Associations of Apolipoprotein e ϵ4 Genotype and Ball Heading with Verbal Memory in Amateur Soccer Players

Liane E. Hunter, Yun Freudenberg-Hua, Peter Davies, Mimi Kim, Richard B. Lipton, Walter F. Stewart, Priyanka Srinivasan, Shanshan Hu, Michael L. Lipton

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Importance: Emerging evidence suggests that long-term exposure to ball heading in soccer, the most popular sport in the world, confers risk for adverse cognitive outcomes. However, the extent to which the apolipoprotein E ϵ4 (APOE ϵ4) allele, a common risk factor for neurodegeneration, and ball heading are associated with cognition in soccer players remains unknown. Objective: To determine whether the APOE ϵ4 allele and 12-month ball heading exposure are associated with verbal memory in a cohort of adult amateur soccer players. Design, Settings, and Participants: A total of 379 amateur soccer players were enrolled in the longitudinal Einstein Soccer Study from November 11, 2013, through January 23, 2018. Selection criteria included participation in soccer for more than 5 years and for more than 6 months per year. Of the 379 individuals enrolled in the study, 355 were genotyped. Three players were excluded for reporting extreme levels of heading. Generalized estimating equation linear regression models were employed to combine data across visits for a cross-sectional analysis of the data. Exposures: At each study visit every 3 to 6 months, players completed the HeadCount 12-Month Questionnaire, a validated, computer-based questionnaire to estimate 12-month heading exposure that was categorized as low (quartiles 1 and 2), moderate (quartile 3), and high (quartile 4). Main Outcome and Measures: Verbal memory was assessed at each study visit using the International Shopping List Delayed Recall task from CogState. Results: A total of 352 soccer players (256 men and 96 women; median age, 23 years [interquartile range, 21-28 years]) across a total of 1204 visits were analyzed. High levels of heading were associated with worse verbal memory performance (β = -0.59; 95% CI, -0.93 to -0.25; P =.001). There was no main association of APOE ϵ4 with verbal memory (β = 0.09; 95% CI, -0.24 to 0.42; P =.58). However, there was a significant association of APOE ϵ4 and heading with performance on the ISRL task (χ2 = 7.22; P =.03 for overall interaction). In APOE ϵ4-positive players, poorer verbal memory associated with high vs low heading exposure was 4.1-fold greater (APOE ϵ4 negative, β = -0.36; 95% CI, -0.75 to 0.03; APOE ϵ4 positive, β = -1.49; 95% CI, -2.05 to -0.93), and poorer verbal memory associated with high vs moderate heading exposure was 8.5-fold greater (APOE ϵ4 negative, β = -0.13; 95% CI, -0.54 to 0.29; APOE ϵ4 positive, β = -1.11, 95% CI, -1.70 to -0.53) compared with that in APOE ϵ4-negative players. Conclusions and Relevance: This study suggests that the APOE ϵ4 allele is a risk factor for worse memory performance associated with higher heading exposure in the prior year, which highlights that assessing genetic risks may ultimately play a role in promoting safer soccer play.

Original languageEnglish (US)
Pages (from-to)419-426
Number of pages8
JournalJAMA Neurology
Issue number4
StatePublished - Apr 2020

ASJC Scopus subject areas

  • Clinical Neurology


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