Lipid and Genetic Predictors of Midlife Cognitive Decline in Treated HIV-1 Infection

Cognitive impairment affects 20-50% of HIV-1-infected (HIV+) adults on antiretroviral therapy (ART), and the search for protective factors has intensified as the population ages [1, 2]. Predictors of cognitive impairment in HIV+ populations are unknown, and multiple factors including ongoing low levels of viral replication, systemic inflammation, coinfection with Hepatitis C, genetic predisposition, irreversible CNS injury prior to ART, and neurotoxicity of ART regimens are potential candidates for influencing cognitive outcomes [3-5]. Furthermore, aging modifies inflammatory responses through molecular mechanisms that include altered lipid metabolism, mitochondrial function, and oxidative stress, coined “inflammaging” [6, 7]. The factors associated with HIV-associated neurocognitive impairment has been largely sought in cohort studies with cross-sectional designs, but these studies are limited by demographic differences that can influence neuropsychological test results, and difficulty in making associations between outcomes and exposures of long duration [4, 8-11]. To date, longitudinal studies investigating similar or overlapping age- and HIV-related mechanisms contributing to cognitive decline in older ART-suppressed HIV+ adults are lacking. In the first portion of this thesis, we describe studies using a mixed-effects approach to model age-related cognitive trajectories of ART-adherent HIV+ and HIV- adults modified by time-varying lipid indices and APOE ε4 genotype. This was a prospective study of HIV+ and HIV- men enrolled in the Multicenter AIDS Cohort Study from 1996-2010, and we showed that dyslipidemia and APOE ε4 allele are independent risk factors for cognitive decline in ART-adherent HIV+ men between ages 50-65. The findings are significant because they identify novel risk factors for midlife cognitive decline in HIV+ men on suppressive ART and suggest that clinical management of dyslipidemia may be an effective strategy to reduce cognitive decline in HIV+ men over age 50. Systemic inflammation, cardiovascular disease (CVD) and APOE ε4 genotype are associated with age-related cognitive decline in the general population [12-16], but the combined extent to which they account for midlife cognitive decline in HIV-infection remains unknown. In the second portion of this thesis, we discuss our strategy to quantify the extent to which cognitive decline is explained by inflammation, CVD, and APOE ε4 genotype in older ART-adherent HIV-adults.