The impact of APOE ε4 on cognitive performance in adults with HIV: a systematic review and meta-analysis

With a rapidly aging population living with HIV that may face a double-hit of neuroHIV and Alzheimer's disease, the objective of this meta-analysis was to evaluate the impact of ε4 on cognitive performance in adults with HIV.

The primary literature search was conducted with PubMed and other databases on studies published between 1997 and 2025. Searches were conducted from inception until June 2025.

Out of 289 initial studies, 17 were identified for inclusion meeting predefined criteria. Data extraction was performed by two independent observers and followed established guidelines (PRISMA).

Pooled data included a total of 2610 adults with HIV, including 765 ε4 carriers (age 45.3 ± 8.1  years, 62.1% male) and 1845 noncarriers (age 44.7 ± 9.2, 67.5% male). There was no significant difference between ε4 carriers and noncarriers in diagnosis of neurocognitive impairment [odds ratio (OR) = 1.10, 95% confidence interval (CI) 0.8-1.5 p = 0.563], nor in performance of any of the examined cognitive domains (Hedges g s < 0.2, p s > 0.17). Meta-regression analysis suggested that less education was associated with increased risk of neurocognitive impairment in carriers ( p  = 0.0143).

After controlling for the potential bias from "overrepresented" cohorts that appeared in multiple publications, this meta-analysis found no significant effects of ε4 on neurocognitive performance or impairment in adults with HIV, despite a weak and nonsignificant trend of low performance in memory and executive function in ε4 carriers. Factors such as a relatively young age may contribute to the null findings. Future studies with relatively older cohorts and more sensitive/interdisciplinary approaches are needed.