Cause and age of death. The age of death reported in 150 CTE cases ranged from 17 to 98 years old, with the median age of death falling in the range of 60 to 69 years. This represents an earlier average age of death compared to the general US male population age of death of 76.2 years. Of the CTE cases, 72.7% died before the age of 70. Of the 111 CTE cases that included cause of death, none listed CTE as cause of death. The majority of the CTE subjects died from natural causes; however, the prevalence of suicide (11.7%) and accidental deaths (17.5%) is much higher in the CTE population than in the general population (1.5% and 4.8%, respectively). The greater percent of suicides and accidental deaths in the CTE case reports thus far have likely contributed to the lower average age of death in this selected group.
Suicide and accidental death are a more recent observation reported in subjects with CTE, with all suicides and 70% of accidental deaths coming after 2002. Researchers have suggested that reported CTE related symptoms such as lack of impulse control, criminal and antisocial behaviors, and mood disorders may be associated with the increased prevalence of suicide and accidental deaths. A review by Iverson (2014), however, points out that suicide and accidental death have been reported more often in less advanced stages of CTE thereby suggesting that such behaviors may not be due to progression of CTE. Selection-bias due to the greater CTE reporting on high profile former football players who have committed suicide or died due to accidental death has contributed to a possible overestimate of this cause of death. Published reports have noted both individuals and families of players who have died by suicide or accidental death have been disproportionately more likely to participate in CTE brain donation programs.
 Neuropathology. Despite the younger average age of death in the CTE population compared to the general population, the typical age of death of subjects diagnosed with CTE can be considered advanced; hence, the effects of other age-related neuro degeneration diseases must also be taken into account. The general pathological characteristics associated with CTE include macroscopic degenerative changes such as cavum septum pellucidum, generalized global atrophy, thinning of the corpus callosum, and ventricular dilatation. Neurofibrillary tangles similar to AD are seen but not the density of senile plaques which are generally observed in AD. Irregular, multifocal, and generally perivascular tau-immunoreactive neurofibrillary tangles (NFTs) are now considered a pathognomonic finding exclusive to CTE distinguishing it from other neurodegenerative diseases. Beta-amyloid (Abeta) deposits are only identified in about 40% of those found to have CTE, as compared to extensive Abeta deposits present in nearly all those pathologically confirmed to have AD.
Large population studies reviewing pathological findings in the general population have shown that neurodegenerative pathological changes similar to CTE can occur naturally with the aging process. In a post mortem study with a non-selected cohort of 2661 subjects, Braak et al. reported that 91.6% of the subjects over the age of 60 had evidence of neurofibrillary tangles (NFT). Braak et al. as well as others have reported tau pathology findings in much younger cases, albeit at much lower frequencies compared to elderly subjects. In addition to tau related pathology, abnormalities in the transactive response (TAR) DNA binding protein with molecular weight of 43-kDa (TDP-43) have also been observed postmortem in the brains of CTE cases. TDP-43 pathology is a proteinopathy similar to tauopathy that is commonly observed in other neurodegenerative diseases such as in frontotemporal lobar degeneration (FTLD) and ALS. The findings of natural age-related pathology including both tau and TDP-43 have been been commonly observed in elderly non-demented controls in a number of studies as well.
 Age. Increasing age is also a major risk factor for other neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson Disease (PD), Lewy body dementia (DLB), and cerebrovascular disease (CVD). McKee et al. 2013 reported that the 20 oldest subject of their 68 CTE cohort also displayed CTE-related neurodegenerative changes consistent with AD, PD, and DLB among other diagnoses. Although the interaction between diseases is unknown, one cannot discount that the presence of a co-morbid condition may distort both the clinical and pathological picture associated with CTE. As stated previously, CTE shares numerous neuropathological abnormalities commonly associated with other neurodegenerative diseases. Consequently, it is unclear what is responsible for specific clinical changes currently attributed to pre-morbid CTE. Omalu et al. (2011) stated that caution should be exercised when diagnosing CTE in those over the age of 65 since normal age related changes in the brain, Alzheimer's disease, chronic ischemic changes and small vessel disease in the brain could lead to confusion with pathological CTE related changes.
Smith et al. has proposed the pathogenesis of CTE may be best described as an interaction between neuropathological changes due to head trauma and natural age related changes of the brain. The exact contribution of prior head trauma on the clinical and neuropathological changes currently associated with CTE remains unclear and clinical symptoms may be a consequence of multiple neurodegenerative conditions including CTE. Importantly, the presence of neurodegenerative changes is not always associated with clinical symptomatic presentation.
Blaylock and Maroon postulated that immunoexcitotoxicity is a central mechanism in the development of CTE. Based on this concept, microglia, which are activated following TBI, initiate injury response mechanisms resulting in the release of various cytokines, chemokines, reactive oxygen and nitrogen species as part of the innate inflammatory response. This is followed by a reparation and regeneration process:provided there is no recurrent blows to the head. With repetitive brain trauma, before the reparative process, immune mediators along with the traumatic release of excitatory intracellular glutamate can trigger a cascade of neuronal damage including dendritic retraction, synaptic injury, damage to microtubules, mitochondrial suppression and the over-production of tau.