| 1. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 2. |
- Ruggeri, Kai, et al.
(författare)
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The globalizability of temporal discounting
- 2022
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Ingår i: Nature Human Behaviour. - : Springer Nature. - 2397-3374. ; 6:10, s. 1386-1397
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Tidskriftsartikel (refereegranskat)abstract
- Economic inequality is associated with preferences for smaller, immediate gains over larger, delayed ones. Such temporal discounting may feed into rising global inequality, yet it is unclear whether it is a function of choice preferences or norms, or rather the absence of sufficient resources for immediate needs. It is also not clear whether these reflect true differences in choice patterns between income groups. We tested temporal discounting and five intertemporal choice anomalies using local currencies and value standards in 61 countries (N = 13,629). Across a diverse sample, we found consistent, robust rates of choice anomalies. Lower-income groups were not significantly different, but economic inequality and broader financial circumstances were clearly correlated with population choice patterns. Ruggeri et al. find in a study of 61 countries that temporal discounting patterns are globally generalizable. Worse financial environments, greater inequality and high inflation are associated with extreme or inconsistent long-term decisions.
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| 3. |
- Sanchez, Erlan, et al.
(författare)
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Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative
- 2024
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Ingår i: Alzheimer's and Dementia. - 1552-5260 .- 1552-5279. ; 20:3, s. 1753-1770
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aβ)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ42/40. DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.
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| 4. |
- Andriuta, Daniela, et al.
(författare)
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Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases
- 2024
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Ingår i: ALZHEIMERS & DEMENTIA. - 1552-5260 .- 1552-5279.
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTIONWe investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases.METHODSA mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative.RESULTSPVS was significantly associated with sEF (c = -0.125 +/- 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH.DISCUSSIONIn this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia.HIGHLIGHTS Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease.
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| 5. |
- Wood, Madeline E., et al.
(författare)
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Sex differences in associations between APOE ε2 and longitudinal cognitive decline
- 2023
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:10, s. 4651-4661
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: We examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples. METHODS: We used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs. ε3/ε3) and sex on cognitive decline in NHW and NHB participants separately. RESULTS: In both Sample 1 (N = 9766) and Sample 2 (N = 915), sex modified the association between APOE ε2 and cognitive decline in NHW participants. Specifically, relative to APOE ε3/ε3, APOE ε2 protected against cognitive decline in men but not women. Among APOE ε2 carriers, men had slower decline than women. Among APOE ε3/ε3 carriers, cognitive trajectories did not differ between sexes. There were no sex-specific associations of APOE ε2 with cognition in NHB participants (N = 2010). DISCUSSION: In NHW adults, APOE ε2 may protect men but not women against cognitive decline. Highlights: We studied sex-specific apolipoprotein E (APOE) ε2 effects on cognitive decline. In non-Hispanic White (NHW) adults, APOE ε2 selectively protects men against decline. Among men, APOE ε2 was more protective than APOE ε3/ε3. In women, APOE ε2 was no more protective than APOE ε3/ε3. Among APOE ε2 carriers, men had slower decline than women. There were no sex-specific APOE ε2 effects in non-Hispanic Black (NHB) adults.
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| 6. |
- Bateman, Randall J, et al.
(författare)
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Gantenerumab: an anti-amyloid monoclonal antibody with potential disease-modifying effects in early Alzheimer's disease.
- 2022
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Ingår i: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- This review describes the research and development process of gantenerumab, a fully human anti-amyloid monoclonal antibody in development to treat early symptomatic and asymptomatic Alzheimer's disease (AD). Anti-amyloid monoclonal antibodies can substantially reverse amyloid plaque pathology and may modify the course of the disease by slowing or stopping its clinical progression. Several molecules targeting amyloid have failed in clinical development due to drug-related factors (e.g., treatment-limiting adverse events, low potency, poor brain penetration), study design/methodological issues (e.g., disease stage, lack of AD pathology confirmation), and other factors. The US Food and Drug Administration's approval of aducanumab, an anti-amyloid monoclonal antibody as the first potential disease-modifying therapy for AD, signaled the value of more than 20 years of drug development, adding to the available therapies the first nominal success since cholinesterase inhibitors and memantine were approved. BODY: Here, we review over 2 decades of gantenerumab development in the context of scientific discoveries in the broader AD field. Key learnings from the field were incorporated into the gantenerumab phase 3 program, including confirmed amyloid positivity as an entry criterion, an enriched clinical trial population to ensure measurable clinical decline, data-driven exposure-response models to inform a safe and efficacious dosing regimen, and the use of several blood-based biomarkers. Subcutaneous formulation for more pragmatic implementation was prioritized as a key feature from the beginning of the gantenerumab development program.The results from the gantenerumab phase 3 programs are expected by the end of 2022 and will add critical information to the collective knowledge on the search for effective AD treatments.
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| 7. |
- Bateman, Randall J., et al.
(författare)
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Two Phase 3 Trials of Gantenerumab in Early Alzheimer's Disease
- 2023
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 389:20, s. 1862-1876
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Tidskriftsartikel (refereegranskat)abstract
- Background: Monoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer's disease. Methods: We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. Results: A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aβ42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. Conclusions: Among persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline.
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| 8. |
- Berne, Olivier, et al.
(författare)
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PDRs4All : A JWST Early Release Science Program on Radiative Feedback from Massive Stars
- 2022
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Ingår i: Publications of the Astronomical Society of the Pacific. - : IOP Publishing. - 0004-6280 .- 1538-3873. ; 134:1035
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Tidskriftsartikel (refereegranskat)abstract
- Massive stars disrupt their natal molecular cloud material through radiative and mechanical feedback processes. These processes have profound effects on the evolution of interstellar matter in our Galaxy and throughout the universe, from the era of vigorous star formation at redshifts of 1-3 to the present day. The dominant feedback processes can be probed by observations of the Photo-Dissociation Regions (PDRs) where the far-ultraviolet photons of massive stars create warm regions of gas and dust in the neutral atomic and molecular gas. PDR emission provides a unique tool to study in detail the physical and chemical processes that are relevant for most of the mass in inter- and circumstellar media including diffuse clouds, proto-planetary disks, and molecular cloud surfaces, globules, planetary nebulae, and star-forming regions. PDR emission dominates the infrared (IR) spectra of star-forming galaxies. Most of the Galactic and extragalactic observations obtained with the James Webb Space Telescope (JWST) will therefore arise in PDR emission. In this paper we present an Early Release Science program using the MIRI, NIRSpec, and NIRCam instruments dedicated to the observations of an emblematic and nearby PDR: the Orion Bar. These early JWST observations will provide template data sets designed to identify key PDR characteristics in JWST observations. These data will serve to benchmark PDR models and extend them into the JWST era. We also present the Science-Enabling products that we will provide to the community. These template data sets and Science-Enabling products will guide the preparation of future proposals on star-forming regions in our Galaxy and beyond and will facilitate data analysis and interpretation of forthcoming JWST observations.
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| 9. |
- Black, Sandra E., et al.
(författare)
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Poor Little Rich Kids? The Role of Nature versus Nurture in Wealth and Other Economic Outcomes and Behaviours
- 2020
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Ingår i: Review of Economic Studies. - : Oxford University Press (OUP). - 0034-6527 .- 1467-937X. ; 87:4, s. 1683-1725
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Tidskriftsartikel (refereegranskat)abstract
- Wealth is highly correlated between parents and their children; however, little is known about the extent to which these relationships are genetic or determined by environmental factors. We use administrative data on the net wealth of a large sample of Swedish adoptees merged with similar information for their biological and adoptive parents. Comparing the relationship between the wealth of adopted and biological parents and that of the adopted child, we find that, even prior to any inheritance, there is a substantial role for environment and a much smaller role for pre-birth factors and we find little evidence that nature/nurture interactions are important. When bequests are taken into account, the role of adoptive parental wealth becomes much stronger. Our findings suggest that wealth transmission is not primarily because children from wealthier families are inherently more talented or more able but that, even in relatively egalitarian Sweden, wealth begets wealth. We further build on the existing literature by providing a more comprehensive view of the role of nature and nurture on intergenerational mobility, looking at a wide range of different outcomes using a common sample and method. We find that environmental influences are relatively more important for wealth-related variables such as savings and investment decisions than for human capital. We conclude by studying consumption as an overall measure of welfare and find that, like wealth, it is more determined by environment than by biology.
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| 10. |
- Hachinski, Vladimir, et al.
(författare)
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Preventing dementia by preventing stroke : The Berlin Manifesto
- 2024
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Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949.
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Forskningsöversikt (refereegranskat)abstract
- The incidence of stroke and dementia are diverging across the world, rising for those in low-and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action.
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