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- Dybjer, Elin, et al.
(författare)
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Polygenic risk of type 2 diabetes is associated with incident vascular dementia : a prospective cohort study
- 2023
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes and dementia are associated, but it is unclear whether the two diseases have common genetic risk markers that could partly explain their association. It is also unclear whether the association between the two diseases is of a causal nature. Furthermore, few studies on diabetes and dementia have validated dementia end-points with high diagnostic precision. We tested associations between polygenic risk scores for type 2 diabetes, fasting glucose, fasting insulin and haemoglobin A1c as exposure variables and dementia as outcome variables in 29 139 adults (mean age 55) followed for 20–23 years. Dementia diagnoses were validated by physicians through data from medical records, neuroimaging and biomarkers in cerebrospinal fluid. The dementia end-points included all-cause dementia, mixed dementia, Alzheimer’s disease and vascular dementia. We also tested causal associations between type 2 diabetes and dementia through two-sample Mendelian randomization analyses. Seven different polygenic risk scores including single-nucleotide polymorphisms with different significance thresholds for type 2 diabetes were tested. A polygenic risk score including 4891 single-nucleotide polymorphisms with a P-value of <5e-04 showed the strongest association with different outcomes, including all-cause dementia (hazard ratio 1.11; Bonferroni corrected P = 3.6e-03), mixed dementia (hazard ratio 1.18; Bonferroni corrected P = 3.3e-04) and vascular dementia cases (hazard ratio 1.28; Bonferroni corrected P = 9.6e-05). The associations were stronger for non-carriers of the Alzheimer’s disease risk gene APOE ϵ4. There was, however, no significant association between polygenic risk scores for type 2 diabetes and Alzheimer’s disease. Furthermore, two-sample Mendelian randomization analyses could not confirm a causal link between genetic risk markers of type 2 diabetes and dementia outcomes. In conclusion, polygenic risk of type 2 diabetes is associated with an increased risk of dementia, in particular vascular dementia. The findings imply that certain people with type 2 diabetes may, due to their genetic background, be more prone to develop diabetes-associated dementia. This knowledge could in the future lead to targeted preventive strategies in clinical practice.
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| 2. |
- Gobom, Johan, et al.
(författare)
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Antibody-free measurement of cerebrospinal fluid tau phosphorylation across the Alzheimer's disease continuum.
- 2022
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Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease is characterized by an abnormal increase of phosphorylated tau (pTau) species in the CSF. It has been suggested that emergence of different pTau forms may parallel disease progression. Therefore, targeting multiple specific pTau forms may allow for a deeper understanding of disease evolution and underlying pathophysiology. Current immunoassays measure pTau epitopes separately and may capture phosphorylated tau fragments of different length depending on the non-pTau antibody used in the assay sandwich pair, which bias the measurement.We developed the first antibody-free mass spectrometric method to simultaneously measure multiple phosphorylated epitopes in CSF tau: pT181, pS199, pS202, pT205, pT217, pT231, and pS396. The method was first evaluated in biochemically defined Alzheimer's disease and control CSF samples (n=38). All seven pTau epitopes clearly separated Alzheimer's disease from non-AD (p<0.001, AUC=0.84-0.98). We proceeded with clinical validation of the method in the TRIAD (n=165) and BioFINDER-2 cohorts (n=563), consisting of patients across the full Alzheimer's disease continuum, including also young controls (<40years), as well as patients with frontotemporal dementia and other neurodegenerative disorders.Increased levels of all phosphorylated epitopes were found in Alzheimer's disease dementia and Aβ positron emission tomography-positive patients with mild cognitive impairment compared with Aβ-negative controls. For Alzheimer's disease dementia compared with Aβ-negative controls, the best biomarker performance was observed for pT231 (TRIAD: AUC=98.73%, fold change=7.64; BioFINDER-2: AUC=91.89%, fold change=10.65), pT217 (TRIAD: AUC=99.71%, fold change=6.33; BioFINDER-2: AUC=98.12%, fold change=8.83) and pT205 (TRIAD: AUC=99.07%, fold change=5.34; BioFINDER-2: AUC=93.51%, fold change=3.92). These phospho-epitopes also discriminated between Aβ-positive and Aβ-negative cognitively unimpaired individuals: pT217 (TRIAD: AUC=83.26, fold change=2.39; BioFINDER-2: AUC=91.05%, fold change=3.29), pT231 (TRIAD: AUC=86.25, fold change=3.80; BioFINDER-2: AUC=78.69%, fold change=3.65) and pT205 (TRIAD: AUC=71.58, fold change=1.51; BioFINDER-2: AUC=71.11%, fold change=1.70).While an increase was found for all pTau species examined, the highest fold change in Alzheimer's disease was found for pT231, pT217 and pT205. Simultaneous antibody-free measurement of pTau epitopes by mass spectrometry avoids possible bias caused by differences in antibody affinity for modified or processed forms of tau, provides insights into tau pathophysiology and may facilitate clinical trials on tau-based drug candidates.
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