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Accumulating evidence highlights the involvement of astrocytes in Alzheimer’s disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes’ processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10−8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care., For complete list of authors see http://dx.doi.org/10.1038/s41586-024-07019-6

Accumulating evidence highlights the involvement of astrocytes in Alzheimer’s disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes’ processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD.

Computerized cognitive tests have the potential to cost-effectively detect and monitor cognitive impairments and thereby facilitate treatment for these conditions. However, relatively few of these tests have been validated in a variety of populations. Brain on Track, a self-administered web-based test, has previously been shown to have a good ability to differentiate between healthy individuals and patients with cognitive impairment in Portuguese populations. The objective of this study was to validate the differential ability and evaluate the usability of Brain on Track in a Swedish memory clinic setting. Brain on Track was administered to 30 patients with mild cognitive impairment/mild dementia and 30 healthy controls, all scheduled to perform the test from home after one week and after three months. To evaluate the usability, the patient group was interviewed after completion of the testing phase. Patients scored lower than healthy controls at both the first (median score 42.4 vs 54.1, p<0.001) and the second test (median score 42.3 vs 55.0, p<0.001). The test-retest intra-class correlation was 0.87. A multiple logistic regression model accounting for effects of age, gender and education rendered an ability of Brain on Track to differentiate between the groups with an area under the receiver operation characteristics curve of 0.90 for the first and 0.88 for the second test. In the subjective evaluation, nine patients left positive comments, nine were negative whereas five left mixed comments regarding the test experience. Sixty percent of patients had received help from relatives to log on to the platform. In conclusion, Brain on Track performed well in differentiating healthy controls from patients with cognitive impairment and showed a high test-retest reliability, on par with results from previous studies. However, the substantial proportion of patients needing help to log in could to some extent limit an independent use of the platform.

Accumulating evidence highlights the involvement of astrocytes in Alzheimer’s disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes’ processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD.

Computerized cognitive tests have the potential to cost-effectively detect and monitor cognitive impairments and thereby facilitate treatment for these conditions. However, relatively few of these tests have been validated in a variety of populations. Brain on Track, a self-administered web-based test, has previously been shown to have a good ability to differentiate between healthy individuals and patients with cognitive impairment in Portuguese populations. The objective of this study was to validate the differential ability and evaluate the usability of Brain on Track in a Swedish memory clinic setting. Brain on Track was administered to 30 patients with mild cognitive impairment/mild dementia and 30 healthy controls, all scheduled to perform the test from home after one week and after three months. To evaluate the usability, the patient group was interviewed after completion of the testing phase. Patients scored lower than healthy controls at both the first (median score 42.4 vs 54.1, p<0.001) and the second test (median score 42.3 vs 55.0, p<0.001). The test-retest intra-class correlation was 0.87. A multiple logistic regression model accounting for effects of age, gender and education rendered an ability of Brain on Track to differentiate between the groups with an area under the receiver operation characteristics curve of 0.90 for the first and 0.88 for the second test. In the subjective evaluation, nine patients left positive comments, nine were negative whereas five left mixed comments regarding the test experience. Sixty percent of patients had received help from relatives to log on to the platform. In conclusion, Brain on Track performed well in differentiating healthy controls from patients with cognitive impairment and showed a high test-retest reliability, on par with results from previous studies. However, the substantial proportion of patients needing help to log in could to some extent limit an independent use of the platform.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10−8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care., For complete list of authors see http://dx.doi.org/10.1038/s41586-024-07019-6

Computerized cognitive tests have the potential to cost-effectively detect and monitor cognitive impairments and thereby facilitate treatment for these conditions. However, relatively few of these tests have been validated in a variety of populations. Brain on Track, a self-administered web-based test, has previously been shown to have a good ability to differentiate between healthy individuals and patients with cognitive impairment in Portuguese populations. The objective of this study was to validate the differential ability and evaluate the usability of Brain on Track in a Swedish memory clinic setting. Brain on Track was administered to 30 patients with mild cognitive impairment/mild dementia and 30 healthy controls, all scheduled to perform the test from home after one week and after three months. To evaluate the usability, the patient group was interviewed after completion of the testing phase. Patients scored lower than healthy controls at both the first (median score 42.4 vs 54.1, p<0.001) and the second test (median score 42.3 vs 55.0, p<0.001). The test-retest intra-class correlation was 0.87. A multiple logistic regression model accounting for effects of age, gender and education rendered an ability of Brain on Track to differentiate between the groups with an area under the receiver operation characteristics curve of 0.90 for the first and 0.88 for the second test. In the subjective evaluation, nine patients left positive comments, nine were negative whereas five left mixed comments regarding the test experience. Sixty percent of patients had received help from relatives to log on to the platform. In conclusion, Brain on Track performed well in differentiating healthy controls from patients with cognitive impairment and showed a high test-retest reliability, on par with results from previous studies. However, the substantial proportion of patients needing help to log in could to some extent limit an independent use of the platform.

Accumulating evidence highlights the involvement of astrocytes in Alzheimer’s disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes’ processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD.

Intra- or extracellular aggregates of proteins are central pathogenic features in most neurodegenerative disorders. The accumulation of such proteins in diseased brains is believed to be the end-stage of a stepwise aggregation of misfolded monomers to insoluble cross-beta fibrils via a series of differently sized soluble oligomers/protofibrils. Several studies have shown how alpha-synuclein, amyloid-beta, tau and other amyloidogenic proteins can act as nucleating particles and thereby share properties with misfolded forms, or strains, of the prion protein. Although the roles of different protein assemblies in the respective aggregation cascades remain unclear, oligomers/protofibrils are considered key pathogenic species. Numerous observations have demonstrated their neurotoxic effects and a growing number of studies have indicated that they also possess seeding properties, enabling their propagation within cellular networks in the nervous system. The seeding behavior of oligomers differs between the proteins and is also affected by various factors, such as size, shape and epitope presentation. Here, we are providing an overview of the current state of knowledge with respect to the "prion-like" behavior of soluble oligomers for several of the amyloidogenic proteins involved in neurodegenerative diseases. In addition to providing new insight into pathogenic mechanisms, research in this field is leading to novel diagnostic and therapeutic opportunities for neurodegenerative diseases.

Computerized cognitive tests have the potential to cost-effectively detect and monitor cognitive impairments and thereby facilitate treatment for these conditions. However, relatively few of these tests have been validated in a variety of populations. Brain on Track, a self-administered web-based test, has previously been shown to have a good ability to differentiate between healthy individuals and patients with cognitive impairment in Portuguese populations. The objective of this study was to validate the differential ability and evaluate the usability of Brain on Track in a Swedish memory clinic setting. Brain on Track was administered to 30 patients with mild cognitive impairment/mild dementia and 30 healthy controls, all scheduled to perform the test from home after one week and after three months. To evaluate the usability, the patient group was interviewed after completion of the testing phase. Patients scored lower than healthy controls at both the first (median score 42.4 vs 54.1, p<0.001) and the second test (median score 42.3 vs 55.0, p<0.001). The test-retest intra-class correlation was 0.87. A multiple logistic regression model accounting for effects of age, gender and education rendered an ability of Brain on Track to differentiate between the groups with an area under the receiver operation characteristics curve of 0.90 for the first and 0.88 for the second test. In the subjective evaluation, nine patients left positive comments, nine were negative whereas five left mixed comments regarding the test experience. Sixty percent of patients had received help from relatives to log on to the platform. In conclusion, Brain on Track performed well in differentiating healthy controls from patients with cognitive impairment and showed a high test-retest reliability, on par with results from previous studies. However, the substantial proportion of patients needing help to log in could to some extent limit an independent use of the platform.

Accumulating evidence highlights the involvement of astrocytes in Alzheimer’s disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes’ processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD.

Computerized cognitive tests have the potential to cost-effectively detect and monitor cognitive impairments and thereby facilitate treatment for these conditions. However, relatively few of these tests have been validated in a variety of populations. Brain on Track, a self-administered web-based test, has previously been shown to have a good ability to differentiate between healthy individuals and patients with cognitive impairment in Portuguese populations. The objective of this study was to validate the differential ability and evaluate the usability of Brain on Track in a Swedish memory clinic setting. Brain on Track was administered to 30 patients with mild cognitive impairment/mild dementia and 30 healthy controls, all scheduled to perform the test from home after one week and after three months. To evaluate the usability, the patient group was interviewed after completion of the testing phase. Patients scored lower than healthy controls at both the first (median score 42.4 vs 54.1, p<0.001) and the second test (median score 42.3 vs 55.0, p<0.001). The test-retest intra-class correlation was 0.87. A multiple logistic regression model accounting for effects of age, gender and education rendered an ability of Brain on Track to differentiate between the groups with an area under the receiver operation characteristics curve of 0.90 for the first and 0.88 for the second test. In the subjective evaluation, nine patients left positive comments, nine were negative whereas five left mixed comments regarding the test experience. Sixty percent of patients had received help from relatives to log on to the platform. In conclusion, Brain on Track performed well in differentiating healthy controls from patients with cognitive impairment and showed a high test-retest reliability, on par with results from previous studies. However, the substantial proportion of patients needing help to log in could to some extent limit an independent use of the platform.

BACKGROUND: Proteomic profiling could potentially disclose new pathophysiological pathways for cardiovascular diseases (CVD) and improve prediction at the individual level. We therefore aimed to study the plasma protein profile associated with the incidence of different CVDs. METHODS: Plasma levels of 245 proteins suspected to be linked to CVD or metabolism were measured in 4 Swedish prospective population-based cohorts (SIMPLER [Swedish Infrastructure for Medical Population-Based Life-Course and Environmental Research], ULSAM (Uppsala Longitudinal Study of Adult Men), EpiHealth, and POEM [Prospective Investigation of Obesity, Energy Production, and Metabolism]) comprising 11 869 individuals, free of CVD diagnoses at baseline. Our primary CVD outcome was defined by a combined end point that included either incident myocardial infarction, stroke, or heart failure. RESULTS: Using a discovery/validation approach, 42 proteins were associated with our primary composite end point occurring in 1163 subjects. In separate meta-analyses for each of the 3 CVD outcomes, 49 proteins were related to myocardial infarction, 34 to ischemic stroke, and 109 to heart failure. Thirteen proteins were related to all 3 outcomes. Of those, urokinase plasminogen activator surface receptor, adrenomedullin, and KIM-1 (kidney injury molecule 1) were also related to several markers of subclinical CVD in Prospective Investigation of Obesity, Energy production and Metabolism, reflecting myocardial or arterial pathologies. In prediction analysis, a lasso selection of 11 proteins in ULSAM improved the discrimination of CVD by 3.3% (P<0.0001) in SIMPLER when added to traditional risk factors. CONCLUSIONS: Protein profiling in multiple samples disclosed several new proteins to be associated with subsequent myocardial infarction, stroke, and heart failure, suggesting common pathophysiological pathways for these diseases. KIM-1, urokinase plasminogen activator surface receptor, and adrenomedullin wer

Background: Neuroinflammatory processes have been suggested to play a role in the pathophysiology of neurodegenerative diseases and post-hemorrhagic hydrocephalus, but have rarely been investigated in patients with idiopathic normal pressure hydrocephalus (iNPH). The aim of this study was to investigate whether levels of inflammatory proteins in CSF are different in iNPH compared to healthy controls and patients with selected neurodegenerative disorders, and whether any of these markers can aid in the differential diagnosis of iNPH. Methods: Lumbar CSF was collected from 172 patients from a single center and represented iNPH (n = 74), Alzheimer's disease (AD) (n = 21), mild cognitive impairment (MCI) due to AD (n = 21), stable MCI (n = 22), frontotemporal dementia (n = 13), and healthy controls (HC) (n = 21). Levels of 92 inflammatory proteins were analyzed using a proximity extension assay. As a first step, differences between iNPH and HC were investigated, and proteins that differed between iNPH and HC were then compared with those from the other groups. The linear regressions were adjusted for age, sex, and plate number. Results: Three proteins showed higher (MCP-1, p = 0.0013; CCL4, p = 0.0008; CCL11, p = 0.0022) and one lower (PD-L1, p = 0.0051) levels in patients with iNPH compared to HC. MCP-1 was then found to be higher in iNPH than in all other groups. CCL4 was higher in iNPH than in all other groups, except in MCI due to AD. PD-L1 was lower in iNPH compared to all other groups, except in stable MCI. Levels of CCL11 did not differ between iNPH and the differential diagnoses. In a model based on the four proteins mentioned above, the mean area under the receiver operating characteristic curve used to discriminate between iNPH and the other disorders was 0.91. Conclusions: The inflammatory cytokines MCP-1 and CCL4 are present at higher-and PD-L1 at lower-levels in iNPH than in the other investigated diagnoses. These three selected cytokines may have diagnosti

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1* 04:07, and intermediary with HLA-DRB1* 04:01 and HLA- DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased A beta 42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used single-nuclei RNA sequencing (snRNA-seq) to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides insight into the initiating events of the neuroinflammatory response in TBI, which has therapeutic implications.

BACKGROUND: Proteomic profiling could potentially disclose new pathophysiological pathways for cardiovascular diseases (CVD) and improve prediction at the individual level. We therefore aimed to study the plasma protein profile associated with the incidence of different CVDs. METHODS: Plasma levels of 245 proteins suspected to be linked to CVD or metabolism were measured in 4 Swedish prospective population-based cohorts (SIMPLER [Swedish Infrastructure for Medical Population-Based Life-Course and Environmental Research], ULSAM (Uppsala Longitudinal Study of Adult Men), EpiHealth, and POEM [Prospective Investigation of Obesity, Energy Production, and Metabolism]) comprising 11 869 individuals, free of CVD diagnoses at baseline. Our primary CVD outcome was defined by a combined end point that included either incident myocardial infarction, stroke, or heart failure. RESULTS: Using a discovery/validation approach, 42 proteins were associated with our primary composite end point occurring in 1163 subjects. In separate meta-analyses for each of the 3 CVD outcomes, 49 proteins were related to myocardial infarction, 34 to ischemic stroke, and 109 to heart failure. Thirteen proteins were related to all 3 outcomes. Of those, urokinase plasminogen activator surface receptor, adrenomedullin, and KIM-1 (kidney injury molecule 1) were also related to several markers of subclinical CVD in Prospective Investigation of Obesity, Energy production and Metabolism, reflecting myocardial or arterial pathologies. In prediction analysis, a lasso selection of 11 proteins in ULSAM improved the discrimination of CVD by 3.3% (P<0.0001) in SIMPLER when added to traditional risk factors. CONCLUSIONS: Protein profiling in multiple samples disclosed several new proteins to be associated with subsequent myocardial infarction, stroke, and heart failure, suggesting common pathophysiological pathways for these diseases. KIM-1, urokinase plasminogen activator surface receptor, and adrenomedullin wer

Background: Neuroinflammatory processes have been suggested to play a role in the pathophysiology of neurodegenerative diseases and post-hemorrhagic hydrocephalus, but have rarely been investigated in patients with idiopathic normal pressure hydrocephalus (iNPH). The aim of this study was to investigate whether levels of inflammatory proteins in CSF are different in iNPH compared to healthy controls and patients with selected neurodegenerative disorders, and whether any of these markers can aid in the differential diagnosis of iNPH. Methods: Lumbar CSF was collected from 172 patients from a single center and represented iNPH (n = 74), Alzheimer's disease (AD) (n = 21), mild cognitive impairment (MCI) due to AD (n = 21), stable MCI (n = 22), frontotemporal dementia (n = 13), and healthy controls (HC) (n = 21). Levels of 92 inflammatory proteins were analyzed using a proximity extension assay. As a first step, differences between iNPH and HC were investigated, and proteins that differed between iNPH and HC were then compared with those from the other groups. The linear regressions were adjusted for age, sex, and plate number. Results: Three proteins showed higher (MCP-1, p = 0.0013; CCL4, p = 0.0008; CCL11, p = 0.0022) and one lower (PD-L1, p = 0.0051) levels in patients with iNPH compared to HC. MCP-1 was then found to be higher in iNPH than in all other groups. CCL4 was higher in iNPH than in all other groups, except in MCI due to AD. PD-L1 was lower in iNPH compared to all other groups, except in stable MCI. Levels of CCL11 did not differ between iNPH and the differential diagnoses. In a model based on the four proteins mentioned above, the mean area under the receiver operating characteristic curve used to discriminate between iNPH and the other disorders was 0.91. Conclusions: The inflammatory cytokines MCP-1 and CCL4 are present at higher-and PD-L1 at lower-levels in iNPH than in the other investigated diagnoses. These three selected cytokines may have diagnosti

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1* 04:07, and intermediary with HLA-DRB1* 04:01 and HLA- DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased A beta 42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used single-nuclei RNA sequencing (snRNA-seq) to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides insight into the initiating events of the neuroinflammatory response in TBI, which has therapeutic implications.

BACKGROUND: Proteomic profiling could potentially disclose new pathophysiological pathways for cardiovascular diseases (CVD) and improve prediction at the individual level. We therefore aimed to study the plasma protein profile associated with the incidence of different CVDs. METHODS: Plasma levels of 245 proteins suspected to be linked to CVD or metabolism were measured in 4 Swedish prospective population-based cohorts (SIMPLER [Swedish Infrastructure for Medical Population-Based Life-Course and Environmental Research], ULSAM (Uppsala Longitudinal Study of Adult Men), EpiHealth, and POEM [Prospective Investigation of Obesity, Energy Production, and Metabolism]) comprising 11 869 individuals, free of CVD diagnoses at baseline. Our primary CVD outcome was defined by a combined end point that included either incident myocardial infarction, stroke, or heart failure. RESULTS: Using a discovery/validation approach, 42 proteins were associated with our primary composite end point occurring in 1163 subjects. In separate meta-analyses for each of the 3 CVD outcomes, 49 proteins were related to myocardial infarction, 34 to ischemic stroke, and 109 to heart failure. Thirteen proteins were related to all 3 outcomes. Of those, urokinase plasminogen activator surface receptor, adrenomedullin, and KIM-1 (kidney injury molecule 1) were also related to several markers of subclinical CVD in Prospective Investigation of Obesity, Energy production and Metabolism, reflecting myocardial or arterial pathologies. In prediction analysis, a lasso selection of 11 proteins in ULSAM improved the discrimination of CVD by 3.3% (P<0.0001) in SIMPLER when added to traditional risk factors. CONCLUSIONS: Protein profiling in multiple samples disclosed several new proteins to be associated with subsequent myocardial infarction, stroke, and heart failure, suggesting common pathophysiological pathways for these diseases. KIM-1, urokinase plasminogen activator surface receptor, and adrenomedullin wer

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1* 04:07, and intermediary with HLA-DRB1* 04:01 and HLA- DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased A beta 42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used single-nuclei RNA sequencing (snRNA-seq) to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides insight into the initiating events of the neuroinflammatory response in TBI, which has therapeutic implications.

BACKGROUND: Proteomic profiling could potentially disclose new pathophysiological pathways for cardiovascular diseases (CVD) and improve prediction at the individual level. We therefore aimed to study the plasma protein profile associated with the incidence of different CVDs. METHODS: Plasma levels of 245 proteins suspected to be linked to CVD or metabolism were measured in 4 Swedish prospective population-based cohorts (SIMPLER [Swedish Infrastructure for Medical Population-Based Life-Course and Environmental Research], ULSAM (Uppsala Longitudinal Study of Adult Men), EpiHealth, and POEM [Prospective Investigation of Obesity, Energy Production, and Metabolism]) comprising 11 869 individuals, free of CVD diagnoses at baseline. Our primary CVD outcome was defined by a combined end point that included either incident myocardial infarction, stroke, or heart failure. RESULTS: Using a discovery/validation approach, 42 proteins were associated with our primary composite end point occurring in 1163 subjects. In separate meta-analyses for each of the 3 CVD outcomes, 49 proteins were related to myocardial infarction, 34 to ischemic stroke, and 109 to heart failure. Thirteen proteins were related to all 3 outcomes. Of those, urokinase plasminogen activator surface receptor, adrenomedullin, and KIM-1 (kidney injury molecule 1) were also related to several markers of subclinical CVD in Prospective Investigation of Obesity, Energy production and Metabolism, reflecting myocardial or arterial pathologies. In prediction analysis, a lasso selection of 11 proteins in ULSAM improved the discrimination of CVD by 3.3% (P<0.0001) in SIMPLER when added to traditional risk factors. CONCLUSIONS: Protein profiling in multiple samples disclosed several new proteins to be associated with subsequent myocardial infarction, stroke, and heart failure, suggesting common pathophysiological pathways for these diseases. KIM-1, urokinase plasminogen activator surface receptor, and adrenomedullin wer

Background: Neuroinflammatory processes have been suggested to play a role in the pathophysiology of neurodegenerative diseases and post-hemorrhagic hydrocephalus, but have rarely been investigated in patients with idiopathic normal pressure hydrocephalus (iNPH). The aim of this study was to investigate whether levels of inflammatory proteins in CSF are different in iNPH compared to healthy controls and patients with selected neurodegenerative disorders, and whether any of these markers can aid in the differential diagnosis of iNPH. Methods: Lumbar CSF was collected from 172 patients from a single center and represented iNPH (n = 74), Alzheimer's disease (AD) (n = 21), mild cognitive impairment (MCI) due to AD (n = 21), stable MCI (n = 22), frontotemporal dementia (n = 13), and healthy controls (HC) (n = 21). Levels of 92 inflammatory proteins were analyzed using a proximity extension assay. As a first step, differences between iNPH and HC were investigated, and proteins that differed between iNPH and HC were then compared with those from the other groups. The linear regressions were adjusted for age, sex, and plate number. Results: Three proteins showed higher (MCP-1, p = 0.0013; CCL4, p = 0.0008; CCL11, p = 0.0022) and one lower (PD-L1, p = 0.0051) levels in patients with iNPH compared to HC. MCP-1 was then found to be higher in iNPH than in all other groups. CCL4 was higher in iNPH than in all other groups, except in MCI due to AD. PD-L1 was lower in iNPH compared to all other groups, except in stable MCI. Levels of CCL11 did not differ between iNPH and the differential diagnoses. In a model based on the four proteins mentioned above, the mean area under the receiver operating characteristic curve used to discriminate between iNPH and the other disorders was 0.91. Conclusions: The inflammatory cytokines MCP-1 and CCL4 are present at higher-and PD-L1 at lower-levels in iNPH than in the other investigated diagnoses. These three selected cytokines may have diagnosti

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1* 04:07, and intermediary with HLA-DRB1* 04:01 and HLA- DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased A beta 42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used single-nuclei RNA sequencing (snRNA-seq) to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides insight into the initiating events of the neuroinflammatory response in TBI, which has therapeutic implications.

Importance An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures Genetically determined modifiable risk factors. Main Outcomes and Measures Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10–mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimiz, Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the enti

Background: Visium Spatial Gene Expression (ST) is a method combining histological spatial information with transcriptomics profiles directly from tissue sections. The use of spatial information has made it possible to discover new modes of gene expression regulations. However, in the ST experiment, the nucleus size of cells may exceed the thickness of a tissue slice. This may, in turn, negatively affect comprehensive capturing the transcriptomics profile in a single slice, especially for tissues having large differences in the size of nuclei. Methods: Here, we defined the effect of Consecutive Slices Data Integration (CSDI) on unveiling accurate spot clustering and deconvolution of spatial transcriptomic spots in human postmortem brains. By considering the histological information as reference, we assessed the improvement of unsupervised clustering and single nuclei RNA-seq and ST data integration before and after CSDI. Results: Apart from the escalated number of defined clusters representing neuronal layers, the pattern of clusters in consecutive sections was concordant only after CSDI. Besides, the assigned cell labels to spots matches the histological pattern of tissue sections after CSDI. Conclusion: CSDI can be applied to investigate consecutive sections studied with ST in the human cerebral cortex, avoiding misinterpretation of spot clustering and annotation, increasing accuracy of cell recognition as well as improvement in uncovering the layers of grey matter in the human brain.

Unique strains of a-synuclein aggregates have been postulated to underlie the spectrum of clinical and pathological presentations seen across the synucleinopathies. Whereas multiple system atrophy (MSA) is associated with a predominance of oligodendroglial a-synuclein inclusions, a-synuclein aggregates in Parkinson's disease (PD) preferentially accumulate in neurons. The G51D mutation in the SNCA gene encoding a-synuclein causes an aggressive, early-onset form of PD that exhibits clinical and neuropathological traits reminiscent of both PD and MSA. To assess the strain characteristics of G51D PD a-synuclein aggregates, we performed propagation studies in M83 transgenic mice by intracerebrally inoculating patient brain extracts. The properties of the induced a-synuclein aggregates in the brains of injected mice were examined using immunohistochemistry, a conformational stability assay, and by performing a-synuclein seed amplification assays. Unlike MSA-injected mice, which developed a progressive motor phenotype, G51D PD-inoculated animals remained free of overt neurological illness for up to 18 months post-inoculation. However, a subclinical synucleinopathy was present in G51D PD-inoculated mice, characterized by the accumulation of a-synuclein aggregates in restricted regions of the brain. The induced a-synuclein aggregates in G51D PD-injected mice exhibited distinct properties in a seed amplification assay and were much more stable than those present in mice injected with MSA extract, which mirrored the differences observed between human MSA and G51D PD brain samples. These results suggest that the G51D SNCA mutation specifies the formation of a slowly propagating a-synuclein strain that more closely resembles a-synuclein aggregates associated with PD than MSA.

Introduction: Parkinson's disease and type 2 diabetes have both elements of local amyloid depositions in their pathogenesis. In Parkinson's disease, alpha-synuclein (aSyn) forms insoluble Lewy bodies and Lewy neurites in brain neurons, and in type 2 diabetes, islet amyloid polypeptide (IAPP) comprises the amyloid in the islets of Langerhans. In this study, we assessed the interaction between aSyn and IAPP in human pancreatic tissues, both ex vivo and in vitro. Material and Methods: The antibody-based detection techniques, proximity ligation assay (PLA), and immuno-TEM were used for co-localization studies. Bifluorescence complementation (BiFC) was used for interaction studies between IAPP and aSyn in HEK 293 cells. The Thioflavin T assay was used for studies of cross-seeding between IAPP and aSyn. ASyn was downregulated with siRNA, and insulin secretion was monitored using TIRF microscopy. Results: We demonstrate intracellular co-localization of aSyn with IAPP, while aSyn is absent in the extracellular amyloid deposits. ASyn reactivity is present in the secretory granules of beta-cells and some alpha-cells in human islets. The BiFC-expression of aSyn/aSyn and IAPP/IAPP in HEK293 cells resulted in 29.3% and 19.7% fluorescent cells, respectively, while aSyn/IAPP co-expression resulted in & SIM;10% fluorescent cells. Preformed aSyn fibrils seeded IAPP fibril formation in vitro, but adding preformed IAPP seeds to aSyn did not change aSyn fibrillation. In addition, mixing monomeric aSyn with monomeric IAPP did not affect IAPP fibril formation. Finally, the knockdown of endogenous aSyn did not affect beta cell function or viability, nor did overexpression of aSyn affect beta cell viability. Discussion: Despite the proximity of aSyn and IAPP in beta-cells and the detected capacity of preformed aSyn fibrils to seed IAPP in vitro, it is still an open question if an interaction between the two molecules is of pathogenic significance for type 2 diabetes.

Growing evidence indicates that the pathological alpha-synuclein (a-syn) aggregation in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) starts at the synapses. Physiologic a-syn is involved in regulating neurotransmitter release by binding to the SNARE complex protein VAMP-2 on synaptic vesicles. However, in which way the SNARE complex formation is affected by a-syn pathology remains unclear. In this study, primary cortical neurons were exposed to either a-syn monomers or preformed fibrils (PFFs) for different time points and the effect on SNARE protein distribution was analyzed with a novel proximity ligation assay (PLA). Short-term exposure to monomers or PFFs for 24 h increased the co-localization of VAMP-2 and syntaxin-1, but reduced the co-localization of SNAP-25 and syntaxin-1, indicating a direct effect of the added a-syn on SNARE protein distribution. Long-term exposure to a-syn PFFs for 7 d reduced VAMP-2 and SNAP-25 co-localization, although there was only a modest induction of ser129 phosphorylated (pS129) a-syn. Similarly, exposure to extracellular vesicles collected from astrocytes treated with a-syn PFFs for 7 d influenced VAMP-2 and SNAP-25 co-localization despite only low levels of pS129 a-syn being formed. Taken together, our results demonstrate that different a-syn proteoforms have the potential to alter the distribution of SNARE proteins at the synapse.

The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. RESULTS The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Bio

Tau deposits in astrocytes are frequently found in Alzheimer's disease (AD) and other tauopathies. Since astrocytes do not express tau, the inclusions have been suggested to be of neuronal origin. However, the mechanisms behind their appearance and their relevance for disease progression remain unknown. Here we demonstrate, using a battery of experimental techniques that human astrocytes serve as an intermediator, promoting cell-to-cell spreading of pathological tau. Human astrocytes engulf and process, but fail to fully degrade dead neurons with tau pathology, as well as synthetic tau fibrils and tau aggregates isolated from AD brain tissue. Instead, the pathogenic tau is spread to nearby cells via secretion and tunneling nanotube mediated transfer. By performing co-culture experiments we could show that tau-containing astrocytes induce tau pathology in healthy human neurons directly. Furthermore, our results from a FRET based seeding assay, demonstrated that the tau proteoforms secreted by astrocytes have an exceptional seeding capacity, compared to the original tau species engulfed by the cells. Taken together, our study establishes a central role for astrocytes in mediating tau pathology, which could be of relevance for identifying novel treatment targets for AD and other tauopathies.

Unique strains of a-synuclein aggregates have been postulated to underlie the spectrum of clinical and pathological presentations seen across the synucleinopathies. Whereas multiple system atrophy (MSA) is associated with a predominance of oligodendroglial a-synuclein inclusions, a-synuclein aggregates in Parkinson's disease (PD) preferentially accumulate in neurons. The G51D mutation in the SNCA gene encoding a-synuclein causes an aggressive, early-onset form of PD that exhibits clinical and neuropathological traits reminiscent of both PD and MSA. To assess the strain characteristics of G51D PD a-synuclein aggregates, we performed propagation studies in M83 transgenic mice by intracerebrally inoculating patient brain extracts. The properties of the induced a-synuclein aggregates in the brains of injected mice were examined using immunohistochemistry, a conformational stability assay, and by performing a-synuclein seed amplification assays. Unlike MSA-injected mice, which developed a progressive motor phenotype, G51D PD-inoculated animals remained free of overt neurological illness for up to 18 months post-inoculation. However, a subclinical synucleinopathy was present in G51D PD-inoculated mice, characterized by the accumulation of a-synuclein aggregates in restricted regions of the brain. The induced a-synuclein aggregates in G51D PD-injected mice exhibited distinct properties in a seed amplification assay and were much more stable than those present in mice injected with MSA extract, which mirrored the differences observed between human MSA and G51D PD brain samples. These results suggest that the G51D SNCA mutation specifies the formation of a slowly propagating a-synuclein strain that more closely resembles a-synuclein aggregates associated with PD than MSA.

Background: Visium Spatial Gene Expression (ST) is a method combining histological spatial information with transcriptomics profiles directly from tissue sections. The use of spatial information has made it possible to discover new modes of gene expression regulations. However, in the ST experiment, the nucleus size of cells may exceed the thickness of a tissue slice. This may, in turn, negatively affect comprehensive capturing the transcriptomics profile in a single slice, especially for tissues having large differences in the size of nuclei. Methods: Here, we defined the effect of Consecutive Slices Data Integration (CSDI) on unveiling accurate spot clustering and deconvolution of spatial transcriptomic spots in human postmortem brains. By considering the histological information as reference, we assessed the improvement of unsupervised clustering and single nuclei RNA-seq and ST data integration before and after CSDI. Results: Apart from the escalated number of defined clusters representing neuronal layers, the pattern of clusters in consecutive sections was concordant only after CSDI. Besides, the assigned cell labels to spots matches the histological pattern of tissue sections after CSDI. Conclusion: CSDI can be applied to investigate consecutive sections studied with ST in the human cerebral cortex, avoiding misinterpretation of spot clustering and annotation, increasing accuracy of cell recognition as well as improvement in uncovering the layers of grey matter in the human brain.

Introduction: Parkinson's disease and type 2 diabetes have both elements of local amyloid depositions in their pathogenesis. In Parkinson's disease, alpha-synuclein (aSyn) forms insoluble Lewy bodies and Lewy neurites in brain neurons, and in type 2 diabetes, islet amyloid polypeptide (IAPP) comprises the amyloid in the islets of Langerhans. In this study, we assessed the interaction between aSyn and IAPP in human pancreatic tissues, both ex vivo and in vitro. Material and Methods: The antibody-based detection techniques, proximity ligation assay (PLA), and immuno-TEM were used for co-localization studies. Bifluorescence complementation (BiFC) was used for interaction studies between IAPP and aSyn in HEK 293 cells. The Thioflavin T assay was used for studies of cross-seeding between IAPP and aSyn. ASyn was downregulated with siRNA, and insulin secretion was monitored using TIRF microscopy. Results: We demonstrate intracellular co-localization of aSyn with IAPP, while aSyn is absent in the extracellular amyloid deposits. ASyn reactivity is present in the secretory granules of beta-cells and some alpha-cells in human islets. The BiFC-expression of aSyn/aSyn and IAPP/IAPP in HEK293 cells resulted in 29.3% and 19.7% fluorescent cells, respectively, while aSyn/IAPP co-expression resulted in & SIM;10% fluorescent cells. Preformed aSyn fibrils seeded IAPP fibril formation in vitro, but adding preformed IAPP seeds to aSyn did not change aSyn fibrillation. In addition, mixing monomeric aSyn with monomeric IAPP did not affect IAPP fibril formation. Finally, the knockdown of endogenous aSyn did not affect beta cell function or viability, nor did overexpression of aSyn affect beta cell viability. Discussion: Despite the proximity of aSyn and IAPP in beta-cells and the detected capacity of preformed aSyn fibrils to seed IAPP in vitro, it is still an open question if an interaction between the two molecules is of pathogenic significance for type 2 diabetes.

Growing evidence indicates that the pathological alpha-synuclein (a-syn) aggregation in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) starts at the synapses. Physiologic a-syn is involved in regulating neurotransmitter release by binding to the SNARE complex protein VAMP-2 on synaptic vesicles. However, in which way the SNARE complex formation is affected by a-syn pathology remains unclear. In this study, primary cortical neurons were exposed to either a-syn monomers or preformed fibrils (PFFs) for different time points and the effect on SNARE protein distribution was analyzed with a novel proximity ligation assay (PLA). Short-term exposure to monomers or PFFs for 24 h increased the co-localization of VAMP-2 and syntaxin-1, but reduced the co-localization of SNAP-25 and syntaxin-1, indicating a direct effect of the added a-syn on SNARE protein distribution. Long-term exposure to a-syn PFFs for 7 d reduced VAMP-2 and SNAP-25 co-localization, although there was only a modest induction of ser129 phosphorylated (pS129) a-syn. Similarly, exposure to extracellular vesicles collected from astrocytes treated with a-syn PFFs for 7 d influenced VAMP-2 and SNAP-25 co-localization despite only low levels of pS129 a-syn being formed. Taken together, our results demonstrate that different a-syn proteoforms have the potential to alter the distribution of SNARE proteins at the synapse.

IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. RESULTS The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Bio

The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Tau deposits in astrocytes are frequently found in Alzheimer's disease (AD) and other tauopathies. Since astrocytes do not express tau, the inclusions have been suggested to be of neuronal origin. However, the mechanisms behind their appearance and their relevance for disease progression remain unknown. Here we demonstrate, using a battery of experimental techniques that human astrocytes serve as an intermediator, promoting cell-to-cell spreading of pathological tau. Human astrocytes engulf and process, but fail to fully degrade dead neurons with tau pathology, as well as synthetic tau fibrils and tau aggregates isolated from AD brain tissue. Instead, the pathogenic tau is spread to nearby cells via secretion and tunneling nanotube mediated transfer. By performing co-culture experiments we could show that tau-containing astrocytes induce tau pathology in healthy human neurons directly. Furthermore, our results from a FRET based seeding assay, demonstrated that the tau proteoforms secreted by astrocytes have an exceptional seeding capacity, compared to the original tau species engulfed by the cells. Taken together, our study establishes a central role for astrocytes in mediating tau pathology, which could be of relevance for identifying novel treatment targets for AD and other tauopathies.

Growing evidence indicates that the pathological alpha-synuclein (a-syn) aggregation in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) starts at the synapses. Physiologic a-syn is involved in regulating neurotransmitter release by binding to the SNARE complex protein VAMP-2 on synaptic vesicles. However, in which way the SNARE complex formation is affected by a-syn pathology remains unclear. In this study, primary cortical neurons were exposed to either a-syn monomers or preformed fibrils (PFFs) for different time points and the effect on SNARE protein distribution was analyzed with a novel proximity ligation assay (PLA). Short-term exposure to monomers or PFFs for 24 h increased the co-localization of VAMP-2 and syntaxin-1, but reduced the co-localization of SNAP-25 and syntaxin-1, indicating a direct effect of the added a-syn on SNARE protein distribution. Long-term exposure to a-syn PFFs for 7 d reduced VAMP-2 and SNAP-25 co-localization, although there was only a modest induction of ser129 phosphorylated (pS129) a-syn. Similarly, exposure to extracellular vesicles collected from astrocytes treated with a-syn PFFs for 7 d influenced VAMP-2 and SNAP-25 co-localization despite only low levels of pS129 a-syn being formed. Taken together, our results demonstrate that different a-syn proteoforms have the potential to alter the distribution of SNARE proteins at the synapse.

The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. RESULTS The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Bio

Tau deposits in astrocytes are frequently found in Alzheimer's disease (AD) and other tauopathies. Since astrocytes do not express tau, the inclusions have been suggested to be of neuronal origin. However, the mechanisms behind their appearance and their relevance for disease progression remain unknown. Here we demonstrate, using a battery of experimental techniques that human astrocytes serve as an intermediator, promoting cell-to-cell spreading of pathological tau. Human astrocytes engulf and process, but fail to fully degrade dead neurons with tau pathology, as well as synthetic tau fibrils and tau aggregates isolated from AD brain tissue. Instead, the pathogenic tau is spread to nearby cells via secretion and tunneling nanotube mediated transfer. By performing co-culture experiments we could show that tau-containing astrocytes induce tau pathology in healthy human neurons directly. Furthermore, our results from a FRET based seeding assay, demonstrated that the tau proteoforms secreted by astrocytes have an exceptional seeding capacity, compared to the original tau species engulfed by the cells. Taken together, our study establishes a central role for astrocytes in mediating tau pathology, which could be of relevance for identifying novel treatment targets for AD and other tauopathies.

Unique strains of a-synuclein aggregates have been postulated to underlie the spectrum of clinical and pathological presentations seen across the synucleinopathies. Whereas multiple system atrophy (MSA) is associated with a predominance of oligodendroglial a-synuclein inclusions, a-synuclein aggregates in Parkinson's disease (PD) preferentially accumulate in neurons. The G51D mutation in the SNCA gene encoding a-synuclein causes an aggressive, early-onset form of PD that exhibits clinical and neuropathological traits reminiscent of both PD and MSA. To assess the strain characteristics of G51D PD a-synuclein aggregates, we performed propagation studies in M83 transgenic mice by intracerebrally inoculating patient brain extracts. The properties of the induced a-synuclein aggregates in the brains of injected mice were examined using immunohistochemistry, a conformational stability assay, and by performing a-synuclein seed amplification assays. Unlike MSA-injected mice, which developed a progressive motor phenotype, G51D PD-inoculated animals remained free of overt neurological illness for up to 18 months post-inoculation. However, a subclinical synucleinopathy was present in G51D PD-inoculated mice, characterized by the accumulation of a-synuclein aggregates in restricted regions of the brain. The induced a-synuclein aggregates in G51D PD-injected mice exhibited distinct properties in a seed amplification assay and were much more stable than those present in mice injected with MSA extract, which mirrored the differences observed between human MSA and G51D PD brain samples. These results suggest that the G51D SNCA mutation specifies the formation of a slowly propagating a-synuclein strain that more closely resembles a-synuclein aggregates associated with PD than MSA.

Background: Visium Spatial Gene Expression (ST) is a method combining histological spatial information with transcriptomics profiles directly from tissue sections. The use of spatial information has made it possible to discover new modes of gene expression regulations. However, in the ST experiment, the nucleus size of cells may exceed the thickness of a tissue slice. This may, in turn, negatively affect comprehensive capturing the transcriptomics profile in a single slice, especially for tissues having large differences in the size of nuclei. Methods: Here, we defined the effect of Consecutive Slices Data Integration (CSDI) on unveiling accurate spot clustering and deconvolution of spatial transcriptomic spots in human postmortem brains. By considering the histological information as reference, we assessed the improvement of unsupervised clustering and single nuclei RNA-seq and ST data integration before and after CSDI. Results: Apart from the escalated number of defined clusters representing neuronal layers, the pattern of clusters in consecutive sections was concordant only after CSDI. Besides, the assigned cell labels to spots matches the histological pattern of tissue sections after CSDI. Conclusion: CSDI can be applied to investigate consecutive sections studied with ST in the human cerebral cortex, avoiding misinterpretation of spot clustering and annotation, increasing accuracy of cell recognition as well as improvement in uncovering the layers of grey matter in the human brain.

Introduction: Parkinson's disease and type 2 diabetes have both elements of local amyloid depositions in their pathogenesis. In Parkinson's disease, alpha-synuclein (aSyn) forms insoluble Lewy bodies and Lewy neurites in brain neurons, and in type 2 diabetes, islet amyloid polypeptide (IAPP) comprises the amyloid in the islets of Langerhans. In this study, we assessed the interaction between aSyn and IAPP in human pancreatic tissues, both ex vivo and in vitro. Material and Methods: The antibody-based detection techniques, proximity ligation assay (PLA), and immuno-TEM were used for co-localization studies. Bifluorescence complementation (BiFC) was used for interaction studies between IAPP and aSyn in HEK 293 cells. The Thioflavin T assay was used for studies of cross-seeding between IAPP and aSyn. ASyn was downregulated with siRNA, and insulin secretion was monitored using TIRF microscopy. Results: We demonstrate intracellular co-localization of aSyn with IAPP, while aSyn is absent in the extracellular amyloid deposits. ASyn reactivity is present in the secretory granules of beta-cells and some alpha-cells in human islets. The BiFC-expression of aSyn/aSyn and IAPP/IAPP in HEK293 cells resulted in 29.3% and 19.7% fluorescent cells, respectively, while aSyn/IAPP co-expression resulted in & SIM;10% fluorescent cells. Preformed aSyn fibrils seeded IAPP fibril formation in vitro, but adding preformed IAPP seeds to aSyn did not change aSyn fibrillation. In addition, mixing monomeric aSyn with monomeric IAPP did not affect IAPP fibril formation. Finally, the knockdown of endogenous aSyn did not affect beta cell function or viability, nor did overexpression of aSyn affect beta cell viability. Discussion: Despite the proximity of aSyn and IAPP in beta-cells and the detected capacity of preformed aSyn fibrils to seed IAPP in vitro, it is still an open question if an interaction between the two molecules is of pathogenic significance for type 2 diabetes.