Associations of Apolipoprotein E ε4 Genotype and Ball Heading With Verbal Memory in Amateur Soccer Players

Study Abstract and Opinion


Associations of Apolipoprotein E ε4 Genotype and Ball Heading With Verbal Memory in Amateur Soccer Players

JAMA Neurol. 2020;77(4):419-426. doi:10.1001/jamaneurol.2019.4828 Published online January 27, 2020.

Liane E. Hunter, PhD; Yun Freudenberg-Hua, MD; Peter Davies, PhD; Mimi Kim, PhD; Richard B. Lipton, MD; Walter F. Stewart, PhD, MPH; Priyanka Srinivasan, BS; ShanShan Hu, MS; Michael L. Lipton, MD, PhD  

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.


For 20-years studies have pointed to a relationship between soccer heading in adults and negative neurocognitive effects (Levitch et al., 2018; Lipton et al., 2013; E. J. T. Matser, 1999; J. T. Matser et al., 1998; Stewart et al., 2018; Witol & Webbe, 2003). In a recently published paper, a group from Albert Einstein Medical School point to a risk of gene Apolipoprotein E ε4+ (APOE4+) for negative cognitive effects due to heading in the absence of frank concussion (Hunter et al., 2020). The presence of APOE4+ was shown to predispose adult soccer players to lower memory scores on a neuropsychological (International Grocery List Test) test based on the amount of self-reported heading they engaged in over the year.    

APOE4+ has long been known as a risk for early onset Alzheimer’s disease and so it has been a candidate for neurodegeneration in concussion studies.  Several studies have documented a relationship between APOE4 and experiencing a concussion  (Terrell et al., 2008), various MRI modalities and history of concussion (Tremblay et al., 2014; Tremblay et al., 2017) , and post-concussion symptoms (Merritt et al., 2018; Merritt & Arnett, 2016).

The significance of this study is identifying the relationships between subconcussive impacts, memory performance and APOE4.  It has long been suspected that individual differences determined much of the vulnerability to HIE including sub-concussive exposures.  Identifying this “due-to” is important for understanding why some show effects of HIE and others do not.

The Hunter study has its share of weaknesses as these studies are exceedingly difficult to do; but taken in the broader context, the effects of soccer heading has long been a source of concern in terms of brain health.  The role of APOE in concussion risks is becoming quite clear, both through the accumulation of direct studies and its association with neurodegeneration. Clearly, efforts to limit exposure and improve soccer heading technique in youth seem worthwhile. At the same time, it is becoming important to establish risk functions for levels of exposure in the presence of APOE4+.  Genotyping to inform participant decision-making and population safety is becoming a realistic goal.


Hunter, L. E., Freudenberg-Hua, Y., Davies, P., Kim, M., Lipton, R. B., Stewart, W. F., Srinivasan, P., Hu, S., & Lipton, M. L. (2020). Associations of Apolipoprotein E ε4 Genotype and Ball Heading With Verbal Memory in Amateur Soccer Players. JAMA Neurology, 77(4), 419.

Levitch, C. F., Zimmerman, M. E., Lubin, N., Kim, N., Lipton, R. B., Stewart, W. F., Kim, M., & Lipton, M. L. (2018). Recent and Long-Term Soccer Heading Exposure Is Differentially Associated With Neuropsychological Function in Amateur Players. Journal of the International Neuropsychological Society, 24(2), 147–155.

Lipton, M. L., Kim, N., Zimmerman, M. E., Kim, M., Stewart, W. F., Branch, C. A., & Lipton, R. B. (2013). Soccer Heading Is Associated with White Matter Microstructural and Cognitive Abnormalities. Radiology, 268(3), 850–857.

Matser, E. J. T. (1999). Neuropsychological Impairment in Amateur Soccer Players. JAMA, 282(10), 971.

Matser, J. T., Kessels, A. G. H., Jordan, B. D., Lezak, M. D., & Troost, J. (1998). Chronic traumatic brain injury in professional soccer players. Neurology, 51(3), 791–796.

Merritt, V. C., & Arnett, P. A. (2016). Apolipoprotein E (APOE) ϵ4 Allele Is Associated with Increased Symptom Reporting Following Sports Concussion. Journal of the International Neuropsychological Society, 22(1), 89–94.

Merritt, V. C., Rabinowitz, A. R., & Arnett, P. A. (2018). The Influence of the Apolipoprotein E (APOE) Gene on Subacute Post-Concussion Neurocognitive Performance in College Athletes. Archives of Clinical Neuropsychology, 33(1), 36–46.

Stewart, W. F., Kim, N., Ifrah, C., Sliwinski, M., Zimmerman, M. E., Kim, M., Lipton, R. B., & Lipton, M. L. (2018). Heading Frequency Is More Strongly Related to Cognitive Performance Than Unintentional Head Impacts in Amateur Soccer Players. Frontiers in Neurology, 9.

Terrell, T. R., Bostick, R. M., Abramson, R., Xie, D., Barfield, W., Cantu, R., Stanek, M., & Ewing, T. (2008). APOE, APOE Promoter, and Tau Genotypes and Risk for Concussion in College Athletes: Clinical Journal of Sport Medicine, 18(1), 10–17.

Tremblay, S., Henry, L. C., Bedetti, C., Larson-Dupuis, C., Gagnon, J.-F., Evans, A. C., Théoret, H., Lassonde, M., & Beaumont, L. D. (2014). Diffuse white matter tract abnormalities in clinically normal ageing retired athletes with a history of sports-related concussions. Brain, 137(11), 2997–3011.

Tremblay, S., Iturria-Medina, Y., Mateos-Pérez, J. M., Evans, A. C., & De Beaumont, L. (2017). Defining a multimodal signature of remote sports concussions. European Journal of Neuroscience, 46(4), 1956–1967.

Witol, A. D., & Webbe, F. M. (2003). Soccer heading frequency predicts neuropsychological deficitsଝ. Archives of Clinical Neuropsychology, 21.

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