Learn what traumatic brain injury is and how it can increase the risk of developing Alzheimer’s disease.
Traumatic brain injury (TBI) occurs when a physical force acts on the head, leading to altered brain function. Examples of trauma-induced abnormalities include a decrease or loss in consciousness, persistent headaches, sleep disturbances and changes in mental functions like memory and attention.1 TBI is a leading cause of disability and death among young people and is most often associated with falls, motor vehicle accidents, assaults, military service and engagement in contact sports (like football, boxing, and hockey).2
TBI severity can range from mild to severe injury. A “mild” TBI is often used interchangeably with “concussion,” and most cases (60-80%) of TBI are mild.3 In general, injury severity is classified based on clinical symptoms such as the level of consciousness, as measured by the Glasgow Coma Scale, which remains the gold standard for moderate and severe TBI. Mild TBI and concussion, however, is more challenging to diagnose, and objective measures including neuroimaging and blood biomarkers tests are actively being studied to better diagnose mild TBI and concussion.
In addition to possible death and long-term disabilities, individuals that sustain a moderate to severe TBI are reported to be two to five times more likely to develop dementia, including Alzheimer’s disease (AD), later in life when compared to uninjured individuals.4-6 It is less clear whether mild injuries are also associated with this increased risk.
Disrupted function of brain cells (“neurons”) and their connections (“axons”) after TBI are believed to be caused by the vigorous mechanical strains and deformations that are sustained during impact.7 Experimental data from animal model studies by our group, as well as others, show that concussions induce the inflammatory response in the brain as soon as a few hours after injury.8 These inflammatory signals activate immune cells, which may persist for months in the brain, creating a sustained chronic inflammatory environment.9 Whereas acute inflammation is necessary for tissue healing and repair, chronic inflammation of the brain may result in prolonged injury to neurons and axons. This may eventually trigger degeneration of the brain and thus lead to dementia.10,11
In addition to chronic inflammation, injured neurons also undergo cellular stress and disrupted metabolism that may result in an abnormal production and/or inefficiency in the clearance of toxic proteins, leading to their accumulation in the brain. One such toxic protein is phosphorylated tau (p-tau).
Recent studies that have examined autopsy brains from retired contact sport athletes suggest that multiple concussions sustained over a career may be associated with a brain degenerative condition called chronic traumatic encephalopathy (CTE).12,13 CTE brains are characterized by shrinkage, or atrophy, of brain tissue and accumulation of p-tau around blood vessels, particularly at the bottom of the folds in the brain.14 Moreover, p-tau is also one of the major pathological accumulations in other brain degenerative diseases, including AD.15 These findings suggest that TBI and brain degeneration may share overlapping pathways, such as chronic brain inflammation and accumulation of toxic proteins.
Several research studies have been performed to investigate genetic risk factors that would negatively impact TBI outcomes. One of the potential gene candidates is called APOE. In humans, there are three common genetic variants of the APOE gene: APOE2, APOE3, and APOE4.16 Under normal circumstances, the protein products of this gene (called apolipoprotein E or apoE) play an integral role in essential aspects like cholesterol metabolism, neuronal repair and the clearance of a toxic substance called A-beta, the accumulation of which is associated with the development of AD.
Clinical studies have established APOE4 as the strongest genetic risk factor for AD, and thus whether APOE variants underlie a potential association between TBI and the later development of AD is of intense interest. In studies using genetically engineered animals, the APOE4 gene is associated with accumulation of A-beta and disruption of brain blood vessel health after TBI.17,18 Human clinical studies, however, do not have a conclusive finding. Some studies suggest that APOE4 may be associated with poorer long-term recovery after TBI.19,20 Other studies showed that APOE4 does not significantly increase risk of concussion or risk of developing CTE.21-23 Overall, the link between APOE and TBI outcome still requires further investigation.
Another major avenue in TBI research is the development of fluid biomarkers. Biomarkers are important because they can assist in diagnosis and can also be used to predict recovery. Currently, there are still no fully validated TBI biomarkers.24 However, we know that damaged brain cells release trace amounts of molecules which leak into cerebrospinal fluid (CSF) and the bloodstream. Improved technology now allows us to measure these molecules in both CSF and blood.
In recent years, a protein called glial fibrillary acidic protein (GFAP) has risen as a potentially important concussion biomarker candidate. GFAP is found in brain cells called astrocytes, and is shown to be present in much higher amounts in blood samples taken from athletes who had concussions compared to athletes who did not.25
Neurofilament light (NF-L) chain, a protein released from damaged axons, is also present at much higher levels in blood from concussion patients. Both GFAP and NF-L may prove to be useful to monitor recovery and predict TBI outcomes.26
TBI research is very complex, as TBI can happen to any person at any time of life, by many causes. Currently, there is no cure for TBI. However, with recent advancements in technology and research, we now have better tools to monitor TBI and predict its outcomes. We are also gaining more insights into how traumatic injury may trigger or exacerbate mechanisms known to be involved in neurodegeneration.
In the future, we hope to be able to identify risk factors for TBI and help improve management strategies. The ultimate goal is, of course, to develop effective treatments for TBI. However, as TBI involves damage to different types of brain cells, disruption of brain blood vessels, accumulation of toxic proteins, chronic inflammation, and brain atrophy, it is unlikely that we will come up with one single magic bullet. The more likely scenario is that we will develop different therapeutic approaches to target different aspects of TBI in a patient-centered approach.
Contributing Authors:
Drs. Wai Hang Cheng, David Baron, Jasmine Gill, and Yu Hang Kang.
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Dr. Wellington obtained her PhD at the University of British Columbia and performed postdoctoral fellowships at Harvard Medical School, the University of Calgary, and the University of British Columbia.
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