CSF Extracellular Vesicle Aβ42 and Tau/Aβ42 Ratio Are Associated with Cognitive Impairment in Older People with HIV

HIV-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Older people with HIV (PWH) are also at risk for amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). β-amyloid (Aβ) and Tau biomarkers are associated with aMCI/AD, but their relationship to HAND is unclear. Given the role of extracellular vesicles (EVs) in age-related neurological disorders, we investigated soluble and EV-associated Aβ42, total Tau, NFL, GFAP, ICAM-1, VCAM-1, and CRP in relation to cognitive impairment in PWH. Plasma and CSF EVs were isolated from 184 participants (98 PWH on ART and 86 HIV- controls). Biomarkers were measured using Meso Scale Discovery assays. The median age of PWH was 53 years, and 52% were diagnosed with mild forms of HAND. PWH had increased plasma NFL (p = 0.04) and CSF Aβ42 (p = 0.0003) compared with HIV- controls but no significant difference in Tau or EV-associated forms of these markers. CSF EV Aβ42 was decreased (p = 0.0002) and CSF EV Tau/Aβ42 ratio was increased (p = 0.001) in PWH with HAND vs. no HAND, while soluble forms of these markers showed no significant differences. Decreased CSF EV Aβ42 (p < 0.0001) and an increased CSF EV Tau/Aβ42 ratio (p = 0.0003) were associated with lower neurocognitive T scores in age-adjusted models; an optimal model included both CSF EV Aβ42 and plasma NFL. Levels of soluble, but not EV-associated, ICAM-1, VCAM-1, and CRP were increased in PWH with HAND vs. no HAND (p < 0.05). These findings suggest that decreased Aβ42 and an increased Tau/Aβ42 ratio in CSF EVs are associated with cognitive impairment in older PWH, and these EV-associated biomarkers may help to distinguish aMCI/AD from HIV-related cognitive disorders in future studies.