Association of apolipoprotein E epsilon 4 and cognitive impairment in adults living with human immunodeficiency virus: a meta-analysis

Background: It is controversial whether the apolipoprotein E epsilon 4 allele (APOE ε4) is a risk gene for human immunodeficiency virus (HIV)-related neurocognitive impairment. This meta-analysis aimed to summarize evidence of the associations between APOE ε4 and cognitive impairment in people living with HIV (PLWH).

Methods: Our study conducted a systematic literature search of PubMed, Web of Science, Embase, Google Scholar, and ProQuest for studies published before April 11, 2022 that evaluated associations between APOE ε4 and cognitive impairment in adult PLWH (aged ≥18 years). We calculated pooled odds ratios (ORs) of global cognitive impairment and 95% confidence intervals (CIs) and standardized mean differences (SMDs) for specific cognitive domains between APOE ε4 carriers and non-carriers. Subgroup meta-analyses were used to evaluate the result profiles across different categorical variables.

Results: Twenty studies met the inclusion criteria, including 19 that evaluated global cognitive impairment. APOE ε4 was significantly associated with global cognitive impairment in PLWH (OR = 1.36, 95% CI = [1.05, 1.78], number of estimates [k] = 19, P = 0.02, random effects). Subgroup meta-analysis based percentage of females showed evident intergroup differences in global cognitive performance between ε4 carriers and non-carriers (P = 0.015). APOE ε4 carriers had lower cognitive test scores than non-carriers in all seven cognitive domains, including fluency (SMD = -0.51, 95% CI = [-0.76, -0.25], P < 0.001, k = 4, I2 = 0%), learning (SMD = -0.52, 95% CI = [-0.75, -0.28], P < 0.001, k = 5, I2 = 0%), executive function (SMD = -0.41, 95% CI = [-0.59, -0.23], P < 0.001, k = 8, I2 = 0%), memory (SMD = -0.41, 95% CI = [-0.61, -0.20], P < 0.001, k = 10, I2 = 36%), attention/working memory (SMD = -0.34, 95% CI = [-0.54, -0.14], P = 0.001, k = 6, I2 = 0%), speed of information processing (SMD = -0.34, 95% CI = [-0.53, -0.16], P < 0.001, k = 8, I2 = 0%), and motor function (SMD = -0.19, 95% CI = [-0.38, -0.01], P = 0.04, k = 7, I2 = 0%).

Conclusions: Our meta-analysis provides significant evidence that APOE ε4 is a risk genotype for HIV-associated cognitive impairment, especially in cognitive domains of fluency, learning, executive function, and memory. Moreover, the impairment is sex specific.

Meta analysis registration: PROSPERO, CRD 42021257775.