| 1. |
- Almkvist, Ove, et al.
(författare)
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Predicting Cognitive Decline across Four Decades in Mutation Carriers and Non-carriers in Autosomal-Dominant Alzheimer's Disease
- 2017
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Ingår i: Journal of the International Neuropsychological Society. - : CAMBRIDGE UNIV PRESS. - 1355-6177 .- 1469-7661. ; 23:3, s. 195-203
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The aim of this study was to investigate cognitive performance including preclinical and clinical disease course in carriers and non-carriers of autosomal-dominant Alzheimer's disease (adAD) in relation to multiple predictors, that is, linear and non-linear estimates of years to expected clinical onset of disease, years of education and age. Methods: Participants from five families with early-onset autosomal-dominant mutations (Swedish and Arctic APP, PSEN1 M146V, H163Y, and I143T) included 35 carriers (28 without dementia and 7 with) and 44 non-carriers. All participants underwent a comprehensive clinical evaluation, including neuropsychological assessment at the Memory Clinic, Karolinska University Hospital at Huddinge, Stockholm, Sweden. The time span of disease course covered four decades of the preclinical and clinical stages of dementia. Neuropsychological tests were used to assess premorbid and current global cognition, verbal and visuospatial functions, short-term and episodic memory, attention, and executive function. Results: In carriers, the time-related curvilinear trajectory of cognitive function across disease stages was best fitted to a formulae with three predictors: years to expected clinical onset (linear and curvilinear components), and years of education. In non-carriers, the change was minimal and best predicted by two predictors: education and age. The trajectories for carriers and non-carriers began to diverge approximately 10 years before the expected clinical onset in episodic memory, executive function, and visuospatial function. Conclusions: The curvilinear trajectory of cognitive functions across disease stages was mimicked by three predictors in carriers. In episodic memory, executive and visuospatial functions, the point of diverging trajectories occurred approximately 10 years ahead of the clinical onset compared to non-carriers.
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| 2. |
- Forsell, Charlotte, et al.
(författare)
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Genetic association to the amyloid plaque associated protein gene COL25A1 in Alzheimer's disease
- 2010
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Ingår i: Neurobiology of Aging. - Fayetteville, N.Y. : Ankho International. - 0197-4580 .- 1558-1497. ; 31:3, s. 409-415
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Tidskriftsartikel (refereegranskat)abstract
- The COL25A1 gene, located in 4q25, encodes the CLAC protein, which has been implicated in Alzheimer's disease (AD) pathogenesis. CLAC was originally identified in amyloid preparations from AD brain and has been shown to be associated with amyloid plaques, inhibition of Abeta-fibril elongation and increased protease resistance of Abeta-fibrils through direct binding to Abeta. These biochemical data as well as the genomic location of the COL25A1 gene in chromosome 4q25 where we previously have reported a weak linkage-signal in Swedish AD families encouraged us to perform a case-control association study of two LD blocks in COL25A1 using 817 AD cases and 364 controls. The LD blocks cover a putative Abeta-binding motif and the variable 3' end of the gene. The analyses indicated association to three of eight analysed SNPs. We found further support for the association by replication in a Swedish population-based longitudinal sample set (n=926). Thus, in addition to the biochemical data, there is now genetic evidence of association between COL25A1 and risk for Alzheimer's disease.
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| 3. |
- Hedskog, Louise, et al.
(författare)
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Biochemical studies of poly t variants in the alzheimer's disease associated tomm40 gene
- 2012
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 31:3, s. 527-536
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Tidskriftsartikel (refereegranskat)abstract
- The apolipoprotein E (APOE) gene remains the most strongly established risk factor for late onset Alzheimer's disease (LOAD). Recently the gene, TOMM40, which is in linkage disequilibrium with APOE, was identified to be associated with LOAD in genome-wide association studies. One of the identified polymorphisms in TOMM40 is rs10524523, which is located in intron 6 and composed of thymidine repeats varying between 14 to 36 base-pairs in length. Reported results are contradictory in regard to the very long poly-T variant that has been associated with both increased and decreased risk of LOAD. Our study aimed to elucidate the functional implication of rs10524523 in an in vitro model of human fibroblast cells obtained from cognitively healthy APOE epsilon 3/epsilon 4 carriers harboring very long or short poly-T variants coupled to their APOE epsilon 3 allele. We have studied (i) expression levels of TOM40 protein and mRNA, (ii) TOM40 mRNA splicing, and (iii) mitochondrial function and morphology; and we have found no significant differences in regards to very long or short poly-T variant.
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| 4. |
- Sillén, Anna, et al.
(författare)
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Expanded high-resolution genetic study of 109 Swedish families with Alzheimer's disease
- 2008
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 16:2, s. 202-208
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is a neurodegenerative disease that affects approximately 20 million persons all over the world. There are both sporadic and familial forms of AD. We have previously reported a genome-wide linkage analysis on 71 Swedish AD families using 365 genotyped microsatellite markers. In this study, we increased the number of individuals included in the original 71 analysed families besides adding 38 new families. These 109 families were genotyped for 1100 novel microsatellite markers. The present study reports on the linkage data generated from the non-overlapping genotypes from the first genome scan and the genotypes of the present scan, which results in a total of 1289 successfully genotyped markers at an average density of 2.85 cM on 468 individuals from 109 AD families. Non-parametric linkage analysis yielded a significant multipoint LOD score in chromosome 19q13, the region harbouring the major susceptibility gene APOE, both for the whole set of families (LOD = 5.0) and the APOE epsilon 4-positive subgroup made up of 63 families (LOD = 5.3). Other suggestive linkage peaks that were observed in the original genome scan of 71 Swedish AD families were not detected in this extended analysis, and the previously reported linkage signals in chromosomes 9, 10 and 12 were not replicated.
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| 5. |
- Sillén, Anna, et al.
(författare)
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Linkage Analysis of Autopsy-Confirmed Familial Alzheimer Disease Supports an Alzheimer Disease Locus in 8q24
- 2011
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 31:2, s. 109-118
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: We have previously reported the results of an extended genome-wide scan of Swedish Alzheimer disease (AD)-affected families; in this paper, we analyzed a subset of these families with autopsy-confirmed AD. Methods: We report the fine-mapping, using both microsatellite markers and single-nucleotide polymorphisms (SNPs), in the observed maximum logarithm of the odds (LOD)-2 unit (LODmax-2) region under the identified linkage peak, linkage analysis of the fine-mapping data with additionally analyzed pedigrees, and association analysis of SNPs selected from candidate genes in the linked interval. The subset was made on the criterion of at least one autopsy-confirmed AD case per family, resulting in 24 families. Results: Linkage analysis of a family subset having at least one autopsy-confirmed AD case showed a significant nonparametric single-point LOD score of 4.4 in 8q24. Fine-mapping under the linkage peak with 10 microsatellite markers yielded an increase in the multipoint (mpt) LOD score from 2.1 to 3.0. SNP genotyping was performed on 21 selected candidate transcripts of the LODmax-2 region. Both family-based association and linkage analysis were performed on extended material from 30 families, resulting in a suggestive linkage at peak marker rs6577853 (mpt LOD score = 2.4). Conclusion: The 8q24 region has been implicated to be involved in AD etiology.
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| 6. |
- Sillén, Anna, et al.
(författare)
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Linkage to 20p13 including the ANGPT4 gene in families with mixed Alzheimer's disease and vascular dementia
- 2010
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Ingår i: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 55:10, s. 649-655
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed at identifying novel susceptibility genes for a mixed phenotype of Alzheimer's disease and vascular dementia. Results from a genome scan showed strongest linkage to 20p13 in 18 families, and subsequent fine mapping was performed with both microsatellites and single-nucleotide polymorphisms in 18 selected candidate transcripts in an extended sample set of 30 families. The multipoint linkage peak was located at marker rs2144151 in the ANGPT4 gene, which is a strong candidate gene for vascular disease because of its involvement in angiogenesis. Although the significance of the linkage decreased, we find this result intriguing, considering that we included additional families, and thus the reduced linkage signal may be caused by genetic heterogeneity.
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| 7. |
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