Familial clustering and genetic risk for dementia in a genetically isolated Dutch population

K. Sleegers, G. Roks, J. Theuns, Y. S. Aulchenko, Rosa V Rademakers, M. Cruts, W. A. Van Gool, C. Van Broeckhoven, P. Heutink, B. A. Oostra, J. C. Van Swieten, C. M. Van Duijn

Research output: Contribution to journalArticle

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Abstract

Despite advances in elucidating the genetic epidemiology of Alzheimer's disease and frontotemporal dementia, the aetiology for most patients with dementia remains unclear. We examined the genetic epidemiology of dementia in a recent genetically isolated Dutch population founded around 1750. The series of 191 patients ascertained comprised 122 probable Alzheimer's disease patients with late onset and 17 with early onset, and 22 with possible Alzheimer's disease. It further included 10 patients with vascular dementia, nine with Lewy body dementia and six with frontotemporal dementia. All patients, except those with vascular dementia, were more closely related than healthy individuals from the same area. Clustering was strongest for patients with early-onset Alzheimer's disease or Lewy body dementia. Although 14% of late-onset Alzheimer's disease patients had evidence of autosomal dominant disease, consanguinity was found in three late-onset Alzheimer's disease patients, suggesting a recessive or polygenic model underlying the trait. We found no clustering of vascular dementia, implying a difference in genetic risk for late-onset Alzheimer's disease and vascular dementia. Mutations in known genes could not explain the occurrence of dementia, but the population attributable proportion of apolipoprotein E gene (APOE*4) was high (45%) due to a high frequency of APOE*4 carriers. Earlier identified regions on chromosomes 10 and 12, nor the effect of the alpha-2-macroglobulin (A2M) I/D polymorphism on Alzheimer's disease could be confirmed in our study. We did find evidence for association between the A2M D-allele and Lewy body dementia. Our data showed a strong familial clustering of various forms of dementia in this isolated Dutch population. A high percentage of late-onset Alzheimer's disease could be explained by APOE*4, but 55% of its origin is still unknown.

Original languageEnglish (US)
Pages (from-to)1641-1649
Number of pages9
JournalBrain
Volume127
Issue number7
DOIs
StatePublished - Jul 2004
Externally publishedYes

Fingerprint

Cluster Analysis
Dementia
Alzheimer Disease
Population
Vascular Dementia
Lewy Body Disease
alpha-Macroglobulins
Frontotemporal Dementia
Molecular Epidemiology
Consanguinity
Chromosomes, Human, Pair 12
Chromosomes, Human, Pair 10
Apolipoproteins E
Genes
Alleles
Mutation

Keywords

  • Dementia
  • Familial aggregation
  • Genetically isolated population

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Sleegers, K., Roks, G., Theuns, J., Aulchenko, Y. S., Rademakers, R. V., Cruts, M., ... Van Duijn, C. M. (2004). Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. Brain, 127(7), 1641-1649. https://doi.org/10.1093/brain/awh179

Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. / Sleegers, K.; Roks, G.; Theuns, J.; Aulchenko, Y. S.; Rademakers, Rosa V; Cruts, M.; Van Gool, W. A.; Van Broeckhoven, C.; Heutink, P.; Oostra, B. A.; Van Swieten, J. C.; Van Duijn, C. M.

In: Brain, Vol. 127, No. 7, 07.2004, p. 1641-1649.

Research output: Contribution to journalArticle

Sleegers, K, Roks, G, Theuns, J, Aulchenko, YS, Rademakers, RV, Cruts, M, Van Gool, WA, Van Broeckhoven, C, Heutink, P, Oostra, BA, Van Swieten, JC & Van Duijn, CM 2004, 'Familial clustering and genetic risk for dementia in a genetically isolated Dutch population', Brain, vol. 127, no. 7, pp. 1641-1649. https://doi.org/10.1093/brain/awh179
Sleegers, K. ; Roks, G. ; Theuns, J. ; Aulchenko, Y. S. ; Rademakers, Rosa V ; Cruts, M. ; Van Gool, W. A. ; Van Broeckhoven, C. ; Heutink, P. ; Oostra, B. A. ; Van Swieten, J. C. ; Van Duijn, C. M. / Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. In: Brain. 2004 ; Vol. 127, No. 7. pp. 1641-1649.
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abstract = "Despite advances in elucidating the genetic epidemiology of Alzheimer's disease and frontotemporal dementia, the aetiology for most patients with dementia remains unclear. We examined the genetic epidemiology of dementia in a recent genetically isolated Dutch population founded around 1750. The series of 191 patients ascertained comprised 122 probable Alzheimer's disease patients with late onset and 17 with early onset, and 22 with possible Alzheimer's disease. It further included 10 patients with vascular dementia, nine with Lewy body dementia and six with frontotemporal dementia. All patients, except those with vascular dementia, were more closely related than healthy individuals from the same area. Clustering was strongest for patients with early-onset Alzheimer's disease or Lewy body dementia. Although 14{\%} of late-onset Alzheimer's disease patients had evidence of autosomal dominant disease, consanguinity was found in three late-onset Alzheimer's disease patients, suggesting a recessive or polygenic model underlying the trait. We found no clustering of vascular dementia, implying a difference in genetic risk for late-onset Alzheimer's disease and vascular dementia. Mutations in known genes could not explain the occurrence of dementia, but the population attributable proportion of apolipoprotein E gene (APOE*4) was high (45{\%}) due to a high frequency of APOE*4 carriers. Earlier identified regions on chromosomes 10 and 12, nor the effect of the alpha-2-macroglobulin (A2M) I/D polymorphism on Alzheimer's disease could be confirmed in our study. We did find evidence for association between the A2M D-allele and Lewy body dementia. Our data showed a strong familial clustering of various forms of dementia in this isolated Dutch population. A high percentage of late-onset Alzheimer's disease could be explained by APOE*4, but 55{\%} of its origin is still unknown.",
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