Apolipoprotein E ε2 allele promotes longevity and protects patients with Downʼs syndrome from dementia

Royston, M.C.; Mann, Dave; Pickering‐Brown, Stuart; Owen, F.; Perry, Rodney T.; Raghavan, Ravi; Khin-Nu, Claire; Tyrer, Stephen; Day, Kenneth; Crook, Richard

doi:10.1097/00001756-199412000-00044

Cited by 87 publications

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“…24,25 Similar to previous studies, this study showed that the Apo E ε2 allele frequency in both the AD and SVaD groups was lower than in the normal group. But the effect of Apo E ε2 on AD has been more controversial than that of Apo E ε4 until now.…”

Section: Discussionsupporting

confidence: 89%

A Comparison of Apolipoprotein E Polymorphism in Alzheimer's Disease and Subcortical Vascular Dementia in Koreans

Kim

Kwon

2015

Dement Neurocognitive Disord

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INTRODUCTIONThe apolipoprotein E gene (Apo E) is located on the 19th chromosome and has 3 alleles, which are ε2, ε3, and ε4.1 Previous studies showed that the Apo E ε4 allele is a risk factor that increases the risk of sporadic Alzheimer's disease (AD) and late-onset AD in addition to decreasing the age of onset. Although disputable, some studies have suggested that Apo E ε4 is related to a high level of low density lipoprotein and may affect nervous system diseases associated with vascular injuries.2,3 Also, vascular pathology has been repeatedly reported in late-stage AD patients. It is also reported that cerebrovascular and cardiovascular risk factors can enhance the progress of AD. In this way, many recent studies have suggested that vascular factors may be common etiologic factors of both AD and vascular dementia (VaD). Subcortical vascular dementia (SVaD) is known to be caused by microangiopathy within the deep brain. SVaD can be divided into arteriosclerotic leukoencephalopathy (Binswanger type), which contains the etiologic factor in the white matter, and multiple subcortical lacunar lesion (lacunar type), which is caused by multiple infarction of deep brain gray matter.Likewise, considering the effect of Apo E ε4 lipid metabolism and the common vascular etiologic factor found in AD Background and Purpose The apolipoprotein E (Apo E) ε4 allele is known to be a risk factor for Alzheimer's disease (AD). However, there are debates about the relationship between Apo E ε4 frequency and subcortical vascular dementia (SVaD). We compared the frequency of the Apo E ε4 allele in AD and SVaD in Koreans.Methods The study was comprised of 400 subjects who visited the Dementia Clinic at Daegu Catholic University from July 2007 to December 2011. Neuropsychological tests, a brain MRI, and blood laboratory tests were performed on all subjects. Two hundred and ninety subjects were AD, 32 subjects were SVaD and 78 subjects were normal. The diagnosis for SVaD was based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and Erkinjuntti criteria, and the diagnosis for AD was based on the DSM-IV and National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's disease and Related Disorders Association criteria. Apo E polymorphism was genotyped in all subjects. ResultsThe Apo E ε4 allele frequency was 17.4% in AD, 10.9% in SVaD and 8.3% in the normal group (p=0.03). The odds ratio (OR) after age adjustment for AD conferred to the Apo E ε4 was 2.04 (p=0.04). But, the OR for SVaD conferred to the Apo E ε4 allele was 1.34 (p=0.62), indicating that the Apo E ε4 allele does not significantly confer the risk of SVaD.Conclusions Apo E ε4 is a reliable predictor of AD but has modest efficacy for predicting SVaD in Koreans.

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Section: Discussionsupporting

confidence: 89%

A Comparison of Apolipoprotein E Polymorphism in Alzheimer's Disease and Subcortical Vascular Dementia in Koreans

Kim

Kwon

2015

Dement Neurocognitive Disord

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“…Additionally, 4 carriers have a more rapid decline in memory function associated with aging (Deary et al, 2002). In contrast, the e2 allele appears to be in some way "protective" even when other genetic risk factors such as mutations associated with familial forms of AD or the 4 allele are present (Corder et al, 1994;Royston et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

HumanAPOEIsoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice

Bales¹,

Liu²,

Wu³

et al. 2009

J. Neurosci.

249

202

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To investigate the role of human apolipoprotein E (apoE) on A␤ deposition in vivo, we crossed PDAPP mice lacking mouse Apoe to targeted replacement mice expressing human apoE (PDAPP/TRE2, PDAPP/TRE3, or PDAPP/TRE4). We then measured the levels of apoE protein and A␤ peptides in plasma, CSF, and brain homogenates in these mice at different ages. We also quantified the amount of brain A␤ and amyloid burden in 18-month-old mice. In young PDAPP/TRE4 mice that were analyzed at an age before brain A␤ deposition, we observed a significant decrease in the levels of apoE in CSF and brain when compared with age-matched mice expressing either human E2 or E3. The brain levels of A␤42 in PDAPP/TRE4 mice were substantially elevated even at this very early time point. In older PDAPP/TRE4 mice, the levels of insoluble apoE protein increased in parallel to the dramatic rise in brain A␤ burden, and the majority of apoE was associated with A␤. In TRE4 only mice, we also observed a significant decrease in the level of apoE in brain homogenates. Since the relative level of apoE mRNA was equivalent in PDAPP/TRE and TRE only mice, it appears that post-translational mechanisms influence the levels of apoE protein in brain (E4 Ͻ E3 Ͻ Ͻ E2), resulting in early and dramatic apoE isoform-dependent effects on brain A␤ levels (E4 Ͼ Ͼ E3 Ͼ E2) that increase with age. Therapeutic strategies aimed at increasing the soluble levels of apoE protein, regardless of isoform, may effectively prevent and (or) treat Alzheimer's disease.

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“…Polymorphisms in genes with important functions in LOAD have similar roles in the development of AD-DS; for example, the apolipoprotein E (APOE) ε4 allele is associated with greater Aβ deposition, as well as with earlier onset and increased risk of AD-DS, whereas the APOE ε2 allele leads to reduced Aβ deposition and a lower risk of disease [132][133][134][135][136][137][138] . Similarly, variants of phosphatidylinositol-binding clathrin assembly protein (PICALM) and sortilin-related receptor 1 (SORL1) influence age of onset in AD-DS, as they do in LOAD 132,139,140 , further supporting the theory that common mechanisms underlie both diseases.…”

Section: Genes Involved In Loadmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

Self Cite

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Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

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Apolipoprotein E ε2 allele promotes longevity and protects patients with Downʼs syndrome from dementia

Cited by 87 publications

References 0 publications

A Comparison of Apolipoprotein E Polymorphism in Alzheimer's Disease and Subcortical Vascular Dementia in Koreans

A Comparison of Apolipoprotein E Polymorphism in Alzheimer's Disease and Subcortical Vascular Dementia in Koreans

HumanAPOEIsoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

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