Exploring the anti-inflammatory effects of cannabis on Alzheimer's disease associated neuropathology HIV infection and aging: An Autopsy Study

About This Grant

People living with HIV (PLWH) in the U.S. and globally are aging, and they are at higher risk for neurocognitive decline despite successful antiretroviral therapy (ART). UNAIDS (2023) estimated that 8.1 million of the 40 million PLWH in the world were 50 years or older, with 41% of PLWH in the U.S. are at least 55 years old. While the majority of aging PLWH globally are infected by subtype C HIV-1, little is known about its neuropathogenesis in this population, representing a critical research gap. Extended lifespan, poor ART penetration of the brain, neuroviral replication, and chronic neuroinflammation with HIV-1 infection may increase the risk for the early onset of age-related neurodegenerative diseases like Alzheimer disease (AD) in PLWH. In 2022, 32 million people globally had AD dementia. However, little is known about whether chronic HIV-1 infection accelerates AD-associated neuropathology due to brain tissue access barriers. Our autopsy program has collected full-body autopsy tissues from 459 decedents with and without HIV-1 to study the size and distribution of HIV-1 tissue reservoirs and the potential effects of cannabis use. We demonstrated that HIV-1 tissue reservoirs were significantly reduced in cannabis users, and the reduction correlates with a decrease in pro-inflammatory cytokines in their tissue reservoirs. In addition, our preliminary study on some collected brain tissues suggests increased AD-associated tauopathy in several PLWH brain tissues analyzed. Our findings support other reports showing an increased risk of AD among PLWH. Interestingly, we found AD-associated neuropathology in PLWH at a younger age than in uninfected individuals. This suggests that HIV-1 may be a potential risk factor for the early onset of AD, with inflammation potentially playing a key role. Our overall goal is to further analyze our archived and additional procured tissues to determine the extent of differential AD-associated neuropathology in PLWH, whether HIV-1 infection and inflammation are associated with the onset of AD at an earlier age (symptom onset before 65), whether cannabis use can mitigate such an effect, and the potential mechanisms involved. We hypothesize that AD- associated neuropathology manifests earlier in PLWH due to HIV-driven neuroinflammation/vascular injury, and can be mitigated by cannabis. Our specific aims are: 1) Determine whether HIV infection enhances and exacerbates AD-associated neuropathology across ages (35-65); 2) Determine whether cannabis use is associated with reduced burdens of AD-associated neuropathology and neuroinflammation in PLWH; 3) Uncover mechanisms linking HIV-1 infection, neuroinflammation, vascular dysfunction, and AD-associated neuropathology. This study will map the spatial distribution of AD-associated neuropathology across age groups in PLWH, identify neurodegeneration mechanisms, and evaluate the potential therapeutic effects of cannabis use. Insights from this research will inform targeted interventions to mitigate brain aging and neurodegeneration in PLWH in the U.S. and throughout the world.