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- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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- Bellenguez, C, et al.
(författare)
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New insights into the genetic etiology of Alzheimer's disease and related dementias
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
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Tidskriftsartikel (refereegranskat)abstract
- Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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- Håkansson, Krister, 1952-, et al.
(författare)
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Depressive signs in midlife : A risk factor for cognitive impairment in later life?
- 2010
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Ingår i: International Conference on Alzheimer's Disease (ICAD) 2010. - Chicago, USA : Alzheimer's Association.
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Konferensbidrag (refereegranskat)abstract
- Background: Although depression has been associated with dementia, the nature of this relation is still unclear. Establishing causality from previous studies has been complicated by the typical use of a short follow-up and participants aged over 70 already at baseline. The main purpose of this study was to evaluate if depressive signs already in midlife are related to cognitive impairment in later life. Methods: Participants were derived from random, population-based samples previously investigated in 1972, 1977, 1982, or 1987. Their mean age at baseline was 50.4 years (SD 6.0). After an average follow-up of 21 years, 1449 individuals (73%) aged 65 to 79 years were re-examined in 1998. At the re-examination some form of cognitive impairment was diagnosed in 139 of the participants: 82 with mild cognitive impairment and 57 with dementia (48 of these with Alzheimer’s disease). Signs of depression were estimated through responses to three questions concerning the perception of a hopeless future, impossible life goals and loneliness. The relation between depressive signs in midlife and cognitive impairment in later life was analyzed with logistic regression with adjustments for age, gender, apolipoprotein e4 status and a number of midlife health and lifestyle indicators, including blood pressure, cholesterol and marital status. Results: Depressive signs in midlife, as measured in this study, were significantly related to general cognitive impairment in later life, but also separately to both mild cognitive impairment and Alzheimer’s disease. When dichotomized into high versus low levels of depressive signs the odds ratios were 2.19 (1.1 to 4.3) for mild cognitive impairment and 3.81 (1.3 to 11.5) for Alzheimer’s disease. Significant associations were also found between the separate measures of hopelessness and loneliness on the one hand and the separate outcomes of mild cognitive impairment and Alzheimer’s disease on the other. Conclusions: The results support a causal relation between depressive signs relatively early in life and cognitive function in later life. Clinical relevance includes the long-term health implications of depressive signs in midlife also for the risk of dementia.
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