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- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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- Khan, Wasim, et al.
(författare)
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A Multi-Cohort Study of ApoE epsilon 4 and Amyloid-beta Effects on the Hippocampus in Alzheimer's Disease
- 2017
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 56:3, s. 1159-1174
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Tidskriftsartikel (refereegranskat)abstract
- The apolipoprotein E (APOE) gene has been consistently shown to modulate the risk of Alzheimer's disease (AD). Here, using an AD and normal aging dataset primarily consisting of three AD multi-center studies (n = 1,781), we compared the effect of APOE and amyloid-beta (A beta) on baseline hippocampal volumes in AD patients, mild cognitive impairment (MCI) subjects, and healthy controls. A large sample of healthy adolescents (n = 1,387) was also used to compare hippocampal volumes between APOE groups. Subjects had undergone a magnetic resonance imaging (MRI) scan and APOE genotyping. Hippocampal volumes were processed using FreeSurfer. In the AD and normal aging dataset, hippocampal comparisons were performed in each APOE group and in epsilon 4 carriers with positron emission tomography (PET) A beta who were dichotomized (A beta+/A beta-) using previous cut-offs. We found a linear reduction in hippocampal volumes with epsilon 4 carriers possessing the smallest volumes, epsilon 3 carriers possessing intermediate volumes, and epsilon 2 carriers possessing the largest volumes. Moreover, AD and MCI epsilon 4 carriers possessed the smallest hippocampal volumes and control epsilon 2 carriers possessed the largest hippocampal volumes. Subjects with both APOE epsilon 4 and A beta positivity had the lowest hippocampal volumes when compared to A beta-epsilon 4 carriers, suggesting a synergistic relationship between APOE epsilon 4 and A beta. However, we found no hippocampal volume differences between APOE groups in healthy 14-year-old adolescents. Our findings suggest that the strongest neuroanatomic effect of APOE epsilon 4 on the hippocampus is observed in AD and groups most at risk of developing the disease, whereas hippocampi of old and young healthy individuals remain unaffected.
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- Sindi, S., et al.
(författare)
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Sleep disturbances and later cognitive status: a multi-centre study
- 2018
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Ingår i: Sleep Medicine. - : Elsevier BV. - 1389-9457 .- 1878-5506. ; 52:December, s. 26-33
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the associations between sleep disturbances in mid-life and late-life and late-life cognitive status. Methods: In four population-based studies (three Swedish studies: H70 study, Kungsholmen Project (KP) and The Swedish Panel Study of Living Conditions of the Oldest Old (SWEOLD); and one Finnish study: Cardiovascular Risk Factors, Aging and Dementia (CAIDE)), participants provided self-reports on insomnia, nightmares and general sleep problems. Late-life cognitive status was measured by the Mini Mental State Exam (MMSE). The associations between late-life sleep disturbances and cognition 3-11 years later were investigated across all studies (n = 3210). Mean baseline ages were 70 (CAIDE, H70 and SWEOLD), and 84 years (KP). Additional analyses examined the association between midlife sleep and late-life cognition using CAIDE (21 and 31 years follow-up, n = 1306, mean age 50 years), and SWEOLD (20-24 years follow-up, n = 2068, mean age 58 years). Ordered logistic regressions, adjusted for potential baseline confounders, were used in the analyses. Results: Late-life sleep disturbances were associated with poorer cognition after 3-11 years (fully adjusted beta = -0.12, 95% CI = -0.24 to -0.01). Midlife nightmares and insomnia were also associated with lower MMSE scores (fully adjusted beta = -0.28, 95% CI = -0.49 to -0.07 and beta = -0.20, 95% CI = -0.39 to -0.01), although the latter association was attenuated after adjusting for lifestyle/health-related confounders. Midlife general sleep problems were not associated with late-life MMSE performance. Conclusions: Sleep disturbances and midlife nightmares were associated with lower MMSE scores, which suggests that sleep disturbances in earlier life stages can be associated with worse late-life cognition. (c) 2017 Published by Elsevier B.V.
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- Sindi, S., et al.
(författare)
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Sleep disturbances and dementia risk: A multicenter study
- 2018
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:10, s. 1235-1242
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Few longitudinal studies assessed whether sleep disturbances are associated with dementia risk. Methods: Sleep disturbances were assessed in three population-based studies (H70 study and Kungsholmen Project [Sweden]; Cardiovascular Risk Factors, Aging and Dementia study [Finland]). Late-life baseline analyses (3-10 years follow-up) used all three studies (N = 1446). Baseline ages 70 years (Cardiovascular Risk Factors, Aging and Dementia, H70), and approximate to 84 years (Kungsholmen Project). Midlife baseline (age approximate to 50 years) analyses used Cardiovascular Risk Factors, Aging and Dementia (21 and 32 years follow-up) (N = 1407). Results: Midlife insomnia (fully adjusted hazard ratio = 1.24, 95% confidence interval = 1.02-1.50) and late-life terminal insomnia (fully adjusted odds ratio = 1.94, 95% confidence interval = 1.08-3.49) were associated with a higher dementia risk. Late-life long sleep duration (>9 hours) was also associated with an increased dementia risk (adjusted odds ratio = 3.98, 95% confidence interval = 1.87-8.48). Discussion: Midlife insomnia and late-life terminal insomnia or long sleep duration were associated with a higher late-life dementia risk. (C) 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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