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

Objective:

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.

Design:

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.

Methods:

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).

Results:

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 gs < 0.2, ps > 0.17). Meta-regression analysis suggested that less education was associated with increased risk of neurocognitive impairment in carriers (p = 0.0143).

Conclusions:

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.

• Epidemiology and Determinants of Health
  • Determinants of Health
• Determinants of Health
  • Education
• Population(s)
  • Older adults (>50 years)
  • General HIV+ population
• Mental Health
  • Neurocognitive disorders