**1. Introduction**

Traumatic brain injury (TBI) affects millions of individuals worldwide, with 1.7 million new cases in the US each year [1]. Although many patients survive the initial lesion, TBI initiates a wide variety of pathologies such as neurological deficits, short and long-term brain damage, neuroinflammation, cognitive and emotional impairments, all of which depend on the severity of the injury and other various factors [2, 3]. Brain injuries are most frequently caused by motor vehicle crashes, sports injuries, or simple falls; males are about twice as likely as females to experience a brain trauma [4]. At least 5.3 million Americans, or approximately 2% of the total US population, currently are burdened with disabilities resulting from TBI [5].

Functional deficits caused by TBI result from an initial impact and secondary damage that continue to develop over time and provide a therapeutic window for treatment to prevent or ameliorate many of the damaging consequences of injury [6]. While single compounds have been reported to be effective for short periods in standardized rodent models of TBI, therapeutic tools currently available to clinicians to treat patients with TBI are minimal*.*

The neuroinflammatory cascade following TBI contributes to neurodegeneration and death through the cumulative action of multiple damaging processes [7]. TBI is one of the most consistent candidates for initiating the molecular cascades that result in neurodegenerative diseases, such as Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS) [8–11]. Notably, there exists a strong epidemiological relationship between the occurrence of TBI and the development of Alzheimer's disease (AD) later in life [12–15]. The link between TBI and AD is strengthened through the identification of acute and chronic AD-like pathologies in the brain in both TBI survivors and animal models of brain injury.

AD is a progressive neurodegenerative disease, which can only be fully diagnosed at autopsy. It is characterized, histologically, by the presence of amyloid plaques and intracellular neurofibrillary tangles (NFT) in the brain [16]. The amyloid plaques consist of aggregated proteinaceous material, a significant component of amyloid β (Aβ). The tangles are composed of paired helical filaments (PHF) of the microtubule-associated phosphoprotein tau [16, 17]. In this chapter, I will describe the main pathological similarities, and differences, between TBI and AD. Although the evidence suggests that TBI is a risk factor for dementia, very little is known about what type, frequency, or severity of trauma is necessary to induce dementia [18].

A chronic disease process is initiated after TBI, known as the secondary injury cascade, and as part of this process, neuroinflammation, neuronal loss, or the production, aggregation and clearance of Aβ peptides occurs [19]. Several of these pathophysiological features have been characterized in patients with AD with similar neuropathology. Furthermore, epidemiological studies have shown how repetitive injury, or a single mild, moderate, or severe TBI, can cause a wide range of proteinopathies [20], and likely contribute to the later onset of debilitating neurodegenerative diseases. Indeed, the human pathology of survival from TBI is best described as a "polypathology", featuring Aβ, tau, and TDP-43 pathologies, together with white matter degradation, neuronal loss, and neuroinflammation [21]. There exist many pathological features common to both acute brain injury and AD, including Aβ deposition, tau phosphorylation, neurite degeneration, synapse loss and microgliosis [22]. Besides, the susceptibility of the patient may be predetermined by multiple factors such as age, sex and the interplay of several genetic factors [23–25].

The purpose of this chapter is to discuss the neuropathology and genetic risk factors associated with TBI that may collectively shed some light on the risk of developing dementia or AD following head trauma, as well as possible treatments in animal models and human studies.
