Search tips
Search criteria 


Logo of molpathLink to Publisher's site
Mol Pathol. 2003 June; 56(3): 132–136.
PMCID: PMC1187307

Genetic vulnerability following traumatic brain injury: the role of apolipoprotein E


Apolipoprotein E (APOE) is thought to be responsible for the transportation of lipids within the brain, maintaining structural integrity of the microtubule within the neurone, and assisting with neural transmission. Possession of the APOE epsilon4 allele has also been shown to influence neuropathological findings in patients who die from traumatic brain injury, including the accumulation of amyloid β protein. Previous clinical studies reporting varying outcome severities of traumatic brain injury, including cognitive and functional recovery, all support the notion that APOE epsilon4 allele possession is associated with an unfavourable outcome. Evidence from experimental and clinical brain injury studies confirms that APOE plays an important role in the response of the brain to injury.

Keywords: apolipoprotein E, genetic vulnerability, outcome, traumatic brain injury

Genetic differences in the ability of the brain to form new connections and undergo neuroplasticity may explain variation in outcome after traumatic brain injury. Recently, an increasing appreciation of the role of apolipoprotein E (APOE) in modifying neurological outcome after traumatic brain injury has been reported, although the mechanisms by which this occurs remain poorly defined. In this brief review, we will discuss the current status of APOE polymorphism and its role in the outcome of patients following traumatic brain injury.


Site of synthesis

APOE is mainly synthesised by astrocytes packed together with cholesterol and phospholipid to form lipid–protein complexes, which are then released into the extracellular space. These complexes bind to APOE receptors on the surfaces of nerve cells, which are internalised into the cell, thereby providing a mechanism for the maintenance and repair of cell membranes, the growth of neurites, and synaptogenesis.1

“Apolipoprotein E assumes the major role in lipid transport in the cerebrospinal fluid”

APOE is the major apolipoprotein in human cerebrospinal fluid, existing as small spherical, discoidal lipoproteins that transport cholesterol and phospholipid. Unlike plasma, in which apolipoprotein B (APOB) containing low density lipoprotein (LDL) is the major lipoprotein involved in lipid transport, the cerebrospinal fluid lacks APOB and LDL, so that APOE assumes the major role in lipid transport in this medium.


APOE is thought to be responsible for the transportation of lipids within the brain and maintaining the structural integrity of the microtubule within the neurone; it may also assist with neural transmission.2–4 Recent reports from transgenic closed traumatic brain injury models also support the role of APOE in the inflammatory response and neuronal repair mechanisms following traumatic brain injury.5,6

Apart from being involved in lipid redistribution, both among the cells of different organs and among the cells within an organ or tissue, APOE has other functions unrelated to lipid transport, as listed below.

  • The extremely high concentrations of APOE produced by macrophages in the distal stump of the rat sciatic nerve and the expression of LDL receptors on the growing tips of neurites and Schwann cells strongly suggest a role for APOE in nerve regeneration. Other speculative roles include the suggestion that APOE could be a neurotrophic factor involved in one of several events required for nerve survival and repair.7
  • APOE is postulated to be involved in smooth muscle cell proliferation, differentiation, or both.
  • APOE modulates the immune response and further investigations may provide an insight into the effects of lipoproteins on tumorigenesis.

Genetic polymorphism

Mature APOE is a 299 amino acid protein, with a relative molecular mass of 34 000 Da, which is the product of a single gene. The APOE gene spans 3.7 kilobases, has four exons, and is located on chromosome 19.8 APOE polymorphism was established using isoelectric focusing and confirmed by two dimensional electrophoresis.9 Three major isoforms of APOE—referred to as APOE 2, APOE 3, and APOE 4—are products of three alleles (epsilon2, epsilon3, and epsilon4) at a single gene locus, and occur with a frequency of 7%, 78%, and 15%, respectively, in white populations.10 Three homozygous phenotypes (APOE 2/2, APOE 3/3, and APOE 4/4) and three heterozygous phenotypes (APOE 2/3, APOE 3/4, and APOE 2/4) arise from the expression of any two of the three alleles. APOE 4 displays normal binding but is associated with raised plasma cholesterol and LDL concentrations.8,9

APOE polymorphism is differentiated by analysis of the amino acid sequences of the three isoforms. Amino acid substitutions account for the differences.

Variation in prevalence rates of the APOE epsilon4 allele

In Western population groups, APOE epsilon4 has been shown to influence the risk of development of Alzheimer’s disease. However the influence of APOE epsilon4 on the development of Alzheimer’s disease in African Americans is still not clear, with conflicting reports showing either little or no increase11–13 or conversely that Alzheimer’s disease in African Americans is associated with the epsilon4 allele.14 Human APOE exhibits genetic polymorphism with varying prevalence rates in all populations examined to date.15–19 Numerous reports document the higher frequency of APOE epsilon4 in people of African heritage,17–19 even in population groups as far south as Southern Africa.20,21

Surprisingly, the association of APOE epsilon4 and Alzheimer’s disease has not been found in sub-Saharan populations of African heritage.20–26 The Indianapolis-Ibadan dementia project—a longitudinal population based study—clearly showed the striking difference in the incidence of Alzheimer’s disease and dementia between African Americans in a developed community and black Africans in a developing community.23,25 This led Corbo and Scacchi15 to propose that the exposure of the APOE epsilon4 gene to contemporary environmental conditions (for example, Western diets, longer life spans) may have rendered APOE epsilon4 a susceptible allele to influence coronary artery disease and Alzheimer’s disease. The absence of the association of APOE epsilon4 with coronary heart disease20 and Alzheimer’s disease in sub-Saharan Africans, and its presence in African Americans, seems to confirm this hypothesis.


The link between Alzheimer’s disease, traumatic brain injury outcome, and the APOE epsilon4 allele

APOE epsilon4 has important direct effects on the nervous system. Possession of the APOE epsilon4 allele has been shown to result in a greater propensity to develop age related cognitive impairment,27,28 a decrease in the synapse–neurone ratio,29 and increased susceptibility to exogenous neurotoxins,30 and hippocampal atrophy.31 It has now been shown that the APOE epsilon4 isoform is associated with an increased risk of late onset familial and sporadic Alzheimer’s disease in Western populations, which results in the standard molecular and cellular neuropathology of Alzheimer’s disease.32,33 In addition, many epidemiological studies have identified a history of a previous head injury as an important environmental risk factor for the development of Alzheimer’s disease.34,35 Mayeux and colleagues36 showed that a history of a previous head injury and APOE epsilon4 interact synergistically; there was a 10 fold increase in the risk of Alzheimer’s disease when both APOE epsilon4 and a history of traumatic head injury were present compared with a twofold increase in risk with APOE epsilon4 alone. Additional evidence has been provided by a study on dementia pugilistica, which is a progressive dementia disorder similar to Alzheimer’s disease, found in boxers and in patients who have been subjected to repeated head injury. A worse outcome was found in a group of boxers with the epsilon4 allele compared with those without.37

“The APOE epsilon4 isoform is associated with an increased risk of late onset familial and sporadic Alzheimer’s disease in Western populations, which results in the standard molecular and cellular neuropathology of Alzheimer’s disease”

Although the mechanisms underlying these effects are unclear, evidence suggests that both APOE epsilon4 and traumatic brain injury may influence the risk of Alzheimer’s disease via interactions with amyloid β protein. Deposition of the amyloid β protein, a molecule proteolytically cleaved from the precursor molecule, amyloid precursor protein (APP), plays a key role in the pathogenesis of Alzheimer’s disease. There is now in vivo evidence linking APOE epsilon4 with amyloid β protein deposition.38 APOE is associated with reduced growth and the branching of neurites in cell culture, an effect that is mediated by the LDL receptor related protein, which mediates the entry of APOE into neurones, and is also increased after injury. APOE epsilon4 also binds less aggressively to cytoskeletal proteins and amyloid β protein, compared with the other isoforms of APOE, reducing any potential protective effect. APOE epsilon4 also promotes more rapid aggregation of amyloid β protein into amyloid fibrils in vitro.39,40

The APOE epsilon4 allele and human traumatic brain injury outcome

It has been reported that head injury triggers amyloid β protein deposition in those with genetic susceptibility conferred by APOE epsilon4, and that amyloid β protein deposition is recorded in one third of severe head injured patients at necropsy.38 It has been postulated that head injury related deposition of amyloid β protein in those who survive may be followed by the development of the full spectrum of Alzheimer’s disease pathology later in life.38

The Glasgow group were the first to report in a clinical setting the influence of APOE epsilon4 and a poor outcome following traumatic brain injury.41 Since then, numerous clinical studies in all types of traumatic brain injury have supported the association of APOE epsilon4 allele possession with an unfavourable outcome.41–44 It was reported recently that the possession of the APOE epsilon4 allele predisposes a patient to a larger sized intracerebral haematoma.45

Similarly, possession of the APOE epsilon4 allele has also been shown to be associated with a poor outcome following spontaneous non-aneurysmal intracerebral haemorrhage,46 haemorrhage associated with amyloid angiopathy,47–49 subarachnoid haemorrhage,50 and, more recently, an increased risk of developing cerebral amyloid angiopathy in patients recovering from traumatic brain injury.51

“It has been reported that head injury triggers amyloid β protein deposition in those with genetic susceptibility conferred by APOE epsilon4”

Presently, very few reports are available documenting the effect of APOE epsilon4 status and human traumatic brain injury. Previous reported studies were on small cohorts and are generally institutionally based, with very few studies looking at moderate to severe traumatic brain injury. Furthermore, most if not all, studies reported to date were conducted in white population groups, with a predominance of males.


Unfortunately, traumatic brain injury is ubiquitous and remains a major cause of considerable morbidity, neuropsychological sequelae, and death. Despite immense advances in the management of clinical traumatic brain injury, no treatment exists to date that can reverse the sequelae of the molecular and cellular mechanisms that lead to post-traumatic death. Understanding the pathobiology of traumatic brain injury is pivotal to halting and reversing the devastating effects of secondary brain injury. Currently, research is primarily focused on the cellular and subcellular mechanisms that are believed to hold the key to understanding the complex networks or cascades unleashed at the time of insult. A brief discussion on potential avenues for future investigation is provided.

Genetically engineered animal models of traumatic brain injury

This form of technology has the potential to recreate many clinical and pathological aspects of traumatic brain injury. Typically, it involves the artificial expression or targeted deletion (knockout) of a specific gene. Thus, genetically engineered animals offer us a unique opportunity to evaluate mechanistic links in specific defined disease entities and provide a basis for the evaluation of potentially effective pharmacological treatment paradigms.

To add to the complexity of this field, certain strains of transgenic mice will accumulate APP following traumatic brain injury, but this has not been associated with amyloid β protein plaque formation, probably because of differences in amino acid composition between different species.52 Following cortical contusion injury in APP transgenic yeast artificial chromosome mice, Murai et al found no post-traumatic differences in cognition or motor deficits.53 However, when a second strain of mice was used, which expressed a mutant APP minigene driven by a platelet derived growth factor promoter, the mice overexpressed mutant APP 10-fold compared with control mice, and plaques were found at 6 months.54 When exposed to cortical contusion injury, these mice showed exacerbation of their cognitive impairments and produced an increase in hippocampal amyloid β protein 1–40 and amyloid β protein 1–42 (two principal forms of β amyloid peptide generated from APP degradation), with 80% cell loss in the CA3 region in the injured hemisphere, leading the investigators to postulate the “two hit hypothesis”. The first insult or hit is the genetic vulnerability (high concentration of amyloid β protein, which is influenced by the individual’s E4 allele status), which is only manifested after the a second independent epigenetic event or insult, such as traumatic brain injury.55

However, Uryu et al were the first to provide the mechanistic link between Alzheimer’s disease and traumatic brain injury.56 Using transgenic mouse models, they were able to prove that repetitive traumatic brain injury accelerates brain amyloid β protein accumulation and oxidative stress, which they suggested could act synergistically to drive the process of Alzheimer’s disease. These studies also confirmed previous epidemiological reports suggesting that the more severe the brain injury, the greater the possibility of developing Alzheimer’s disease,57 and that lipid peroxidation is enhanced by traumatic brain injury and is linked to increased amyloid accumulation and deposition. Other transgenic mouse model studies have also confirmed the role of APOE epsilon4 in influencing the neurodegenerative cascade following traumatic brain injury via the effect of amyloid β protein.58,59 Many studies have suggested that oxidative stress promotes amyloid deposition and fibril formation.56,60,61

Ethnic and regional differences: influence on APOE polymorphism

As previously mentioned, numerous reports have clearly documented the differences in the prevalence rate of the APOE epsilon4 allele. Furthermore, all reports documenting the effect of the APOE epsilon4 allele on traumatic brain injury outcome have been performed almost exclusively in white populations or those derived from white individuals. Contrary to reports from developed regions, it has been reported recently that the APOE epsilon4 allele has no significant effect on traumatic brain injury outcome in an exclusive black African cohort with homogenous traumatic brain injury.62

This racial difference in the effect of the expression of the APOE epsilon4 allele on traumatic brain injury outcome may be related to: (1) interpopulation differences in the sequence variation underlying the three protein isoforms of APOE; (2) the presence of other modifier gene(s); or (3) more importantly, gene–environment interactions that play an important role in modifying the response to traumatic brain injury. Despite the higher frequency of the APOE epsilon4 allele in sub-Saharan population groups (pygmies, Khoi-San (bushmen), and black Africans),15,19–21,24,63,64 the low prevalence of Alzheimer’s disease and the non-significant effect of the APOE epsilon4 allele on closed traumatic brain injury in black Africans supports the susceptibility of the APOE epsilon4 allele to varying contemporary environmental conditions.

Sex based differences and traumatic brain injury outcome: role of APOE polymorphism

Current knowledge of the central nervous system response to traumatic brain injury, in addition to potential treatments, are limited primarily to male subjects. Recent attention to sex based variation following experimental traumatic brain injury has revealed striking differences between the sexes.65,66 It has been postulated that the reduced vulnerability of the female brain may result from the neuroprotective effects of oestrogen67–69 and progesterone.70,71

Currently, it is not clear whether the effects of oestrogen are receptor or non-genomic based. Recently, it has been shown that Premarin, which is widely used for hormonal replacement therapy, has a greater effect on APOE gene expression than glial fibrillary acid protein expression in mixed glial cell cultures.72 This not only adds further support for the neuroprotective effect of oestrogens, but also serves as evidence that APOE induction supports neurite outgrowth as compared with glial fibrillary acid protein induction, which inhibits neurite outgrowth, thereby promoting glial scarring. To date, no clinical report exists documenting the influence of APOE on sex differences.


Evidence from experimental and clinical traumatic brain injury studies has confirmed the important role that APOE plays in the inflammatory response and neuronal repair mechanisms following traumatic brain injury. Sporadic clinical reports have supported the association between APOE e4 status and human traumatic brain injury outcome. Currently, there are many unanswered questions. Is the effect of APOE epsilon4 on traumatic brain injury outcome confined to white or white derived population groups only? It is presently unknown whether APOE polymorphism is consistent in modifying the genetic response to traumatic brain injury in all major racial groups and in different geographical regions. Given the high interpopulation and regional variation, together with the genetic susceptibility of the APOE epsilon4 allele to contemporary environmental factors, further clinical studies are warranted. In addition, it is unknown presently how observations recorded in transgenic animal models will translate to human conditions.

How does the APOE epsilon4 allele influence traumatic brain injury severity, or the type of injury—diffuse versus focal? What is the effect of APOE epsilon4 on sex based human traumatic brain injury outcome? Is this effect confined to adults only or does it apply to a developing brain also, and what is the influence of APOE epsilon4 status on injury to other parts of the neuraxis, such as the spinal cord?

“It is presently unknown whether APOE polymorphism is consistent in modifying the genetic response to traumatic brain injury in all major racial groups and in different geographical regions”

Another alarming facet of APOE status is that the prognostication of traumatic brain injury outcome may have serious medicolegal and financial ramifications for patients and their families. It may be possible in the future that patients are biased by insurance companies according to their expression of genetic and molecular markers. In addition, insurance companies may preclude an individual on the basis of his or her APOE epsilon4 status from pursuing certain high risk sports or occupations where the potential for traumatic brain injury is greater. The ramifications of APOE epsilon4 status may assume a whole new dimension with “genetic stereotyping” taking on greater importance in the future.

Take home messages

  • Apolipoprotein E (APOE) epsilon4 has been shown to contribute to the development of Alzheimer’s disease, although there appear to be racial and geographical variations, and this may not be true for African populations
  • This variation may the result of Western environmental conditions, such as diet and longer life spans
  • APOE epsilon4 and traumatic brain injury appear to act synergistically in the development of Alzheimer’s disease
  • APOE epsilon4 is associated with a poor outcome in traumatic brain injury, but again there may be racial and geographical variations
  • The mechanisms underlying these effects are unclear but the amyloid β protein is thought to be involved
  • More research into APOE epsilon4 and traumatic brain injury is needed


As a result of recent reports, the role of APOE epsilon4 in contributing to the development of Alzheimer’s disease is gaining increasing importance. However, APOE genotyping is not yet part of current medical practice. Undoubtedly, despite the extensive investigation of APOE in lipid metabolism, ischaemic cardiovascular disease, and Alzheimer’s disease, more investigations are needed to determine a clear cut effect of APOE epsilon4 status on human traumatic brain injury in all its facets. A greater research effort needs to be undertaken and the interest in APOE status and traumatic brain injury should be cultivated more extensively and not confined to a few selected groups. Neurosurgeons, in particular, are uniquely placed to play a more meaningful role in this quest to determine the effect of APOE status on traumatic brain injury outcome.


We would like to thank Ms M Tobin from the Department of Neurosurgery, Cleveland Clinic Foundation for help in the preparation of this manuscript


  • APOE, apolipoprotein E
  • APP, amyloid precursor protein
  • LDL, low density lipoprotein


1. Graham DI, Horsburgh K, Nicoll JAR, et al. Apolipoprotein E and the response of the brain to injury. Acta Neurochir 1999;73(suppl):89–92. [PubMed]
2. Herz J. Lipoprotein receptors: beacons to neurons? Trends Neurosci 2001;24:193–5. [PubMed]
3. Mauch DH, Nagler K, Schumacher S, et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science 2001;294:1354–7. [PubMed]
4. Veinsbergs I, Mante M, Jung MW, et al. Synaptotagmin and synaptic transmission alterations in apolipoprotein e-deficient mice. Prog Neuropsychopharmacol Biol Psychiatry 1999;23:519–31. [PubMed]
5. Chen Y, Lomnitski L, Michaelson DM, et al. Motor and cognitive deficits in apolipoprotein E-deficient mice after closed head injury. Neuroscience 1997;80:1255–62. [PubMed]
6. Lynch JR, Pineda JA, Morgan D, et al. Apolipoprotein E affects the central nervous system response to injury and the development of cerebral edema. Ann Neurol 2002;51:113–17. [PubMed]
7. Boyles JK, Zoellner CD, Anderson LJ, et al. A role for apolipoprotein E, apolipoprotein A-1, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. J Clin Invest 1989;83:1015–31. [PMC free article] [PubMed]
8. Houlston RS, Snowden C, Green F, et al. Apolipoprotein (apo) E genotypes by polymerase chain reaction and allele-specific oligonucleotide probes: no detectable linkage disequilibrium between Apo E and Apo C11. Hum Genet 1989;83:364–8. [PubMed]
9. Mahley R. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988;240:622–9. [PubMed]
10. Roses AD. Apolipoprotein E alleles as risk factors in AD. Annu Rev Med 1996;47:387–400. [PubMed]
11. Evans DA, Bennett DA, Wilson RS, et al. Incidence of Alzheimers disease in a bi-racial urban community: relation to apolipoprotein E allele status. Arch Neurol 2003;60:185–9. [PubMed]
12. Sahota A, Yang M, Gao S, et al. Apolipoprotein E-associated risk for Alzheimer’s disease in the African American population is genotype dependent. Ann Neurol 1997;42:659–61. [PubMed]
13. Tang MX, Maestre G, Tsai WY, et al. Relative risk of Alzheimer’s disease and age onset distributions, based on APOE genotypes among elderly African American, Caucasians, and Hispanics in New York city. Am J Hum Genet 1996;58:574–84. [PubMed]
14. Graff-Radford NR, Green RC, Go RC, et al. Association between apolipoprotein E genotype and Alzheimer’s disease in African American subjects. Arch Neurol 2002;59:594–600. [PubMed]
15. Corbo RM, Scacchi R. Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a “thrifty” allele. Ann Hum Genet 1999;63:301–10. [PubMed]
16. Hallman DM, Boerwinkle E, Saha N, et al. The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations. Am J Hum Genet 1991;49:338–49. [PubMed]
17. Sepehrnia B, Kamboh MI, Adams-Campbell LL, et al. Genetic studies of human apolipoproteins. V11. Population distribution of polymorphisms of apolipoproteins A-1, A-11, A-1V, C-11, E, and H in Nigeria. Am J Hum Genet 1988;43:847–53. [PubMed]
18. Kamboh MI, Bunker CH, Aston CE, et al. Genetic association of five apolipoprotein polymorphisms with serum lipoprotein-lipid levels in African blacks. Genet Epidemiol 1999;16:205–22. [PubMed]
19. Zekraoui L, Lagarde JP, Raisonnier A, et al. High frequency of the apolipoprotein E *4 allele in African pygmies and most of the African populations in sub-Saharan Africa. Hum Biol 1997;69:575–81. [PubMed]
20. Loktionov A, Vorster H, O’Neil IK, et al. Apolipoprotein E and methylenetetrahydrofolate reductase in relation to risk factors for cardiovascular disease in UK Caucasians and Black South Africans. Atherosclerosis 1999;145:125–35. [PubMed]
21. Chikosi AB, Moodley J, Pegoraro RJ, et al. Apolipoprotein E polymorphism in South African Zulu women with preeclampsia. Hypertens Pregnancy 2000;19:309–14. [PubMed]
22. Kalaria RN, Ogeng’o JA, Patel NB, et al. Evaluation of risk factors for Alzheimer’s disease in elderly east Africans. Brain Res Bull 1997;44:573–7. [PubMed]
23. Hendrie HC, Ogunniyi A, Hall KS, et al. Incidence of dementia and Alzheimer disease in 2 communities. Yoruba residing in Ibadan, Nigeria, and African American residing in Indianapolis, Indiana. JAMA 2001;285:739–47. [PubMed]
24. Sandholzer C, Delport R, Vermaak H, et al. High frequency of the Apo epsilon 4 allele in Khoi San from South Africa. Hum Genet 1995;95:46–8. [PubMed]
25. Ogunniyi A, Baiyewu O, Gureje O, et al. Epidemiology of dementia in Nigeria: results from the Indianapolis-Ibadan study. Eur J Neurol 2000;7:485–90. [PubMed]
26. Osuntokun BO, Sahota A, Ogunniyi AO, et al. Lack of an association between apolipoprotein E epsilon 4 and Alzheimer’s disease in elderly Nigerians. Ann Neurol 1995;38:463–5. [PubMed]
27. Carmelli D, DeCarli C, Swan GE, et al. The joint effect of apolipoprotein E epsilon 4 and MRI findings on lower-extremity function and decline in cognitive function. J Gerontol A Biol Sci Med Sci 2000;55:M103–9. [PubMed]
28. Small BJ, Graves AB, McEvoy CL, et al. Is APOE-epsilon 4 a risk factor for cognitive impairment in normal ageing? Neurology 2000;54:2082–8. [PubMed]
29. Cambon K, Davies HA, Stewart MG. Synaptic loss is accompanied by an increase in synaptic area in the dentate gyrus of aged human apolipoprotein epsilon4 transgenic mice. Neuroscience 2000;97:685–92. [PubMed]
30. Buttini M, Orth M, Bellosta S, et al. Expression of human apolipoprotein epsilon3 or epsilon4 in the brains of Apoe−/− mice: isoform-specific effects on neurodegeneration. J Neurosci 1999;19:4867–80. [PubMed]
31. Juottonen K, Lehtovirta M, Helisalmi S, et al. Major decrease in the volume of the entorhinal cortex in patients with Alzheimer’s disease carrying apolipoprotein E epsilon4 allele. J Neurol Neurosurg Psychiatry 1998;65:322–7. [PMC free article] [PubMed]
32. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late onset familial and sporadic Alzheimer’s disease. Neurology 1994;43:1467–72. [PubMed]
33. Strittmatter WJ, Weisgraber KH, Huang DY, et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer’s disease. Proc Natl Acad Sci U S A 1993;90:8098–102. [PubMed]
34. Mayneux R, Ottman R, Rang MX, et al. Genetic susceptibility and head injury as risk factors for Alzheimers disease among community-dwelling elderly persons and their first-degree relatives. Ann Neurol 1993;33:494–501. [PubMed]
35. Mortimer JA, van Duijn CM, Chandra V. Head trauma as a risk factor for Alzheimer’s disease: a collaborative re-analysis of case controlled studies. Int J Epidemiol 1991;20(suppl2):S28–S35. [PubMed]
36. Mayeux R, Ottman R, Maestre G, et al. Synergistic effects of traumatic head injury and apolipoprotein epsilon4 in patients with Alzheimer’s disease. Neurology 1995;45:555–7. [PubMed]
37. Jordan BD, Relkin NR, Ravdin LD, et al. Apolipoprotein E epsilon-4 associated with chronic traumatic brain injury in boxing. JAMA 1997;278:136–40. [PubMed]
38. Nicoll JA, Roberts GW, Graham DI. Apolipoprotein E epsilon4 allele is associated with deposition of amyloid β-protein following head injury. Nat Med 1995;1:135–7. [PubMed]
39. Strittmatter WJ, Saunders AM, Goedert M, et al. Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer’s disease. Proc Natl Acad Sci U S A 1994;91:11183–6. [PubMed]
40. Ma J, Yee A, Brewer HB, Jr, et al. Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer’s β-protein into filaments. Nature 1994;57:419–25. [PubMed]
41. Teasdale GM, Nicoll JAR, Murray G, et al. Association of apolipoprotein E polymorphism with outcome after head injury. Lancet 1997;350:1069–71. [PubMed]
42. Crawford FC, Vanderploeg RD, Freeman MJ, et al. APOE genotype influences acquisition and recall following traumatic brain injury. Neurology 2002;58:1115–18. [PubMed]
43. Friedman G, Froom P, Sazbon L, et al. Apolipoprotein E-epsilon 4 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology 1999;52:244–8. [PubMed]
44. Lichtman SW, Seliger G, Tycko B, et al. Apolipoprotein E and functional recovery from brain injury following postacute rehabilitation. Neurology 2000;55:1536–1. [PubMed]
45. Liaquat I, Dunn LT, Nicoll JA, et al. Effect of apolipoprotein E genotype on hematoma volume after trauma. J Neurosurg 2002;96:90–6. [PubMed]
46. Alberts MJ, Graffagnino C, McClenny C, et al. Apo E genotype and survival from intracerebral haemorrhage [letter]. Lancet 346:575:1995. [PubMed]
47. Greenberg SM, Briggs ME, Hyman BT, et al. Apolipoprotein E e4 is associated with the presence and early onset of cerebral amyloid angiopathy. Stroke 1996;27:1333–7. [PubMed]
48. McCarron MO, Hoffman KL, DeLong DM, et al. Intracerebral hemorrhage outcome: apolipoprotein E genotype, hematoma and oedema volumes. Neurology 1999;53:2176–9. [PubMed]
49. Nicoll JA, Burnett C, Love S, et al. High frequency of apolipoprotein E e2 in patients with cerebral hemorrhage due to amyloid angiopathy. Ann Neurol 1996;39:682–3. [PubMed]
50. Niskakangas T, Ohman J, Niemala M, et al. Association of apolipoprotein E polymorphism with outcome after aneurysmal subarachnoid hemorrhage: a preliminary study. Stroke 2001;32:1181–4. [PubMed]
51. Leclercq PD, Graham DI, Nicoll JA, et al. Influence of ApoE genotype on cerebral amyloid angiopathy after closed head-injury. Neuropathol Appl Neurobiol 2002;28:161–2.
52. Pierce JE, Trojanowski JQ, Graham DI, et al. Immunohistochemical characterization of alterations in the distribution of amyloid precursor protein and beta-amyloid peptide after experimental brain injury in rat. J Neurosci 1996;16:1083–109. [PubMed]
53. Murai H, Pierce JE, Raghupathi R, et al. Twofold over expression of human beta-amyloid precursor protein in transgenic mice does not affect the neuromotor, cognitive, or neurodegenerative sequelae following experimental brain injury. J Comp Neurol 1998;392:428–38. [PubMed]
54. Games D, Adams D, Alessandrini R, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717 beta-amyloid precursor protein. Nature 1995;373:523–7. [PubMed]
55. Smith DH, Nakamura M, McIntosh TK, et al. Brain trauma induces massive hippocampal neuron death linked to a surge in beta amyloid levels in mice overexpressing mutant amyloid precursor protein. Am J Pathol 1998;153:1005–10. [PubMed]
56. Uryu K, Laurer H, McIntosh T, et al. Repetitive mild brain trauma accelerates Aβ deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci 2002;22:446–54. [PubMed]
57. Plassman BL, Havlik RJ, Steffens DC, et al. Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology 2000;55:1158–66. [PubMed]
58. Sabo T, Lomnitski L, Nyska A, et al. Susceptibility of transgenic mice expressing human apolipoprotein E to closed head injury: the allele E3 is neuroprotective whereas E4 increases fatalities. Neurosciences 2000;101:897–84. [PubMed]
59. Hartman RE, Laurer H, Longhi L, et al. Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer’s disease. J Neurosci 2002;22:10083–7. [PubMed]
60. Yanagisawa K, Odaka A, Suzuki N, et al. GM1 ganglioside-bound amyloid-beta-protein (A beta): a possible form of preamyloid in Alzheimers disease. Nat Med 1995;1:1062–6. [PubMed]
61. Koppaka V, Axelsen PH. Accelerated accumulation of amyloid beta proteins on oxidatively damaged lipid membranes. Biochemistry 2000;39:10011–16. [PubMed]
62. Nathoo N, Chetty R, van Dellen JR, et al. Apolipoprotein E polymorphism and outcome following closed traumatic brain injury: influence of ethnic and regional differences. J Neurosurg 2003;98:302–6. [PubMed]
63. Gerdes LU, Klausen CIB, Sihm I, et al. Apolipoprotein E polymorphism in a Danish population compared to findings in 45 other study populations around the world. Genet Epidemiol 1992;9:155–67. [PubMed]
64. Kamboh MI, Bunker CH, Aston CE, et al. Genetic association of five apolipoprotein polymorphisms with serum lipoprotein-lipid levels in African blacks. Genet Epidemiol 1999;16:205–22. [PubMed]
65. Roof RL, Duvdevani R, Stein DG. Gender influences outcome of brain injury: progesterone plays a protective role. Brain Res 1993;607:333–6. [PubMed]
66. Roof RL, Hall ED. Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma 2000;17:367–88. [PubMed]
67. Alkayad NJ, Murphy SJ, Traystman RJ, et al. Neuroprotective effects of female gonadal steroids in reproductively senescent female rats. Stroke 2000;31:161–8. [PubMed]
68. Wang Q, Santizo R, Feinstein DL, et al. Estrogen provides neuroprotection in transient forebrain ischemia through perfusion-independent mechanisms in rats. Stroke 1999;30:630–7. [PubMed]
69. Pelligrino DA, Santizo R, Baughman VL, et al. Cerebral vasodilating capacity during forebrain ischemia: effects of chronic estrogen depletion and repletion and the role of neuronal nitric oxide synthetase. Neuroreport 1998;9:3285–91. [PubMed]
70. Roof RL, Zhang Q, Glasier MM, et al. Gender-specific impairment on Morris water maze task after entorhinal cortex lesion. Behav Brain Res 1993;57:47–51. [PubMed]
71. Roof RL, Duvdevani R, Heyburn JW, et al. Progesterone rapidly decreases brain edema: treatment delayed up to 24 hours is still effective. Exp Neurol 1996;138:246–51. [PubMed]
72. Rozovsky I, Hoving S, Anderson CP, et al. Equine estrogens induce apolipoprotein E and glial fibrillary acidic protein in mixed glial cultures. Neurosci Lett 2002;323:191–4. [PubMed]

Articles from Molecular Pathology : MP are provided here courtesy of BMJ Publishing Group