Does apolipoprotein E genotype modify the clinical expression of ALS?

Apolipoprotein E (ApoE) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk for cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. ApoE–lipoproteins bind to several cell-surface receptors to deliver lipids and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. ApoE isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on ApoE in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different ApoE isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link ApoE4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting ApoE.

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“…The APOE genotypes do not seem to influence the risks of Huntington disease 89 nor amyotrophic lateral sclerosis. 90 …”

Section: Apoe Genotypes Ad and Cognitionmentioning

confidence: 99%

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy

et al. 2013

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“…It was suggested that the ε4 allele has a deleterious effect on ALS survival (271, 272) and association with younger age at ALS onset (273), but these findings were not subsequently confirmed (274). ApoE is a widely distributed, well-characterized cholesterol transport protein that circulates in the plasma after being synthesized by the liver, spleen, and kidneys (275).…”

Section: Modifier Genes Associated With Sals and Oxidative Stressmentioning

confidence: 99%

Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis

D’Amico

Factor-Litvak

Santella

et al. 2013

Free Radical Biology and Medicine

275

213

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Sporadic amyotrophic lateral sclerosis (sALS) is one of the most devastating neurological diseases; most patients die within 3 to 4 years after symptom onset. Oxidative stress is a disturbance in the pro-oxidative/anti-oxidative balance favoring the pro-oxidative state. Autopsy and laboratory studies in ALS indicate that oxidative stress plays a major role in motor neuron degeneration and astrocyte dysfunction. Oxidative stress biomarkers in cerebrospinal fluid, plasma, and urine, are elevated, suggesting that abnormal oxidative stress is generated outside of the central nervous system. Our review indicates that agricultural chemicals, heavy metals, military service, professional sports, excessive physical exertion, chronic head trauma, and certain foods might be modestly associated with ALS risk, with a stronger association between risk and smoking. At the cellular level, these factors are all involved in generating oxidative stress. Experimental studies indicate that a combination of insults that induce modest oxidative stress can exert additive deleterious effects on motor neurons, suggesting multiple exposures in real-world environments are important. As the disease progresses, nutritional deficiency, cachexia, psychological stress, and impending respiratory failure may further increase oxidative stress. Moreover, accumulating evidence suggests that ALS is possibly a systemic disease. Laboratory, pathologic, and epidemiologic evidence clearly support the hypothesis that oxidative stress is central in the pathogenic process, particularly in genetically susceptive individuals. If we are to improve ALS treatment, well-designed biochemical and genetic epidemiological studies, combined with a multidisciplinary research approach, are needed and will provide knowledge crucial to our understanding of ALS etiology, pathophysiology, and prognosis.

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“…In addition to the aforementioned genetic mutations, a number of other genetic mutations and polymorphisms have been identified to be associated with sporadic ALS (Chen et al, 2013). Studies on the influence of apoE genotype on ALS have provided conflicting results (Jawaid et al, 2011; Praline et al, 2011). A recent study in a large cohort of French patients with sporadic ALS (n=1,482) and matched controls (n=955) found that APOE -ε4 allele was associated with an increased risk of bulbar-onset ALS in men (Praline et al, 2011).…”

Section: Genetic Clinical and Experimental Evidence For Protective Ementioning

confidence: 99%

HDL and cognition in neurodegenerative disorders

Hottman

Chernick

Cheng

et al. 2014

Neurobiology of Disease

139

129

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High-density lipoproteins (HDL) are a heterogeneous group of lipoproteins composed of various lipids and proteins. HDL is formed both in the systemic circulation and in the brain. In addition to being a crucial player in the reverse cholesterol transport pathway, HDL possesses a wide range of other functions including anti-oxidation, anti-inflammation, pro-endothelial function, anti-thrombosis, and modulation of immune function. It has been firmly established that high plasma levels of HDL protect against cardiovascular disease. Accumulating evidence indicates that the beneficial role of HDL extends to many other systems including the central nervous system. Cognition is a complex brain function that includes all aspects of perception, thought, and memory. Cognitive function often declines during aging and this decline manifests as cognitive impairment/dementia in age-related and progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. A growing concern is that no effective therapy is currently available to prevent or treat these devastating diseases. Emerging evidence suggests that HDL may play a pivotal role in preserving cognitive function under normal and pathological conditions. This review attempts to summarize recent genetic, clinical and experimental evidence for the impact of HDL on cognition in aging and in neurodegenerative disorders as well as the potential of HDL-enhancing approaches to improve cognitive function.

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Does apolipoprotein E genotype modify the clinical expression of ALS?

Abstract: Our results suggest that ApoE genotype does not modify clinical course of sporadic ALS, in stark contrast to the influence of ApoE genotype on the disease course of AD and other neurodegenerative disorders.

Cited by 19 publications

References 38 publications

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy

Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis

HDL and cognition in neurodegenerative disorders

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