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Further analysis of previously implicated linkage regions for Alzheimer’s disease in affected relative pairs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
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2009 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 10, 122- p.Article in journal (Refereed) Published
Abstract [en]

Background: Genome-wide linkage studies for Alzheimer's disease have implicated several chromosomal regions as potential loci for susceptibility genes. Methods: In the present study, we have combined a selection of affected relative pairs (ARPs) from the UK and the USA included in a previous linkage study by Myers et al. (Am J Med Genet, 2002), with ARPs from Sweden and Washington University. In this total sample collection of 397 ARPs, we have analyzed linkage to chromosomes 1, 9, 10, 12, 19 and 21, implicated in the previous scan. Results: The analysis revealed that linkage to chromosome 19q13 close to the APOE locus increased considerably as compared to the earlier scan. However, linkage to chromosome 10q21, which provided the strongest linkage in the previous scan could not be detected. Conclusion: The present investigation provides yet further evidence that 19q13 is the only chromosomal region consistently linked to Alzheimer's disease.

Place, publisher, year, edition, pages
2009. Vol. 10, 122- p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97803DOI: 10.1186/1471-2350-10-122ISI: 000272822700001PubMedID: 19951422OAI: oai:DiVA.org:uu-97803DiVA: diva2:172880
Available from: 2008-11-21 Created: 2008-11-21 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Genetic Studies of Alzheimer's Disease
Open this publication in new window or tab >>Genetic Studies of Alzheimer's Disease
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Patients with Alzheimer's disease (AD) often have a family history of the disease, implicating genetics as a major risk factor. Three genes are currently known to cause familial early-onset AD (<65 years): the amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2). For the much more common late-onset disease (>65 years), only the APOE gene has repeatedly been associated to AD, where the ε4 allele increases disease risk and decreases age at onset. As APOE ε4 only explains part of the total estimated disease risk, more genes are expected to contribute to AD.

This thesis has focused on the study of genetic risk factors involved in AD. In the first study, we conducted a linkage analysis of six chromosomes previously implicated in AD in a collection of affected relative pairs from Sweden, the UK and the USA. An earlier described linkage peak on chromosome 10q21 could not be replicated in the current sample, while significant linkage was demonstrated to chromosome 19q13 where the APOE gene is located. The linkage to 19q13 was further analyzed in the second study, demonstrating no significant evidence of genes other than APOE contributing to this peak.

In the third study, the prevalence of APP duplications, a recently reported cause of early-onset AD, was investigated. No APP duplications were identified in 141 Swedish and Finnish early-onset AD patients, implying that this is not a common disease mechanism in the Scandinavian population.

In the fourth study, genes with altered mRNA levels in the brain of a transgenic AD mouse model (tgAPP-ArcSwe) were identified using microarray analysis. Differentially expressed genes were further analyzed in AD brain. Two genes from the Wnt signaling pathway, TCF7L2 and MYC, had significantly increased mRNA levels in both transgenic mice and in AD brains, implicating cell differentiation and possibly neurogenesis in AD.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 47 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 401
Keyword
Alzheimer's disease, Linkage, Affected sib-pairs, APOE, APP duplication, 10q21, 19q13, Wnt signaling
National Category
Geriatrics
Identifiers
urn:nbn:se:uu:diva-9397 (URN)978-91-554-7346-4 (ISBN)
Public defence
2008-12-12, the Rudbeck hall, Rudbeck laboratory, Dag Hammarskjölds väg 20, Uppsala, 13:15
Opponent
Supervisors
Available from: 2008-11-21 Created: 2008-11-21Bibliographically approved

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