**7. Conclusions**

*Amyloid Diseases*

APOE4 gene [11, 16, 30, 104, 105].

the protein: apoE2, apoE3, and apoE4, distinguished by three alleles [99]. The apoE ε4 allele confers strong susceptibility for AD and is also the factor for the development of amyloid plaques after TBI. Furthermore, the apoE ε4 allele has been associated with increased Aβ in the cerebral cortex and unfavorable outcome after TBI [100]. ApoE4 individuals were over 10 times more likely to develop AD after severe TBI than those who did not posse the allele [101], and the presence of an apoE4 allele is linked to poor recovery from extended coma. Professional boxers containing the apoE ε4 allele were at increased risk of CTE compared to boxers without the apoE ε4 allele [102]. This finding suggests that genetic factors may strongly influence the risk of CTE after brain injury. However, the possibility remains that certain boxers may be innately 'resistant' to developing AD or dementia following CTE; definitely, not all boxers go on to develop AD, despite repetitive injury and having the higher risk genotype. Consistent with a role of ApoE protein in amyloid deposition in humans, apoE4 also increases amyloid plaque formation in mice. Aβ deposition is also significantly increased following head trauma in PDAPP (platelet-derived growth factor promoter expressing amyloid precursor protein) mice carrying the human apoE ε4 allele versus those carrying apoE ε3 or no apoE (**Table 2**) [103]. Finally, transgenic APOE ε4 mice, which also overexpress APP, show accelerated deposition of Aβ following injury, suggesting apoE ε4 may reduce the clearance of Aβ, thereby favoring its deposition [100] (**Table 2**). Some recent reports are controversial clinical and preclinical studies about the link between poor outcome after severe and mild TBI and the

**6. Similarities and differences in the neuropathology of TBI and AD**

The similarities and differences in the neuropathology associated to TBI and AD are complex. Aβ formation and aggregation, tau phosphorylation, including other proteins found in the brain and CSF following TBI, share a lot of similarities with AD, but also several evident differences. Principally, the localization and distribution of proteins in TBI patients are fundamentally distinct from the characteristic pattern commonly observed in AD [13]. However, one strong similarity between TBI and AD is in the Aβ plaque formation; both are primarily composed of Aβ 41–42, furthermore, CSF levels of Aβ are increased similarly for both [106]. However, in AD there are numerous, compact, core Aβ aggregates in addition to neurofibrillary tangles and neuropil threads, this in contrast to TBI where there appears to be a higher prevalence of diffuse Aβ plaques [34, 36]. Notably, Aβ plaques in TBI are typically described as diffuse and do not display the histochemical or morphological features of the senile plaques that are characteristic of AD [35]. Aβ toxicity only emerges when levels exceed a certain threshold, and unaggregated oligomeric forms of Aβ may contribute to toxicity. As such, rapid aggregation of Aβ into plaques may be a protective event following TBI [73]. In CTE, the tau inclusions are morphologically most similar to those found in AD, with pyramidal neurons maintaining their shape, and tangles consisting of hyperphosphorylated and ubiquitinated tau [84]. This phospho-tau staining was also observed in axons and clusters of neuronal cell bodies in the cerebral cortex and hippocampus (**Figure 2G** and **H**). Such studies have also noted the existence of tau-positive reactive astrocytes in AD, a pathology that is not usually associated with AD. Finally, the tau immunoreactive profile of CTE is characteristically very patchy and irregular, with preferential deposition in the superficial neocortical layers, while tangles in AD are found in deep and in superficial layers [33]. In summary, while there are certain important differences between mild, moderate, and severe TBI and dementia or AD, given the significant overlap

**146**

The association between trauma and the onset of neurodegenerative diseases, such as AD, is extremely convoluted, further complicated by the absence of appropriate animal models able to reproduce human pathologies. Elucidation of this nature of this link remains in its infancy, requiring extensive further research to chip away at the underlying relationship. Moreover, quantification of the relative contributions of various risk factors for developing these pathologies, such as cellular and molecular mechanisms, frequency and severity of the injury, age, sex, and potential genetic predisposition, remain mostly imprecise. Although we do not know how TBI fundamentally impacts the long-term outcome and affects the risk of dementia, it remains clear that amyloid pathways play an important role in secondary injury and acute cell death after trauma. Continued efforts to investigate why TBI, and repeat concussions, may lead to AD and other associated dementias are required. Further understanding of the molecular mechanism underlying these events is required, achievable via better designed animal models able to more closely and accurately mimic the observed behavioral and pathological changes. Only then will we be well equipped to precisely evaluate novel therapeutic agents that may intervene in the disease process. Future research will be required to uncover the mechanisms through which TBI increases the risk of AD, opening the door to designer treatment strategies for the full scope of posttraumatic injuries.

## **Acknowledgements**

This work was supported by R21NS106640 (SV) and R03NS09503 (SV) from the National Institute for Neurological Disorders and Stroke (NINDS).
