Traumatic brain injury (TBI) has devastating acute effects and in many cases seems to initiate long-term neurodegeneration. the intense media attention on the high incidence of TBI in ongoing military conflicts. In addition there has been a growing awareness of the epidemiological association between a history of TBI and the development of Alzheimer’s disease (AD) later in life3-12. This link is supported by the identification of acute and chronic AD-like pathologies in the brains of TBI patients and in animal models of TBI. There are several possible mechanisms linking an episode of TBI to later development of neurodegenerative disease such as neuronal loss13-15 persistent inflammation16 17 and cytoskeletal pathology18 19 However the pathophysiological link that has received the most attention is PXD101 the production accumulation and clearance of amyloid-β (Aβ) peptides following TBI. Here we will examine the current understanding of how a single TBI can trigger both rapid and insidiously progressive AD-like pathological changes. In particular we will examine the association between TBI and Aβ turnover. TBI and AD: epidemiological link Compelling data from several studies demonstrate that a history of TBI is one of the strongest epigenetic risk factors PXD101 for AD3-12 20 Pax1 However there is not a complete consensus as some epidemiological studies have failed to find such an association21-28. A major point of contention has been the retrospective nature of some reports that may have led to recall bias – a systematic error due to inaccuracies in subjects’ ability to recall their history of TBI. This is of particular concern when gathering information from patients with cognitive impairments or from secondary informants. Nevertheless larger more controlled studies including level 1 evidence (which requires prospective examination and randomization)11 has led to a general acceptance that TBI is a risk factor for developing AD29. It has also been suggested that a history of TBI accelerates the onset of AD10 30 and that the more severe the injury the greater the risk of developing AD9 11 Indeed because TBI is a complex and heterogeneous disorder the type and extent of the acute pathology probably has an important role in determining the risk of developing AD. In addition the baseline susceptibility of the patient may be predetermined by multiple factors such as age sex and the interplay of several known or unknown genetic factors. For example there is evidence that genetic predisposition as a result of an apolipoprotein E (?? allele were more likely to have a poor outcome following injury139-147. However there have also been reports that failed to show any association between ε4 carriers and outcome148-150. Indeed a recent prospective study examining 984 cases only found an association with possession of an ε4 allele and outcome in younger adults and children with the association PXD101 being strongest in patients aged less than 15 years150. Thus despite a general acceptance that possession of an ε4 allele worsens outcome after TBI there is renewed debate in this regard. Epidemiological data have provided additional information by implicating genotype as a risk factor for the later development of AD following TBI7 9 11 25 151 However considerable debate remains over whether APOE and TBI operate in a synergistic manner to increase the risk of AD development or alternatively act as independent but additive risk factors. Carriers of the ε4 allele were found to be at increased risk of amyloid-β (Aβ) deposition following TBI154. A??deposition was also significantly increased following head trauma in PDAPP (platelet-derived growth factor promoter expressing amyloid precursor protein) mice carrying the human ε4 allele versus those carrying ε3 or no APOE155. The mechanism by which APOE is able to exert an effect on Aβ deposition remains elusive. In addition the interplay PXD101 of polymorphism with the microsatellite polymorphism in neprilysin also shown to contribute to Aβ deposition112 will be of interest. Indeed when combined these polymorphisms could potentially provide useful predictive information. TBI and AD: pathological links Human TBI and Aβ plaques The first clue indicating a pathological link between TBI.