UC San Diego

Rationale: HIV and aging are associated with an increased risk for HIV-associated neurocognitive disorders (HAND) and Alzheimer’s disease (AD). Cross-sectional research among people with HIV (PWH) has shown that the apolipoprotein e4 (APOE-e4) allele and family history of dementia (FHD+) are independently associated with worse neurocognition. However, these cross-sectional data do not address the potential additive effect of FHD and APOE-e4 on rates of global and domain-specific neurocognitive decline among older PWH.Design: This study utilized longitudinal data from the CNS HIV Antiretroviral Therapy Effects Research programs (N=283 PWH; ages 45-69). Aim 1 used a 2x2 factorial analysis of covariance to model independent and interactive effects of FHD and APOE-e4 status. Aim 2 used linear mixed-effects modeling to examine global- and domain-specific neurocognitive trajectories (average follow-up = 7.0 visits over 5.4 years) in the four FHD/APOE-e4 groups linearly and non-linearly. The exploratory aim examined if demographic, neuropsychiatric, substance use, daily functioning factors, comorbidities, and HIV disease characteristics impact neurocognitive trajectories by FHD and APOE-e4 status, using linear mixed-effects modeling. Results: Cross-sectional analyses revealed lower executive functioning (p = .03) and motor skills (p = .04) T-scores among FHD+. Global T-scores trended towards significance (p = .07), with lower scores among FHD+. Mean differences in motor skills trended towards significance by APOE-e4 status (p = .08), with worse scores among APOE-e4 carriers. Longitudinal analyses revealed significant and trend-level differences in curvilinear trajectories between the FHD-/APOE-e4- and FHD+/APOE-e4+ groups in global performance (p = .01), executive functioning (p = .08), learning (p = .02), delayed recall (p = .07), and motor skills (p = .004). Lastly, demographics, depression, substance use history, cardiovascular conditions, and HIV-disease characteristics significantly predicted poorer neurocognitive outcomes, with worse global- and domain-specific trajectories in the FHD+/APOE-e4+ compared to the FHD-/APOE-e4- group. Conclusions: FHD+ and APOE-e4 jointly heighten risk of cognitive decline among middle-to-older age PWH with compounding medical and psychiatric burdens. Additional research is needed to clarify whether domain-specific differences in curvilinear cognitive trajectories between FHD+/APOE-e4+ and FHD-/APOE-e4- reflect HAND or early-stages of AD, considering there were limited sample sizes in follow-up visits and the possibility that cohorts may have been too young to detect expected neurocognitive decline.