<i>APOE</i>
            genotype influences acquisition and recall following traumatic brain injury

Crawford, Fiona; Vanderploeg, Rodney D.; Freeman, Melissa J.; Singh, Sumit; Waisman, M; Michaels, L.; Abdullah, Laila; Warden, Deborah L.; Lipsky, Robert H.; Salazar, Andres M.; Mullan, Michael

doi:10.1212/wnl.58.7.1115

Cited by 193 publications

(147 citation statements)

References 10 publications

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“…Furthermore, APOE4ϩ individuals were twice as likely as APOE4Ϫ individuals to be dead, comatose, or severely disabled 6 months after TBI (Teasdale et al, 1997). In addition to the poor general clinical outcome associated with APOE4, memory performance within 6 months of head injury was worse in APOE4ϩ patients compared with APOE4Ϫ patients (Crawford et al, 2002), whereas APOE4 led to worse motor function after TBI (Lichtman et al, 2000). Mild, repetitive head injury also appears to interact with APOE.…”

Section: Discussionmentioning

confidence: 97%

Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

et al. 2002

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The ⑀4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). These factors may act synergistically, in that APOE4ϩ individuals are more likely to develop dementia after TBI. Because the mechanism underlying these effects is unclear, we questioned whether APOE4 and TBI interact either through effects on amyloid-␤ (A␤) or by enhancing cell death/tissue injury. We assessed the effects of TBI in PDAPP mice (transgenic mice that develop AD-like pathology) expressing human APOE3 (PDAPP: E3), human APOE4 (PDAPP:E4), or no APOE (PDAPP:EϪ/Ϫ). Mice were subjected to a unilateral cortical impact injury at 9-10 months of age and allowed to survive for 3 months. A␤ load, hippocampal/cortical volumes, and hippocampal CA3 cell loss were quantified using stereological methods. All of the groups contained mice with A␤-immunoreactive deposits (56% PDAPP: E4, 20% PDAPP:E3, 75% PDAPP:EϪ/Ϫ), but thioflavine-Spositive A␤ (amyloid) was present only in the molecular layer of the dentate gyrus in the PDAPP:E4 mice (44%). In contrast, our previous studies showed that in the absence of TBI, PDAPP:E3 and PDAPP:E4 mice have little to no A␤ deposition at this age. After TBI, all of the A␤ deposits present in PDAPP:E3 and PDAPP: EϪ/Ϫ mice were diffuse plaques. In contrast to the effect of APOE4 on amyloid, PDAPP:E3, PDAPP:E4, and PDAPP:EϪ/Ϫ mice did not differ in the amount of brain tissue or cell loss. These data support the hypothesis that APOE4 influences the neurodegenerative cascade after TBI via an effect on A␤.Key words: Alzheimer's disease; amyloid; APP; traumatic brain injury; apoE; hippocampus The ⑀4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). It was first found that APOE4 was a risk factor for AD in 1993 (Strittmatter et al., 1993), and numerous studies have confirmed this association. Several studies have found that individuals who sustained moderate to severe head injury are more likely to develop dementia and AD (Mayeux et al., 1993(Mayeux et al., , 1995Plassman et al., 2000). These risk factors appear to act synergistically, in that individuals who are APOE4ϩ are even more likely to develop dementia if they sustain TBI at some time in their life. For example, APOE4ϩ individuals were 10 times more likely to develop AD after TBI than those who were APOE4Ϫ, whereas APOE4 in the absence of injury was associated with only twice the risk (Mayeux et al., 1995;Tang et al., 1996).Although the mechanisms underlying these effects are unclear, some evidence suggests that both APOE4 and TBI may influence the risk of AD via interactions with the amyloid-␤ (A␤) peptide.For example, A␤ deposition can be found in ϳ30% of people who die shortly after TBI (Roberts et al., 1991(Roberts et al., , 1994; a significant percentage of these patients are APOE4ϩ (Nicoll et al., 1995(Nicoll et al., , 1996. In addition, analysis of CSF from TBI patients revealed elevated levels of ...

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Section: Discussionmentioning

confidence: 97%

Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

et al. 2002

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“…Previous work from the veteran population have shown that APOE‐ ε 4(+) patients experienced more difficulty with memory compared to those who were APOE‐ ε 4(−) following equally severe TBI, as measured on the CVLT‐II verbal memory and fluency measures at 6 months (Crawford et al., 2002). Similarly, Anderson et al.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, Han and colleagues reported improved neuropsychological outcome at 1 month was associated with APOE‐ ε 4 in the military population (Han et al., 2007), whereas Crawford et al. (2002) reported memory and verbal impairment in military personnel with APOE‐ ε 4 within 6 months of injury. Using an extensive neuropsychological battery at 3 and 6 weeks postinjury, Liberman et al.…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E epsilon 4 (APOE‐ε4) genotype is associated with decreased 6‐month verbal memory performance after mild traumatic brain injury

et al. 2017

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IntroductionThe apolipoprotein E (APOE) ε4 allele associates with memory impairment in neurodegenerative diseases. Its association with memory after mild traumatic brain injury (mTBI) is unclear.Methods mTBI patients (Glasgow Coma Scale score 13–15, no neurosurgical intervention, extracranial Abbreviated Injury Scale score ≤1) aged ≥18 years with APOE genotyping results were extracted from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK‐TBI Pilot) study. Cohorts determined by APOE‐ε4(+/−) were assessed for associations with 6‐month verbal memory, measured by California Verbal Learning Test, Second Edition (CVLT‐II) subscales: Immediate Recall Trials 1–5 (IRT), Short‐Delay Free Recall (SDFR), Short‐Delay Cued Recall (SDCR), Long‐Delay Free Recall (LDFR), and Long‐Delay Cued Recall (LDCR). Multivariable regression controlled for demographic factors, seizure history, loss of consciousness, posttraumatic amnesia, and acute intracranial pathology on computed tomography (CT).ResultsIn 114 mTBI patients (APOE‐ε4(−)=79; APOE‐ε4(+)=35), ApoE‐ε4(+) was associated with long‐delay verbal memory deficits (LDFR: B = −1.17 points, 95% CI [−2.33, −0.01], p = .049; LDCR: B = −1.58 [−2.63, −0.52], p = .004), and a marginal decrease on SDCR (B = −1.02 [−2.05, 0.00], p = .050). CT pathology was the strongest predictor of decreased verbal memory (IRT: B = −8.49, SDFR: B = −2.50, SDCR: B = −1.85, LDFR: B = −2.61, LDCR: B = −2.60; p < .001). Seizure history was associated with decreased short‐term memory (SDFR: B = −1.32, p = .037; SDCR: B = −1.44, p = .038).ConclusionThe APOE‐ε4 allele may confer an increased risk of impairment of 6‐month verbal memory for patients suffering mTBI, with implications for heightened surveillance and targeted therapies. Acute intracranial pathology remains the driver of decreased verbal memory performance at 6 months after mTBI.

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“…In some, 40-80% of patients with AD possess at least one apoE4 allele (12). Likewise, apoE4 is associated with earlier onset, progression, or severity of head trauma (13)(14)(15)(16)(17)(18)(19), stroke (20,21), complications after coronary artery bypass surgery (22,23), Parkinson's disease (24)(25)(26)(27), amyotrophic lateral sclerosis (28)(29)(30)(31)(32), multiple sclerosis (33,34), diabetic neuropathy (35), sleep apnea (36), Lewy body disorders (37), and CNS ischemia (38).…”

Section: Apoe and Neuropathologymentioning

confidence: 99%

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

Mahley

Weisgraber

Huang

2006

Proc. Natl. Acad. Sci. U.S.A.

834

801

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The premise of this review is that apolipoprotein (apo) E4 is much more than a contributing factor to neurodegeneration. ApoE has critical functions in redistributing lipids among CNS cells for normal lipid homeostasis, repairing injured neurons, maintaining synaptodendritic connections, and scavenging toxins. In multiple pathways affecting neuropathology, including Alzheimer's disease, apoE acts directly or in concert with age, head injury, oxidative stress, ischemia, inflammation, and excess amyloid ␤ peptide production to cause neurological disorders, accelerating progression, altering prognosis, or lowering age of onset. We envision that unique structural features of apoE4 are responsible for apoE4-associated neuropathology. Although the structures of apoE2, apoE3, and apoE4 are in dynamic equilibrium, apoE4, which is detrimental in a variety of neurological disorders, is more likely to assume a pathological conformation. Importantly, apoE4 displays domain interaction (an interaction between the N-and C-terminal domains of the protein that results in a compact structure) and molten globule formation (the formation of stable, reactive intermediates with potentially pathological activities). In response to CNS stress or injury, neurons can synthesize apoE. ApoE4 uniquely undergoes neuron-specific proteolysis, resulting in bioactive toxic fragments that enter the cytosol, alter the cytoskeleton, disrupt mitochondrial energy balance, and cause cell death. Our findings suggest potential therapeutic strategies, including the use of ''structure correctors'' to convert apoE4 to an ''apoE3-like'' molecule, protease inhibitors to prevent the generation of toxic apoE4 fragments, and ''mitochondrial protectors'' to prevent cellular energy disruption. mitochondria ͉ neurodegeneration ͉ cytoskeleton ͉ protein folding A polipoprotein (apo) E plays a fundamental role in the maintenance and repair of neurons, but its three isoforms differ in their abilities to accomplish these critical tasks (1-3). ApoE4 is associated with a wide variety of neuropathological processes. We hypothesize that different insults associated with a variety of disorders, in concert with apoE4, can lead to neuropathology. We believe that those processes are mediated by the cellular origin of apoE (astrocytes, neurons, or microglia), the nature of various injurious factors (''second hits''), and the structure of apoE4. Thus, understanding the structure and function of the apoE isoforms will yield new strategies for treating neuropathologies.Although apoE is involved in many neuropathologies, we will focus on its role in Alzheimer's disease (AD). We will consider the unique structural features that distinguish apoE4 from apoE3 and apoE2, the sites of synthesis and normal roles of apoE in the nervous system, and the pathological roles of apoE4 with or without amyloid ␤ (A␤) peptide. The evidence suggests that apoE4 is considerably more than a simple contributing factor in AD pathogenesis. ApoE and NeuropathologyApoE4's involvement in neuropathology is we...

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APOE genotype influences acquisition and recall following traumatic brain injury

Cited by 193 publications

References 10 publications

Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

Apolipoprotein E epsilon 4 (APOE‐ε4) genotype is associated with decreased 6‐month verbal memory performance after mild traumatic brain injury

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

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