and the right entorhinal cortex.Low CD4 nadir predicted additional hippocampal volume loss independent of depressive symptoms. Taking antidepressants did not have a detectable effect on hippocampal volume. In summary, having more depressive symptoms is associated with smaller hippocampal volume in PWH, and a history of severe immunosuppression (i.e., low CD4 nadir) correlates with additional hippocampal volume reduction. However, the impact of depression on hippocampal volume may be independent of HIVdisease severity such as low CD4 nadir.

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