Apolipoprotein E controls the risk and age at onset of Parkinson disease

Li, Y.J.; Hauser, Michael A.; Scott, William K.; Martin, Eden R.; Booze, Michael W.; Qin, Xue; Walter, Jeffrey W.; Nance, Martha; Hubble, Jean; Koller, William C.; Pahwa, Rajesh; Stern, Matthew B.; Hiner, Bradley C.; Jankovic, Joseph; Goetz, Christopher G.; Small, Gary W.; Mastaglia, Francis; Haines, Jonathan L.; Pericak‐Vance, M. A.; Vance, Jeffery M.

doi:10.1212/01.wnl.0000128089.53030.ac

Cited by 127 publications

(93 citation statements)

References 35 publications

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“…APOE is a confirmed gene that affects the risk and AAO of AD [3] and PD [7]. In addition, the AAO effect of APOE was also confirmed by our previous genomic screen study with a LOD score of 3.28 [9].…”

Section: The Effect On Aao By Snpsupporting

confidence: 62%

Revealing the role of glutathione S-transferase omega in age-at-onset of Alzheimer and Parkinson diseases

Scott

Zhang

et al. 2006

Neurobiology of Aging

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We previously reported a linkage region on chromosome 10q for age-at-onset (AAO) of Alzheimer (AD) and Parkinson (PD) diseases. Glutathione S-transferase, Omega-1 (GSTO1) and the adjacent gene GSTO2, located in this linkage region, were then reported to associate with AAO of AD and PD. To examine whether GSTO1 and GSTO2 (hereafter referred to as GSTO1h) are responsible for the linkage evidence, we identified 39 families in AD that lead to our previous linkage and association findings. The evidence of linkage and association was markedly diminished after removing these 39 families from the analyses, thus providing support that GSTO1h drives the original linkage results. The maximum average AAO delayed by GSTO1h SNP 7-1 (rs4825, A nucleotide) was 6.8 (± 4.41) years for AD and 8.6(± 5.71) for PD, respectively. This is comparable to the magnitude of AAO difference by APOE-4 in these same AD and PD families. These findings suggest the presence of genetic heterogeneity for GSTO1h's effect on AAO, and support GSTO1h's role in modifying AAO in these two disorders.

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Section: The Effect On Aao By Snpsupporting

confidence: 62%

Revealing the role of glutathione S-transferase omega in age-at-onset of Alzheimer and Parkinson diseases

Scott

Zhang

et al. 2006

Neurobiology of Aging

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“…Best known as a risk factor for Alzheimer's disease, apoE4 also seems to have a negative impact on the risk, age of onset, progression, or outcome of Parkinson's disease, 15 fronto-temporal dementia, 55 multiple sclerosis, 18 neuromuscular disease, 56 and traumatic brain injury. 16,17 Excitotoxicity has been implicated in all of these conditions, 39,57 whereas increased accumulation of A␤ is seen mainly in Alzheimer's disease.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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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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“…190,191 Several recent studies have found the ⑀4 allele to be associated with PD [192][193][194] ; however, an earlier meta-analysis found a marginal association only with the ⑀2 allele. 195 A more consistent association of the ⑀4 allele has been with an increased risk of dementia within a PD sample.…”

Section: Apoementioning

confidence: 99%

Genetics of Parkinson disease

Pankratz

Foroud

2007

Genetics in Medicine

110

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During the past decade five genes have been identified that are important in autosomal dominant and autosomal recessive forms of Parkinson disease. The identification of these genes has increased our understanding of the likely pathogenic mechanisms resulting in disease. However, mutations in these genes likely contribute to disease in fewer than 5% of all cases of Parkinson disease. Thus, researchers have continued to search for genes that may influence disease susceptibility. Molecular diagnostic testing is currently available for four of the genes mutated in Parkinson disease. Evidence for reduced penetrance, possible effects of haploinsufficiency, and the identification of nondisease causing polymorphisms within several of these genes has made genetic counseling challenging.Current recommendations are to limit molecular testing only to those individuals who are symptomatic. Furthermore, because treatment is unaltered by the presence or absence of mutations in these genes, restraint is recommended when considering the value of screening for mutations in a clinical setting. Genet Med 2007:9(12): 801-811.

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Apolipoprotein E controls the risk and age at onset of Parkinson disease

Abstract: The APOE-4 allele increases risk and decreases age at onset of PD, an association that may not be dependent upon cognitive impairment.

Cited by 127 publications

References 35 publications

Revealing the role of glutathione S-transferase omega in age-at-onset of Alzheimer and Parkinson diseases

Revealing the role of glutathione S-transferase omega in age-at-onset of Alzheimer and Parkinson diseases

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

Genetics of Parkinson disease

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