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- Vogel, Jacob W., et al.
(författare)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 5. |
- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 6. |
- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 9. |
- Kazakos, K., et al.
(författare)
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A real-time IVR platform for community radio
- 2016
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Ingår i: Conference on Human Factors in Computing Systems - Proceedings. - New York, NY, USA : ACM.
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Konferensbidrag (refereegranskat)abstract
- Interactive Voice Response (IVR) platforms have been widely deployed in resource-limited settings. These systems tend to afford asynchronous push interactions, and within the context of health, provide medication reminders, descriptions of symptoms and tips on self-management. Here, we present the development of an IVR system for resource-limited settings that enables real-time, synchronous interaction. Inspired by community radio, and calls for health systems that are truly local, we developed ’Sehat ki Vaani’. Sehat ki Vaani is a real-time IVR platform that enables hosting and participation in radio chat shows on community-led topics. We deployed Sehat ki Vaani with two communities in North India on topics related to the management of Type 2 diabetes and maternal health. Our deployments highlight the potential for synchronous IVR systems to offer community connection and localised sharing of experience, while also highlighting the complexity of producing, hosting and participating in radio shows in real time through IVR. We discuss the relative strengths and weaknesses of synchronous IVR systems, and highlight lessons learnt for interaction design in this area.
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| 10. |
- Hoscheidt, S. M., et al.
(författare)
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Insulin Resistance is Associated with Increased Levels of Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults
- 2016
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Ingår i: Journal of Alzheimers Disease. - 1387-2877. ; 52:4, s. 1373-1383
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Tidskriftsartikel (refereegranskat)abstract
- Background: Type 2 diabetes is associated with an increased risk for Alzheimer's disease (AD). Regulation of normal insulin function may be important in reducing the prevalence of dementia due to AD, particularly in individuals who harbor genetic risk for or have a parental family history of AD. The relationship between insulin resistance (IR) and AD pathology remains poorly understood, particularly in midlife prior to the onset of clinical metabolic disease or cognitive decline. Objective: We examined associations between IR as indexed by HOMA-IR, cerebrospinal fluid (CSF) biomarkers of AD pathology, and memory in middle-aged adults enriched for AD. We postulated that higher HOMA-IR and APOE epsilon 4 carriage would be associated with greater CSF AD pathology and poor memory performance. Methods: Cognitively asymptomatic middle-aged adults (N = 70, mean age = 57.7 years) from the Wisconsin Alzheimer's Disease Research Center with a parental family history of dementia due to AD underwent lumbar puncture, blood draw, and neuropsychological testing. CSF AD biomarkers including soluble amyloid-beta protein precursor beta (sA beta PP beta), amyloid-beta 42 (A beta(42)), and phosphorylated tau (P-tau(181)) were examined with respect to HOMA-IR and APOE epsilon 4 status. Delayed memory performance was examined with respect to HOMA-IR, CSF AD biomarkers, and APOE epsilon 4 status. Results: Higher HOMA-IR was associated with higher sA beta PP beta and A beta(42). APOE epsilon 4 carriers had significantly higher levels of sA beta PP beta, sA beta PP beta, and P-tau(181)/A beta(42) compared to noncarriers. The concurrent presence of higher HOMA-IR and CSF AD pathology predicted worse delayed memory performance. Conclusion: Overall, the findings suggest that IR and APOE epsilon 4 are contributing factors to the development of AD pathology in midlife, and provide support for targeting insulin function as a potentially modifiable risk factor for AD.
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