Genes conferring risk for Alzheimer's disease

Their role in the development of dementia in Down's syndrome

M. Gill, J. Tyrell, M. Cosgrave, Z. Hawi, B. Lawlor

Research output: Contribution to journalArticleResearchpeer-review

Abstract

It is thought that all Down's individuals over the age of 35 have the neuropathological changes of Alzheimer's disease, namely neurofibrillary tangles and plaques, and that they will eventually develop clinical dementia with an average onset in the early to mid 50s. Increased expression of the amyloid precursor protein on chromosome 21 is thought to be responsible. In the general population, common genetic variation at the apolipoprotein E (ApoE), the Alphal-antichimotrypsin and the Presenilin-1 genes confers differential risk to the age of onset and progression of dementia of the Alzheimer's type. In case control studies Alzheimer's sufferers as a group show a higher frequency of the ApoE-E4, PS-1-A1, and ACT-A1 alleles than age matched control subjects. The ApoE E2 allele is thought to be protective, and occurs less frequently in Alzheimer's cases compared to controls. We have considered if a similar effect might apply to a Down's population by examining these genotypes in a group of 200 subjects as part of a study on age of onset and rate of progression of dementia. We should expect frequencies in the group as a whole similar to that of the general population. Epidemiological studies, however, indicate that less than 50% of DS subjects of our cohort survived to adulthood. This may allow for the selective demise of those with detrimental genotypes. Thus we expected and found a significantly lower frequency of the Alzheimer's disease associated E4 allele in our DS sample compared to population controls (11.5% vs 19.2%, Chi-square 8.33 p = .004). We also found a lower frequency of the Alzheimer's associated PS-1 allele A1, although this did not reach significance. For the case control design, we compared the frequency of 30 dementing DS subjects with a sample of age matched non-dementing subjects. We found a significantly lower frequency of the ApoE E2 allele in the DS cases compared to age matched DS non-cases (Fisher exact 1-tailed p = .017), and a non-significant increase in ApoE E4. In summary, ApoE E 4 alleles appear to have a detrimental effect on longevity in DS similar to the effect seen in a population of French centenarians. In addition, the ApoE E2 allele is protective, and the E4 allele detrimental development of dementia in DS. The effect size as measured by the Odds Ratio is less than for Alzheimer's dementia in the general population, suggesting that genes on chromosome 21 may also be important in this respect.

Original languageEnglish
Pages (from-to)258
Number of pages1
JournalGenetic Counseling
Volume8
Issue number3
Publication statusPublished - 1997
Externally publishedYes

Cite this

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title = "Genes conferring risk for Alzheimer's disease: Their role in the development of dementia in Down's syndrome",
abstract = "It is thought that all Down's individuals over the age of 35 have the neuropathological changes of Alzheimer's disease, namely neurofibrillary tangles and plaques, and that they will eventually develop clinical dementia with an average onset in the early to mid 50s. Increased expression of the amyloid precursor protein on chromosome 21 is thought to be responsible. In the general population, common genetic variation at the apolipoprotein E (ApoE), the Alphal-antichimotrypsin and the Presenilin-1 genes confers differential risk to the age of onset and progression of dementia of the Alzheimer's type. In case control studies Alzheimer's sufferers as a group show a higher frequency of the ApoE-E4, PS-1-A1, and ACT-A1 alleles than age matched control subjects. The ApoE E2 allele is thought to be protective, and occurs less frequently in Alzheimer's cases compared to controls. We have considered if a similar effect might apply to a Down's population by examining these genotypes in a group of 200 subjects as part of a study on age of onset and rate of progression of dementia. We should expect frequencies in the group as a whole similar to that of the general population. Epidemiological studies, however, indicate that less than 50{\%} of DS subjects of our cohort survived to adulthood. This may allow for the selective demise of those with detrimental genotypes. Thus we expected and found a significantly lower frequency of the Alzheimer's disease associated E4 allele in our DS sample compared to population controls (11.5{\%} vs 19.2{\%}, Chi-square 8.33 p = .004). We also found a lower frequency of the Alzheimer's associated PS-1 allele A1, although this did not reach significance. For the case control design, we compared the frequency of 30 dementing DS subjects with a sample of age matched non-dementing subjects. We found a significantly lower frequency of the ApoE E2 allele in the DS cases compared to age matched DS non-cases (Fisher exact 1-tailed p = .017), and a non-significant increase in ApoE E4. In summary, ApoE E 4 alleles appear to have a detrimental effect on longevity in DS similar to the effect seen in a population of French centenarians. In addition, the ApoE E2 allele is protective, and the E4 allele detrimental development of dementia in DS. The effect size as measured by the Odds Ratio is less than for Alzheimer's dementia in the general population, suggesting that genes on chromosome 21 may also be important in this respect.",
author = "M. Gill and J. Tyrell and M. Cosgrave and Z. Hawi and B. Lawlor",
year = "1997",
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Genes conferring risk for Alzheimer's disease : Their role in the development of dementia in Down's syndrome. / Gill, M.; Tyrell, J.; Cosgrave, M.; Hawi, Z.; Lawlor, B.

In: Genetic Counseling, Vol. 8, No. 3, 1997, p. 258.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Genes conferring risk for Alzheimer's disease

T2 - Their role in the development of dementia in Down's syndrome

AU - Gill, M.

AU - Tyrell, J.

AU - Cosgrave, M.

AU - Hawi, Z.

AU - Lawlor, B.

PY - 1997

Y1 - 1997

N2 - It is thought that all Down's individuals over the age of 35 have the neuropathological changes of Alzheimer's disease, namely neurofibrillary tangles and plaques, and that they will eventually develop clinical dementia with an average onset in the early to mid 50s. Increased expression of the amyloid precursor protein on chromosome 21 is thought to be responsible. In the general population, common genetic variation at the apolipoprotein E (ApoE), the Alphal-antichimotrypsin and the Presenilin-1 genes confers differential risk to the age of onset and progression of dementia of the Alzheimer's type. In case control studies Alzheimer's sufferers as a group show a higher frequency of the ApoE-E4, PS-1-A1, and ACT-A1 alleles than age matched control subjects. The ApoE E2 allele is thought to be protective, and occurs less frequently in Alzheimer's cases compared to controls. We have considered if a similar effect might apply to a Down's population by examining these genotypes in a group of 200 subjects as part of a study on age of onset and rate of progression of dementia. We should expect frequencies in the group as a whole similar to that of the general population. Epidemiological studies, however, indicate that less than 50% of DS subjects of our cohort survived to adulthood. This may allow for the selective demise of those with detrimental genotypes. Thus we expected and found a significantly lower frequency of the Alzheimer's disease associated E4 allele in our DS sample compared to population controls (11.5% vs 19.2%, Chi-square 8.33 p = .004). We also found a lower frequency of the Alzheimer's associated PS-1 allele A1, although this did not reach significance. For the case control design, we compared the frequency of 30 dementing DS subjects with a sample of age matched non-dementing subjects. We found a significantly lower frequency of the ApoE E2 allele in the DS cases compared to age matched DS non-cases (Fisher exact 1-tailed p = .017), and a non-significant increase in ApoE E4. In summary, ApoE E 4 alleles appear to have a detrimental effect on longevity in DS similar to the effect seen in a population of French centenarians. In addition, the ApoE E2 allele is protective, and the E4 allele detrimental development of dementia in DS. The effect size as measured by the Odds Ratio is less than for Alzheimer's dementia in the general population, suggesting that genes on chromosome 21 may also be important in this respect.

AB - It is thought that all Down's individuals over the age of 35 have the neuropathological changes of Alzheimer's disease, namely neurofibrillary tangles and plaques, and that they will eventually develop clinical dementia with an average onset in the early to mid 50s. Increased expression of the amyloid precursor protein on chromosome 21 is thought to be responsible. In the general population, common genetic variation at the apolipoprotein E (ApoE), the Alphal-antichimotrypsin and the Presenilin-1 genes confers differential risk to the age of onset and progression of dementia of the Alzheimer's type. In case control studies Alzheimer's sufferers as a group show a higher frequency of the ApoE-E4, PS-1-A1, and ACT-A1 alleles than age matched control subjects. The ApoE E2 allele is thought to be protective, and occurs less frequently in Alzheimer's cases compared to controls. We have considered if a similar effect might apply to a Down's population by examining these genotypes in a group of 200 subjects as part of a study on age of onset and rate of progression of dementia. We should expect frequencies in the group as a whole similar to that of the general population. Epidemiological studies, however, indicate that less than 50% of DS subjects of our cohort survived to adulthood. This may allow for the selective demise of those with detrimental genotypes. Thus we expected and found a significantly lower frequency of the Alzheimer's disease associated E4 allele in our DS sample compared to population controls (11.5% vs 19.2%, Chi-square 8.33 p = .004). We also found a lower frequency of the Alzheimer's associated PS-1 allele A1, although this did not reach significance. For the case control design, we compared the frequency of 30 dementing DS subjects with a sample of age matched non-dementing subjects. We found a significantly lower frequency of the ApoE E2 allele in the DS cases compared to age matched DS non-cases (Fisher exact 1-tailed p = .017), and a non-significant increase in ApoE E4. In summary, ApoE E 4 alleles appear to have a detrimental effect on longevity in DS similar to the effect seen in a population of French centenarians. In addition, the ApoE E2 allele is protective, and the E4 allele detrimental development of dementia in DS. The effect size as measured by the Odds Ratio is less than for Alzheimer's dementia in the general population, suggesting that genes on chromosome 21 may also be important in this respect.

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