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Common mechanisms and pathways in Stroke and Alzheimer's disease.

Periodic Reporting for period 4 - CoSTREAM (Common mechanisms and pathways in Stroke and Alzheimer's disease.)

Reporting period: 2020-06-01 to 2021-05-31

Stroke and Alzheimer’s (AD) are on the rise and often occur in the same patient. 1 in 4 patients develops dementia within 10 years of suffering from a stroke. Similarly, many elderly patients with AD suffer from stroke. Risk factors of stroke are seen often in patients with AD. Stroke risk factors such as diabetes, high blood pressure and cholesterol, and obesity co-occur in AD. Both diseases have long been considered partners in crime, with overlapping mechanisms causing them. It’s important to find out the connection and origins of these two disorders.

The CoSTREAM project aimed to address major gaps in our understanding of the relationship between both diseases. Current model systems focus on each disease separately while the interplay between the two has remained an area unexplored in the prevention and treatment of patients.

The project used a multidisciplinary approach that incorporated new analytical strategies and emerging technologies in the fields of genetics, metabolomics, brain imaging and clinical prediction.

CoSTREAM managed to:
• identify joint genetic & environmental determinant that explain the co-occurrence of the two diseases
• discover metabolic pathways may be key players in the occurrence of AD in stroke patients
• whether & how genetic, environmental and metabolic pathways relate to alterations in the brain, as seen through medical imaging using MRI & PET
• discover compensatory mechanisms protecting against both stroke & AD
• improve accuracy of imaging markers for stroke & AD
• determine the directions with the highest chances of success for therapeutic interventions based on the genetic, metabolic, as well as imaging markers
• develop a model system of the neurovascular unit for high-throughput research on both underlying pathways and possibly therapeutics
CoSTREAM performed and validated genetics, metabolomics, imaging and epidemiologic analyses.

The project pinpointed specific genomic regions that mediate risk to stroke or AD, elucidated the common genetic pathogenesis of the disorders and created a polygenic risk score based on genes implicated in stroke that predict AD. Our conclusion is that there is ample evidence of common genetic determinants but that the impact of genes on the co-occurrence is rather small.

NMR-based metabolomics have delivered promising metabolic markers and pathways for stroke as well as AD, and common pathways for both. In contrast to the findings on genetics, we find very strong and significant evidence that the metabolome is a key player in the co-occurrence of stroke, dementia and AD. A novel platform to assess circulating metabolites in epidemiological and clinical populations at high throughput in a cost & time efficient way has been established.

CoSTREAM has successfully analysed MRI data from multiple sites using automated tractography and found consistent relationships between tract measures, age, and memory ability across sites. A major finding is that vascular pathology emerges as independent risk factor from amyloid and tau. We further improved the measurement using new high field scanners. Metabolic changes have also been shown to be associated with neurodegeneration and vascular brain pathology.

Multiple risk factors, including demographic factors, vascular risk factors and cardiovascular diseases have been related to incident AD and stroke. A large range of vascular, social and medical risk factors have been evaluated. New findings suggest that stroke and AD risk may be reduced by targeting shared risk and protective factors. Shared protective factors can compensate for the risk factors. Linking to the imaging field, we discovered that cognitive reserve may reduce the effect of brain vascular pathologies. Moreover, we found that in a community‐dwelling population, impaired global brain perfusion increased the risk of TIA, but not of ischemic stroke. We find that amyloid positivity at PET in the general population is strongly associated to genetic and metabolic profiles.

Combining all findings, we have developed an app to predict the risk of dementia in those with and without stroke or vascular pathology.

We found that genetic predisposition to diabetes and higher HbA1c levels are associated with higher risk of strokes. We also found associations of genetically predicted insulin resistance and β-cell dysfunction with large artery and small vessel stroke that might have implications for antidiabetic treatments targeting these mechanisms. Also, we find that components of the intrinsic and common pathways of the clotting cascade, as well as other haematological traits, in the pathogenesis of cardioembolic stroke and possibly large artery stroke, but not small vessel stroke. We identified plateletcrit and factor XI as potentially tractable new targets for secondary prevention of ischaemic stroke, while factor VIII and γ' fibrinogen require further population-based studies to ascertain their aetiological roles. As to metabolic profiles, we uncovered distinct metabolic signatures associated with imaging markers of small vessel disease, cognition, and conversion to dementia that may improve the prediction of dementia in those with small vessel disease and the development new treatments.

We published >135 scientific publications and gave >75 oral and poster presentations.
CoSTREAM improved our understanding of the common mechanisms of stroke and AD. The project used a multidisciplinary approach, combining genetics, metabolomics, epidemiology, biomedical imaging and biotechnology to investigate knowledge gaps in the co-morbidity of both diseases and identify specific pathways triggering AD in stroke patients.

This was the 1st time a consortium combines clinical, epidemiological, genetic and metabolic research with state-of-the art pre-clinical genetic, metabolomics and imaging data to understand the co-occurrence of stroke & AD. Working in a multidisciplinary framework for discovery, replication and validation, the project was able to achieve breakthroughs in the most cost- & time efficient way.

New biomarkers related to specific pathways underlying the co-occurrence of both diseases have been identified. These may open the opportunity for treatment monitoring, improving the chances of success and enabling effective precision medicine and prevention through specific pathways. CoSTREAM also provided a start to a prediction toolbox combining genomic, metabolomic, imaging and epidemiological data on both risk increasing and protective factors to accurately identify persons at risk of stroke, AD, or both. The ambition of the CoSTREAM consortium remains that stroke patients will undergo comprehensive AD risk modelling based on a blood sample and a brain scan and that through CoSTREAM’s results the opportunity to prevent progression of vascular and AD pathology will be seized.

The major barrier in the development of new evidence-based treatment is the lack of animal or cellular models. To overcome this obstacle CoSTREAM developed a novel model for the neurovascular unit that can be used for mechanistic and therapeutic research.

CoSTREAM’s results enable early identification of persons at risk, strategies for optimal prevention, and important insights into effective therapies. This will lead to significant health benefits at an individual and societal level, informed directions for therapy development, and coordinated therapeutic management aimed at reducing co-morbidity.
CoSTREAM schematic overview