Apolipoprotein E epsilon4 and the risk of dementia with stroke. A population-based investigation

Slooter, Arjen J. C.

doi:10.1001/jama.277.10.818

Cited by 201 publications

(139 citation statements)

References 28 publications

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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.

827

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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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.

827

801

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“…43,44 This is partly based on the fact that abnormal amyloid precursor protein processing is facilitated by ApoE e4 in normal cellular repair reactions triggered by environmental factors, such as head injury, herpes simplex reactivations or stroke. 45,46 Based on some case-control studies, prevention of head trauma could be considered primary prevention for dementia, particularly in individuals with increased genetic susceptibility such as the presence of ApoE e4. The use of helmets for sports activities, safety belts in cars and maneuvers to reduce falls in the elderly are worthy in themselves and may, in addition, reduce later risk of dementia.…”

Section: Head Trauma and Other Brain Injuriesmentioning

confidence: 99%

“…109 Thus, reduction in cerebrovascular disease may also be considered an important preventative measure for the dementia associated with AD; this may apply particularly to individuals with ApoE e4. 45 Treatment of hypertension, heart disease, hypercholesterolemia, diabetes and reduction of smoking all contribute to the THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES Suppl. 1 -S62 reduction of stroke and indirectly of dementia.…”

Section: Prevention Of Dementia Due To Strokementioning

confidence: 99%

Preventing Dementia

Black

Patterson

Feightner

2001

Can. J. Neurol. Sci.

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Suppl. 1 -S56The concept of primary prevention of dementia is relatively new but will assume increasing importance as dementia prevalence increases in our graying population 1 and as the etiological factors and molecular pathogenetic mechanisms of primary degenerative dementias become better understood. 2Current definitions of dementia require memory impairment and cognitive dysfunction in at least one other domain of sufficient degree to interfere with social functioning.3 In this review we emphasize prevention of dementia in individuals who are cognitively normal but may be at risk for dementia, or who are cognitively impaired but not yet demented. Potential preventative measures include avoidance or control of modifiable risk factors to prevent progression to clinically manifest dementia. Secondary prevention of the degenerative dementias is equivalent to treatment, which is discussed in a companion article in this series. Recent clinical trials have provided evidence for modest symptomatic stabilization with socalled cognitive enhancing agents. If effective retardive therapies or neuroregenerative strategies are developed, in the future it may be possible to delay progression or even partially reverse dementing illness.ABSTRACT: Primary prevention will become increasingly important as dementia prevalence increases and effective retardive therapies are developed. To date, only one randomized controlled trial (involving treatment of systolic hypertension) has demonstrated that the incidence of dementia can be reduced. Physicians should remain alert to possible secondary causes of dementia and correct these whenever possible. Primary and secondary prevention of stroke should reduce dementia related to cerebrovascular disease either directly or as a comorbid factor in Alzheimer's disease (AD). Epidemiological studies have revealed a number of risk factors for AD including genetic mutation, susceptibility genes, positive family history, Down's syndrome, age, sex, years of education, head trauma and neurotoxins. In casecontrol studies non-steroidal anti-inflammatory medication and estrogen replacement therapy appear to decrease the relative risk of developing AD. Further research to develop and test preventative therapies in AD and other dementias should be strongly encouraged.RÉSUMÉ: Prévention de la démence. La prévention primaire va devenir de plus en plus importante à mesure que la prévalence de la démence augmente et que des stratégies efficaces pour en retarder l'apparition sont développées. Pour l'instant, une seule étude randomisée contrôlée (traitement de l'hypertension systolique) a démontré que l'incidence de la démence peut être réduite. Les médecins devraient demeurer vigilants pour détecter la présence causes secondaires de démence et les corriger si possible. La prévention primaire et secondaire de l'accident vasculaire cérébral devrait diminuer l'incidence de la démence reliée à la maladie cérébrovasculaire, soit directement ou comme facteur de comorbidité dans la maladie d'Alzheimer (MA). Des étud...

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“…8 -11 Three apoE isoforms are found in humans: apoE2, apoE3 (the most common), and apoE4. 12 ApoE4 is associated with increased risk of Alzheimer's disease 13,14 and Parkinson's disease, 15 poor outcome after head injury 16 and stroke, 17 accelerated progression of multiple sclerosis, 18 and subtle neurological impairments in individuals without overt neurological disease. 19,20 Thus, apoE4 may contribute to diverse neurological conditions.…”

mentioning

confidence: 99%

Cellular Source of Apolipoprotein E4 Determines Neuronal Susceptibility to Excitotoxic Injury in Transgenic Mice

Buttini

Masliah

et al. 2010

The American Journal of Pathology

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The lipid transport protein apolipoprotein E (apoE) is abundantly expressed in the brain. Its main isoforms in humans are apoE2, apoE3, and apoE4. ApoE4 is the major known genetic risk factor for Alzheimer's disease and also contributes to the pathogenesis of various other neurological conditions. In the central nervous system, apoE is synthesized by glial cells and neurons, but it is unclear whether the cellular source affects its biological activities. To address this issue, we induced excitotoxic injury by systemic kainic acid injection in transgenic Apoe knockout mice expressing human apoE isoforms in astrocytes or neurons. Regardless of its cellular source, apoE3 expression protected neuronal synapses and dendrites against the excitotoxicity seen in apoE-deficient mice. Astrocyte-derived apoE4 , which has previously been shown to have detrimental effects in vitro, was as excitoprotective as apoE3 in vivo. In contrast, neuronal expression of apoE4 was not protective and resulted in loss of cortical neurons after excitotoxic challenge, indicating that neuronal apoE4 promotes excitotoxic cell death. Thus, an imbalance between astrocytic (excitoprotective) and neuronal (neurotoxic) apoE4 expression may increase susceptibility to diverse neurological diseases involving excitotoxic mechanisms.

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Apolipoprotein E epsilon4 and the risk of dementia with stroke. A population-based investigation

Cited by 201 publications

References 28 publications

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

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

Preventing Dementia

Cellular Source of Apolipoprotein E4 Determines Neuronal Susceptibility to Excitotoxic Injury in Transgenic Mice

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