31 Jan 2020

Soccer players who repeatedly bonk their noggins against the ball have losses in episodic memory. The losses are subtle and likely unnoticeable. This subclinical effect is strongest in ApoE4 carriers, according to a study published January 27 in JAMA Neurology.

Researchers led by Michael Lipton of Albert Einstein College of Medicine in New York correlated the previous year’s heading exposure with memory scores. They questioned amateur players about their degree of heading, and found that people who were ApoE4-positive and regularly headed the ball had the worst delayed recall. Whether these memory blips signify a brewing subclinical pathology that could develop into neurodegenerative disease over time remains unclear, but Lipton said the findings suggest players might do best to at least tone down the number of headers they make in each game.

Multiple studies have linked participation in the military or in rough-and-tumble contact sports, such as American football, ice hockey, and boxing, to neuropsychological problems and subsequent neurodegenerative disease. However, evidence has also been mounting that that milder, subconcussive blows to the head—such as those sustained during intentional heading of the ball by soccer players—also take a cognitive toll and might even spark neurodegeneration (Matser et al., 2001; Feb 2017 news; Nov 2019 news). 

Little is known about how or if ApoE4, the strongest genetic risk factor for AD, influences cognitive consequences of these repetitive actions, although previous studies reported that American football players or boxers who inherited the ApoE4 allele were at greater risk of cognitive impairment than noncarriers (Jordan et al., 1997; Kutner et al., 2000). 

First author Liane Hunter and colleagues investigated verbal memory loss experienced by amateur soccer players in the New York City area. Previously, the researchers had reported that the number of times a player headed the ball over a year correlated with poorer scores on tasks of verbal learning and memory (Levitch et al., 2018). Now, they factored ApoE genotype into the equation. The Einstein Soccer Study enrolled 379 participants who had been playing soccer regularly for more than five years. Of those, 355 were genotyped for ApoE. They answered a detailed computerized questionnaire, called HeadCount-12m, which incorporated information about the number of games or practices per month, months of play per year, and the average number of headers per game, to estimate the total number of headers over the prior year. They also underwent cognitive testing.

Three of the genotyped volunteers reported heading the ball more than 100,000 times over the past year, and were excluded as extreme outliers. The remaining 352 players averaged 23 years of age; 256 were men. Eighty-one carried at least one copy of ApoE4. The players headed the ball an average of more than 600 times, ranging from 70 to 3,800 headers over the year. The researchers split the volunteers into quartiles, with the lowest two considered low heading exposure, the third moderate, the fourth high. Players in the moderate and high exposure quartiles had lower scores on the CogState International Shopping List Delayed Recall (ISRL) test, a measure of verbal memory in which participants attempt to recall a 12-item shopping list 20 minutes after having it read to them. While players with low exposure recalled an average of 10 items, those in the moderate and high exposure groups recalled 9.3 and 9.2, respectively. The ISRL serves as an outcome measure in some Alzheimer’s clinical trials.

ApoE4 strengthened the association between heading and poor performance on the ISRL. Among carriers, the difference in ISRL scores between high- and low-frequency heading quartiles was fourfold greater than in noncarriers. When comparing scores in people with high versus moderate exposure, ApoE4 carriers had an 8.5-fold greater deficit than did noncarriers. ApoE4 seemed to amplify the differences between groups. Translated into absolute terms, noncarriers in the highest heading quartile scored 0.36 points lower on the ISRL than noncarriers with lowest heading exposure. For ApoE4 carriers, the most eager headers scored 1.49 points lower than those in the lowest quartile. Essentially, more frequent heading caused ApoE4 carriers to forget one more item on the shopping list than did noncarriers.

Lipton told Alzforum that this dip in memory is unlikely to be noticed in daily life. The mechanism behind it is unknown. The authors speculated that, as a carrier of lipids in the brain, ApoE could play a role in repairing damaged synapses following injury, and ApoE4 may do a subpar job. Lipton previously reported that high levels of soccer heading associated with microstructural damage to myelin, and considers it possible that ApoE could play a role in myelin repair (Lipton et al., 2013). 

Henrik Zetterberg of the University of Gothenburg in Sweden noted that the effect on memory attributable to ApoE4 is small, and it is unclear how the allele would contribute to memory loss in response to injury at such a young age. He speculated that differences in the way microglia or astrocytes respond to injury in ApoE4 carriers could explain subtle changes in memory. He added that serum markers of axonal injury and neuroinflammation—neurofilament light (NfL) and glial fibrillary acidic protein (GFAP)—could connect pieces of the puzzle in future studies. Zetterberg previously reported elevated NfL in response to soccer heading (Wallace et al., 2018). 

Zetterberg thinks the verbal memory dip by itself is unlikely to portend AD or other neurodegenerative diseases. To Lipton, that is the big question left open by the study. While forgetting the milk on the shopping list may not pose an issue now, could it signify a brewing subclinical pathology that could hasten neurodegeneration?

In an accompanying editorial, Sarah Banks of the University of California, San Diego, and Jesse Mez of Boston University School of Medicine emphasize that the data from this paper cannot answer this question: “It should be stated explicitly that the intellectual jump from the current study findings to late-life cognitive decline and neurodegeneration, including chronic traumatic encephalopathy, is substantial.”

These authors cautioned that the findings should not be used to enact policy changes—such as using ApoE screening to inform decisions about soccer play. Lipton thinks that, conceptually, using genetics to inform decisions about risk is no longer a stretch. Even without ApoE4 in the picture, reducing heading exposure among players who do it most frequently would be feasible, Lipton noted, given that the players with high heading exposure are a minority of players. Among this NYC cohort of amateurs, roughly a third of the players fell into the highest quartile of heading.—Jessica Shugart

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References

News Citations

1. Do 'Headers' Rack Up Brain Damage in Soccer Players? 17 Feb 2017
2. Older Retired Soccer Players Prone to Neurodegeneration 8 Nov 2019

Paper Citations

1. Matser JT, Kessels AG, Lezak MD, Troost J. A dose-response relation of headers and concussions with cognitive impairment in professional soccer players. J Clin Exp Neuropsychol. 2001 Dec;23(6):770-4. PubMed.
2. Jordan BD, Relkin NR, Ravdin LD, Jacobs AR, Bennett A, Gandy S. Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA. 1997 Jul 9;278(2):136-40. PubMed.
3. Kutner KC, Erlanger DM, Tsai J, Jordan B, Relkin NR. Lower cognitive performance of older football players possessing apolipoprotein E epsilon4. Neurosurgery. 2000 Sep;47(3):651-7; discussion 657-8. PubMed.
4. Levitch CF, Zimmerman ME, Lubin N, Kim N, Lipton RB, Stewart WF, Kim M, Lipton ML. Recent and Long-Term Soccer Heading Exposure Is Differentially Associated With Neuropsychological Function in Amateur Players. J Int Neuropsychol Soc. 2018 Feb;24(2):147-155. Epub 2017 Aug 22 PubMed.
5. Lipton ML, Kim N, Zimmerman ME, Kim M, Stewart WF, Branch CA, Lipton RB. Soccer heading is associated with white matter microstructural and cognitive abnormalities. Radiology. 2013 Sep;268(3):850-7. Epub 2013 Jun 11 PubMed.
6. Wallace C, Smirl JD, Zetterberg H, Blennow K, Bryk K, Burma J, Dierijck J, Wright AD, van Donkelaar P. Heading in soccer increases serum neurofilament light protein and SCAT3 symptom metrics. BMJ Open Sport Exerc Med. 2018;4(1):e000433. Epub 2018 Aug 27 PubMed.

Further Reading

Papers

1. Stewart WF, Kim N, Ifrah C, Sliwinski M, Zimmerman ME, Kim M, Lipton RB, Lipton ML. Heading Frequency Is More Strongly Related to Cognitive Performance Than Unintentional Head Impacts in Amateur Soccer Players. Front Neurol. 2018;9:240. Epub 2018 Apr 24 PubMed.
2. Witol AD, Webbe FM. Soccer heading frequency predicts neuropsychological deficits. Arch Clin Neuropsychol. 2003 May;18(4):397-417. PubMed.

News

1. In Former Footballers, MRI Links Cognitive Problems to Axon Damage 11 Jan 2013