A Protective Effect of Apolipoprotein E e2 Allele on Dementia in Down’s Syndrome

Tyrrell, Janette; Cosgrave, Mary; Hawi, Ziarih; McPherson, Janet; O’Brien, Catherine; McCalvert, John; McLaughlin, Martin; Lawlor, Brian; Gill, Michael

doi:10.1016/s0006-3223(97)00481-2

Cited by 32 publications

(20 citation statements)

References 22 publications

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“…The robust effect of the ApoE e4 allele on increasing the risk of dementia in the general population is reduced in the DS population with some studies showing an effect [Schupf et al, 1996] and others not [Van Gool et al, 1995]. In our DS population we were able to demonstrate a protective effect for ApoE e2, but no significant effect for ApoE e4 suggesting that amyloid overproduction was cancelling out the e4 effect [Tyrrell et al, 1998]. Alternatively, we proposed that the e4 allele had an effect of longevity which became apparent at an earlier age than in the general population [Schacter et al, 1994].…”

contrasting

confidence: 51%

“…In a post-mortem series of 22 DS cases, those with an e2 allele were significantly older at death [Royston et al, 1994]. We have demonstrated previously a protective effect of the e2 allele in the development of AD in DS [Tyrrell et al, 1998]. We have also found that DS subjects have a lower frequency of e4 compared to the general population, suggesting an effect on longevity [ Cosgrave et al, 1996].…”

mentioning

confidence: 91%

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Presenilin 1 and ?-1-antichymotrypsin polymorphisms in down syndrome: No effect on the presence of dementia

Tyrrell

Cosgrave

McPherson³

et al. 1999

Am. J. Med. Genet.

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As people with Down syndrome (DS) age, they are at greater risk for Alzheimer disease (AD) than the general population. It has been suggested that polymorphisms at the genes for presenilin-1 (PS-1) and alpha-1-antichymotrypsin (ACT) confer an increased risk for AD in the general population, and therefore potentially to AD in people with DS. We obtained DNA from 231 individuals with DS and 233 population controls. People with DS were evaluated for dementia. Allele frequencies at PS-1 and ACT polymorphisms in people with DS were compared to those in age-matched controls. There were no frequency differences between the control sample and DS sample for PS-1 or ACT alleles or genotypes. Similarly, there were no differences in allele frequencies between the demented and age-matched non-demented DS samples. However a higher frequency of PS-1 heterozygotes in the demented DS group was noted. We conclude that unlike the general population, neither PS-1 nor ACT polymorphisms appear to have a similar detrimental effect on dementia in DS. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:616-620, 1999.

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confidence: 51%

mentioning

confidence: 91%

Presenilin 1 and ?-1-antichymotrypsin polymorphisms in down syndrome: No effect on the presence of dementia

Tyrrell

Cosgrave

McPherson³

et al. 1999

Am. J. Med. Genet.

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“…The Â4 allele of APOE has been shown to be a major risk factor for the development of sporadic AD. Similarly, recent studies have shown that DS subjects who possess one or two alleles of Â4 develop dementia and more severe AD pathology at an earlier age than those DS subjects who lack an Â4 allele (Holtzman, 1997;Tyrrel et al, 1998).…”

Section: Discussionmentioning

confidence: 95%

Preferential occurrence of chromosome 21 malsegregation in peripheral blood lymphocytes of Alzheimer disease patients

Migliore¹,

Botto²,

Scarpato³

et al. 1999

Cytogenet Genome Res

111

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To further investigate our finding of high levels of spontaneous aneuploidy in somatic cells of Alzheimer’s disease (AD) patients (Migliore et al. 1997), we studied the molecular cytogenetics of eight patients with sporadic AD and six healthy controls of similar age. Cytochalasin B-blocked binucleated peripheral blood lymphocytes from the AD patients and unaffected controls were used to measure micronucleus induction or other aneuploidy events, such as the presence of malsegregation in interphase nuclei (representing chromosome loss and gain). Dual-color fluorescence in situ hybridization (FISH) with differential labeled DNA probes was applied. We used a probe specific for the centromeres of chromosomes 13 and 21 combined with a single cosmid for the Down’s syndrome region (21q22.2) to obtain information on spontaneous chromosome loss and gain frequencies for both chromosomes (13 and 21). FISH data showed that AD lymphocytes had higher frequencies of chromosome loss (evaluated as fluorescently labeled micronuclei) for both chromosomes, as well as higher frequencies of aneuploid interphase nuclei, again involving both chromosomes, compared to control lymphocytes. However, aneuploidy for chromosome 21 was more frequent than for chromosome 13 in AD patients. This preferential occurrence of chromosome 21 in malsegregation in somatic cells of AD patients raises the hypothesis that mosaicism for trisomy of chromosome 21 could underlie the dementia phenotype in AD patients, as well as in elderly Down’s syndrome patients.

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“…To gather insight, we analyzed DNAs from individuals with familial AD (FAD), adults with DS, and healthy normal individuals (younger and older) for the C282Y and H63D mutations. As the apolipoprotein E (ApoE) E4 allele on chromosome 19 is a confirmed risk factor for AD [Strittmatter et al, 1993;Roses, 1998;Tang et al, 1998] and possibly also for DAT in DS [van Gool et al, 1995;Lambert et al, 1996;Schupf et al, 1996;Alexander et al, 1997;Evenhuis, 1997;Farrer et al, 1997;Prasher et al, 1997;Sekijima et al, 1998;Tyrrell et al, 1998;Rubinsztein et al, 1999], DNAs were also ApoE genotyped and considered in our data interpretation. …”

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confidence: 99%

Are hereditary hemochromatosis mutations involved in Alzheimer disease?

et al. 2000

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Mutations in the class I-like major histocompatibility complex gene called HFE are associated with hereditary hemochromatosis (HHC), a disorder of excessive iron uptake. We screened DNA samples from patients with familial Alzheimer disease (FAD) (n = 26), adults with Down syndrome (DS) (n = 50), and older (n = 41) and younger (n = 52) healthy normal individuals, for two HHC point mutations-C282Y and H63D. Because the apolipoprotein E (ApoE) E4 allele is a risk factor for AD and possibly also for dementia of the AD type in DS, DNA samples were also ApoE genotyped. Chi-squared analyses were interpreted at the 0.05 level of significance without Bonferroni corrections. In the pooled healthy normal individuals, C282Y was negatively associated with ApoE E4, an effect also apparent in individuals with DS but not with FAD. Relative to older normals, ApoE E4 was overrepresented in both males and females with FAD, consistent with ApoE E4 being a risk factor for AD; HFE mutations were overrepresented in males and underrepresented in females with FAD. Strong gender effects on the distribution of HFE mutations were apparent in comparisons among ApoE E4 negative individuals in the FAD and healthy normal groups (P < 0.002). Our findings are consistent with the proposition that among ApoE E4 negative individuals HFE mutations are predisposing to FAD in males but are somewhat protective in females. Further, ApoE E4 effects in our FAD group are strongest in females lacking HFE mutations. Relative to younger normals there was a tendency for ApoE E4 and H63D to be overrepresented in males and underrepresented in females with DS. The possibility that HFE mutations are important new genetic risk factors for AD should be pursued further.

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A Protective Effect of Apolipoprotein E e2 Allele on Dementia in Down’s Syndrome

Cited by 32 publications

References 22 publications

Presenilin 1 and ?-1-antichymotrypsin polymorphisms in down syndrome: No effect on the presence of dementia

Presenilin 1 and ?-1-antichymotrypsin polymorphisms in down syndrome: No effect on the presence of dementia

Preferential occurrence of chromosome 21 malsegregation in peripheral blood lymphocytes of Alzheimer disease patients

Are hereditary hemochromatosis mutations involved in Alzheimer disease?

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