| 11. |
- Nikpay, Majid, et al.
(författare)
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A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:10, s. 1121-1121
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Tidskriftsartikel (refereegranskat)abstract
- Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of similar to 185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
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| 12. |
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| 13. |
- Philipson, Ola, 1979-, et al.
(författare)
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Biochemical and morphological analyses of Aβ deposits in postmortem brain of Arctic APP mutation carriers
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The clinical symptoms associated with the Arctic (E693G) mutation in the amyloid-β precursor protein (APP) are those of typical Alzheimer’s disease (AD), beginning with insidious loss of recent memories. However, an unusual neuropathology of ring-like amyloid-β (Aβ) plaques is identified in postmortem brain. Here, the neuropathology of subjects carrying the Arctic mutation was compared to that of sporadic AD. Different types of Aβ-deposits were examined with light, confocal and electron microscopy, and their composition was analyzed with biochemical techniques. Parenchymal deposits of the Arctic mutant brain were homogenous in structure, lacked an amyloid core and were immunostained differentially by antibodies recognizing C- or N-terminal epitopes of Aβ. Superficially, Arctic Aβ plaques bore considerable resemblance to cotton wool plaques (CWP), namely their large size, the presence of healthy neuronal nuclei and the absence of marked neuritic dystrophy within the plaques, and the sparsity of astro- or microgliosis in the surrounding tissue. Both parenchymal deposits and cerebral amyloid angiopathy of Arctic mutant brain contained a mixture of Arctic and wild-type Aβ. While Aβ peptides in parenchymal plaques were often N-terminally truncated, a substantial amount of full-length Aβ1-40 was deposited in the vessel walls as cerebral amyloid angiopathy (CAA). Thus, the absence of amyloid cores in parenchymal plaques of Arctic mutant brain was likely due to the scarcity of full-length Aβ species, although other mechanisms could also be involved. Our findings are discussed in relation to the clinical features of patients carrying the Arctic mutation and neuropathological observations made with other intra-Aβ mutations in human and transgenic mouse brain.
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| 14. |
- Philipson, Ola, et al.
(författare)
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The Arctic amyloid-β precursor protein (AβPP) mutation results in distinct plaques and accumulation of N- and C-truncated Aβ
- 2012
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 33:5, s. 1010.e1-1010.e13
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Tidskriftsartikel (refereegranskat)abstract
- The Arctic (p. E693G) mutation in the amyloid-β precursor protein (AβPP) facilitates amyloid-β (Aβ) protofibril formation and generates clinical symptoms of Alzheimer's disease (AD). Here, molecular details of Aβ in post mortem brain were investigated with biochemical and morphological techniques. The basic structure of Arctic plaques resembled cotton wool plaques. However, they appeared ring-formed with Aβ42-specific antibodies, but were actually targetoid, since the periphery and center of many parenchymal Aβ deposits stained differently with mid-domain, N- and C-terminal Aβ antibodies. Aβ fibrils were similar in shape, albeit shorter than in sporadic AD brain, when examined by electron microscopy. Aβwild-type and Aβarctic codeposited and parenchymal deposits were highly enriched in both N- and C-terminally truncated Aβ. In contrast, cerebral amyloid angiopathy (CAA) contained a substantial amount of Aβ1-40. The absence of plaques with cores of fibrillary Aβ might be due to the scarcity of full-length Aβ, although other mechanisms could be involved. Our findings are discussed in relation to mechanisms and relevance of amyloid formation and to the clinical features of AD.
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| 15. |
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| 16. |
- Abu Hamdeh, Sami, et al.
(författare)
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Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury
- 2018
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Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 28:4, s. 451-462
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Tidskriftsartikel (refereegranskat)abstract
- Deposition of amyloid-β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.
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| 17. |
- 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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| 18. |
- Basun, Hans, et al.
(författare)
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Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease
- 2008
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Ingår i: Archives of neurology. - : American Medical Association (AMA). - 0003-9942 .- 1538-3687. ; 65:4, s. 499-505
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A majority of mutations within the beta-amyloid region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral hemorrhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra-beta-amyloid mutation to date causing the more typical clinical picture of Alzheimer disease. OBJECTIVE: To describe features of 1 Swedish and 1 American family with the previously reported Arctic APP mutation. DESIGN, SETTING, AND PARTICIPANTS: Affected and nonaffected carriers of the Arctic APP mutation from the Swedish and American families were investigated clinically. In addition, 1 brain from each family was investigated neuropathologically. RESULTS: The clinical picture, with age at disease onset in the sixth to seventh decade of life and dysfunction in multiple cognitive areas, is indicative of Alzheimer disease and similar to the phenotype for other Alzheimer disease APP mutations. Several affected mutation carriers displayed general brain atrophy and reduced blood flow of the parietal lobe as demonstrated by magnetic resonance imaging and single-photon emission computed tomography. One Swedish case and 1 American case with the Arctic APP mutation came to autopsy, and both showed no signs of hemorrhage but revealed severe congophilic angiopathy, region-specific neurofibrillary tangle pathological findings, and abundant amyloid plaques. Intriguingly, most plaques from both of these cases had a characteristic ringlike character. CONCLUSIONS: Overall, our findings corroborate that the Arctic APP mutation causes a clinical and neuropathological picture compatible with Alzheimer disease.
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| 19. |
- Benedict, Christian, et al.
(författare)
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Self-reported sleep disturbance is associated with Alzheimer's disease risk in men
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:9, s. 1090-1097
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To study the association between self-reported sleep disturbances and dementia risk.METHODS: Self-reported sleep disturbances and established risk factors for dementia were measured in men at ages 50 (n = 1574) and 70 (n = 1029) years. Dementia incidence was determined by reviewing their patient history between ages 50 and 90 years. In addition, plasma levels of β-amyloid (Aβ) peptides 1-40 and 1-42 were measured at ages 70, 77, and 82 years.RESULTS: Cox regression demonstrated that men with self-reported sleep disturbances had a higher risk of developing dementia (+33%) and Alzheimer's disease (AD, +51%) than men without self-reported sleep disturbances (both P < .05). Binary logistic regression showed the increased risk for both dementia (+114%) and AD (+192%) were highest when sleep disturbance was reported at age 70 years (both P < .001). No group differences were found in Aβ levels.CONCLUSION: Improving sleep quality may help reduce the neurodegenerative risk in older men.
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| 20. |
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