Research Kristel Sleegers

Abstract

The gene ABCA7 contributes significantly to the risk of developing Alzheimer's. 1 in 10 Alzheimer's patients carries a genetic risk factor in this gene. If an intervention could counteract the risk-increasing effect of ABCA7, it would benefit a substantial number of people. To develop such an intervention, we first need a better understanding of the cell types in which ABCA7 functions, and how this is altered by a genetic risk factor in ABCA7. We will investigate this research question with a cell type specific analysis of human brain tissue. We will investigate cell type-specific differences between different genetic forms of ABCA7, and determine what effects loss of ABCA7 has on cellular processes. We will investigate whether the observed differences can explain some of the differences in disease severity between patients.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

• VIB CMN - Genetics of Alzheimer’s Disease

Project type(s)

• Research Project

Abstract

Genome wide association studies pinpointed a strong genetic component of sporadic Alzheimer's disease (AD). Premature termination codon (PTC) variants and rare missense mutations in ATP-binding cassette transporter subfamily A member 7 (ABCA7) have recently been shown to confer AD risk, suggesting a central role of lipid homeostasis in AD. However, the mechanism of their pathogenicity remains unclear. Here, I propose a project combining the advances in genetic research with state–of–the-art molecular biology and nanobody (Nb) technology aimed at understanding the role of ABCA7 in AD risk. Accordingly, I will decipher the effects of selected AD-linked and protective variants on ABCA7 biology and investigate the endogenous interactome of wild type and mutant ABCA7 to uncover pathways in which ABCA7 operates to modulate AD risk. To address these points, I will generate immunoprobes – Nbs, synthetic Nbs (Sybodies) and antibodies. I will assess in vitro ABCA7 ATPase, floppase and lipid transport activities of the variants and explore their (sub)cellular expression in post mortem brain samples. I will employ innovative Nb-based proximity biotinylation with Nb-TurboID and proteomic analysis for the discovery of ABCA7 interactome in human brain. In silico and transcriptomics approaches will be used to put interactomics data into biological context and to identify pathways affected by ABCA7 variants in AD. The outcomes will provide key insights into ABCA7-related pathophysiology.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

• VIB CMN - Genetics of Alzheimer’s Disease

Project type(s)

• Research Project

Abstract

In the most recent meta-analysis of Alzheimer's disease (AD) genome-wide association studies by Sleegers Lab and collaborators, 39 known and 44 novel variants were reported to have significant genome-wide signals. Pathway- and single cell enrichment analysis points to microglia as the major responsible for this genetic risk. However, none of these risk factors - not even APOE e4 - can explain alone the development of AD. We hypothesized that unknown combinations of these variants may significantly modify the impact of APOE e4 and have the potential to better stratify AD patients and controls. To test this hypothesis, as a proof of concept, we first used multifactor dimensionality reduction and logistic regression over the AD-Belgian-Flemish Cohort to search for the putative combinations (combos) of 85 genetic risk factors. The preliminary analysis identified numerous high-risk statistically significant combos, composed by APOE e4 and low-risk genetic factors. In this project, we aim to validate these fundings in a larger cohort, and provide functional evidence to link these genetic combos to microglial functional alterations. To this end, we are currently running the same pipeline in the largest European cohort of AD patients, the European AD Biobank consortium, where we will at the same time correlate several clinical parameters with the presence of the combos described. To validate the in silico analysis from a functional perspective, we will use cutting-edge CRISPR technology to A) recapitulate top 3 combos' effect in human microglia by multiplex gene editing and B) xenotransplant the edited microglia into the brain of AD-like mice following the MIGRATE protocol recently published by the Mancuso Lab. We believe that the unique combination of GWAS-based significant combos with microglia xenotransplantation technology offers us a way to peer deeper than ever before into the complex genetic etiology of Alzheimer's disease, charting new genetic interactions with APOE and investigating in vivo phenotypical changes in the AD-like brain.

Researcher(s)

• Promoter: Mancuso Renzo
• Co-promoter: Sleegers Kristel

Research team(s)

• VIB CMN - Microglia and Inflammation in Neurological Disorders (MIND) lab

Project type(s)

• Research Project

Abstract

Neurofibrillary tangles (NFT) are lesions found in Alzheimer's disease and composed of intraneuronal aggregates of abnormally phosphorylated tau proteins (PHF-tau). The mechanism of NFT formation is still poorly understood. Interestingly, during disease development, NFT formation follows neuroanatomical pathways suggesting that synaptically connected neurons could transmit tau pathology by the recruitment of normal tau by abnormal tau proteins. Several studies have shown that aggregated tau can recruit and seed murine or human mutant tau protein following intracerebral injections of brain homogenates or of PHFtau proteins from AD brain tissues. Even if the propagation of tau pathology could explain the sequential expansion of NFT in Alzheimer's disease, the mechanism by which the abnormal tau protein can recruit normal tau remains unknown. Tau phosphorylation seems to be a key event for tau aggregation as phosphorylated tau proteins do not assemble anymore into filaments after dephosphorylation. The etiopathogenesis of AD is relatively unknown as only 5 % of AD cases are caused by familial mutations. However, several risk factors have been identified in AD. Among them, epidemiological studies showed a clear link between AD and type 2 diabetes mellitus (T2D). Indeed, T2D increases the risk of AD by at least twice. Moreover, a study has shown that T2D in elderly population with mild cognitive impairment influences the progression to dementia. Under conditions of insulin resistance, GSK3beta is converted to its active form by the decrease of the inhibitory serine 9 phosphorylation therefore conducting to the phosphorylation of IRS1 (Insulin receptor 1) and finally to the degradation of this receptor leading to insulin pathway disturbances. As the activity of GSK3beta is increased in AD and probably responsible for tau phosphorylation in this disease, this kinase could be the possible link between these two pathologies. In this study, we will analyse the effect of diabetic conditions or antidiabetic treatment (exenatide) on GSK3beta activity, on tau seeding and on the propagation of tau pathology in high fat diet animal models in which tau pathology is induced by PHF-tau proteins from AD brain.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

• VIB CMN - Genetics of Alzheimer’s Disease

Project type(s)

• Research Project

Abstract

In the recent meta-analysis of Alzheimer's disease (AD) genome-wide association studies by Sleegers Lab, 39 known and 44 novel variants were reported to have significant genome-wide signals. Pathway- and single cell enrichment analysis points to microglia as the major responsible for this genetic risk. However, none of these risk factors can explain alone the development of AD. I hypothesized that unknown combinations of these variants may have the potential to better stratify AD patients and controls. To test my hypothesis, I used multifactor dimensionality reduction and logistic regression over the AD-Belgian-Flemish Cohort to search for the putative combinations of 85 genetic risk factors. The preliminary analysis identified numerous high-risk statistically significant combinations, mainly composed by APOE ?4 and low-risk genetic factors. To validate my results, I am running the same pipeline in the largest European cohort of AD patients, the European AD Biobank consortium, where I will parallelly correlate several clinical parameters with the presence of the combos described. To functionally validate the in silico analysis, I will employ cutting-edge technology to A) recapitulate top 3 combos' effect in human microglia (MG) by multiplex gene editing and B) xenotransplant the edited MG into the brain of AD-like mice following the MIGRATE protocol recently published by the Mancuso Lab.

Researcher(s)

• Promoter: Mancuso Renzo
• Co-promoter: Sleegers Kristel
• Fellow: Leguía Fauró Gonzalo

Research team(s)

• VIB CMN - Microglia and Inflammation in Neurological Disorders (MIND) lab

Project type(s)

• Research Project

Abstract

Over the last decade, organoids emerged as an attractive middle ground between 2D cell cultures, which do not fully recapitulate the 3D environment and animal models, which pose technical and ethical limits. In particular, cerebral organoids are emerging as the next step in patient-derived in vitro models for both neurodevelopmental as well as neurodegenerative diseases. However, cerebral organoids have mostly been based on neuronal cells alone, while evidence increases that the role of non-neuronal types (microglia, astrocytes, endothelial cells) is critical in these conditions. Integration of these cell types will more closely mimic the in vivo cellular environment in health and disease and constitutes the major challenge of this project. The established neuroimmune organoid technology will find a wide range of applications as models for studying fundamental mechanisms underlying cellular biology and genetic pathophysiology as well as for efficient drug screening.

Researcher(s)

• Promoter: Sleegers Kristel
• Co-promoter: Jordanova Albena
• Co-promoter: Malysheva Valeriya
• Co-promoter: Mancuso Renzo
• Co-promoter: Weckhuysen Sarah

Research team(s)

• VIB CMN - Genetics of Alzheimer’s Disease

Project type(s)

• Research Project

Abstract

The primary mission of the Neuromics Support Facility (NSF) is to provide technological support and services in its core fields of expertise: long- and short-read sequencing, optionally followed by streamlined data analysis. Subsidised as a UA Core Facility since 2007 with the initial assignment of providing high quality Sanger sequencing services, NSF has since evolved into a much needed center of competence, offering affordable support with cutting-edge genomic technology. Since its inception, NSF has provided support to over 40 different UA groups and collaborated with over 230 research groups and companies. Embedded in the Center for Molecular Neurology (CMN) and affiliated with the Faculty of Pharmaceutical, Biomedical and Veterinary Sciences (UA) and VIB, NSF is optimally positioned to offer support in life science research, and understands and caters to the needs of diverse research groups. NSF was established in 2017 by merging the Genetics Support Facility (GSF) with central support in data analysis and imaging, to centralise the existing expertise. In 2017, NSF also expanded its services and is now supporting a variety of sought-after, wet- and dry- lab applications, including sequencing, quality control, sample prep, library prep and data analysis, using standardised in-house analytical pipelines. As a UA Core Facility, NSF will continue to provide extensive expertise to the researchers across UA, VIB and third party collaborators and will continue collaborating, consulting and troubleshooting in all their proficiencies for a very affordable fee for UA affiliates.

Researcher(s)

• Promoter: Rademakers Rosa
• Co-promoter: Sleegers Kristel
• Co-promoter: Strazisar Mojca

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project website

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is an incurable neurodegenerative dementia with a very long prodromal phase. There is an increasing scientific, clinical and industrial awareness of the need to intervene in the disease process before too much damage is done, and an increasing interest among the general public to be informed of Alzheimer risk or diagnosis while there is still time to make decisions and arrangements for the future, get access to treatment, services and care, or participate in clinical trials. In parallel, there is a growing demand on the healthcare system due to the aging of the population. Currently existing biomarkers are too costly and invasive to be available for everyone. Polygenic risk scores (PRS) that reflect an individual's genetic susceptibility to AD are gaining in interest for individualized risk prediction. Because PRS are based on indirect associations, however, they are ignorant to the genes and genetic variants that directly contribute to increased disease risk, resulting in limited accuracy and clinical validity. We will perform a systematic, high throughput multi-omics analysis of all known and novel AD risk loci to identify culprit variants for AD to boost performance of PRS. We will start from our 2022 GWAS in which we more than doubled the number of AD risk loci known sofar, and perform a comprehensive multi-omics analysis to prioritize genes in risk loci. Next, we will use state-of-the-art long read DNA and RNA sequencing to identify variants that drive the GWAS association at each locus, and that direct impact AD risk. These directly associated variants will in turn be used to construct a novel, molecularly informed PRS which we will call directPRS, and we will compare performance of directPRS to classical PRS based on indirect signals. We anticipate that directPRS will greatly increase predictive accuracy, thus addressing the urgent societal need of improved prediction of AD risk.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

• VIB CMN - Genetics of Alzheimer’s Disease

Project type(s)

• Research Project

Abstract

The identification of genetic risk variants in the GWAS-identified Alzheimer risk gene ABCA7 has been remarkably fruitful, with identification of >50 premature termination codon (PTC) variants, as well as a pathogenic variable number of tandem repeats (VNTR) expansion. While both types of risk variants are predicted to lead to a loss of function, interpretation of the effect of these alleles is challenging, due to a complex splicing pattern and poor correlation between transcript and protein levels, and lack of knowledge of the cell types and tissues in which ABCA7 variants exert their effect. We will combine long-read sequencing and spatial RNA and protein profiling on brain regions and patient-derived cell types to enhance insights of the cellular patterns of ABCA7 expression and splicing in relation to AD. A better understanding of the mode of action of ABCA7 risk alleles will in the long run benefit a significant portion of those at risk of AD, whether through improved risk prediction or targeted intervention. At the shorter term, identification of the cell type(s) in which ABCA7 exerts its risk increasing effects and better insight in the link between transcript and protein expression will inform downstream in vitro modeling and deliver targets for therapy development. Identification of a biomarker for penetrance of ABCA7 risk alleles will benefit risk prediction in research as well as in a clinical setting.

Researcher(s)

• Promoter: Sleegers Kristel
• Fellow: De Deyn Lara

Research team(s)

• VIB CMN - Genetics of Alzheimer’s Disease

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder, which is characterized by specific pathological hallmark lesions. These lesions develop first in a limited area of the brain and then expand into further brain regions until nearly the entire brain is involved in these pathologies. The first lesions are usually seen in cognitively normal individuals and are considered to represent a preclinical stage of AD. Such stepwise expansion patterns of AD lesions allow to determine the stage of the disease of a patient. Because treatment of symptomatic patients has not yet been successful, one strategy currently used is testing preventive treatments that may stop disease progression. In familial AD, single gene mutations cause the disease and can identify individuals at risk. In sporadic AD, such a direct genetic link is not given. However, a "polygenic hazard score" has been established to describe the genetic risk for AD. In this project, we want to make use of risk genes for sporadic AD to determine their effects on the expansion of the pathological hallmark lesions of AD, including different types of neuronal cell death, and to use these data to predict the individual age-of-onset of distinct AD lesions. Prediction of the age-of-onset of preclinical AD lesions will help to detect individuals that are potential candidates for AD prevention trials.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

• VIB CMN - Genetics of Alzheimer’s Disease

Project type(s)

• Research Project

Abstract

Evidence is accumulating that the gene ABCA7 contributes substantially to a person's risk to develop Alzheimer's disease. Approximately 1 in 10 Alzheimer patients carries a genetic risk factor in this gene. If an intervention could counteract the risk-increasing effect of these genetic risk factors this would benefit a substantial number of people. For such risk-reducing intervention to be developed, we first need a better understanding of the cell types in which ABCA7 performs its functions, and how this is altered in people carrying a genetic risk factor in ABCA7. We will explore this research question by a cell-type specific analysis of three brain regions variably affected by the disease process, and of cerebrospinal fluid. We will investigate cell-type specific differences between different forms of ABCA7, and test the hypothesis that ABCA7 genetic risk factors lead to a loss of ABCA7 protein in these cell types. Finally, we will investigate if the observed differences can explain some of the differences in disease severity between patients. This project will demonstrate for the first time in which cell types ABCA7 exerts its risk increasing effect, informing future research towards development of risk-reducing strategies.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

• VIB CMN - Genetics of Alzheimer’s Disease

Project type(s)

• Research Project

Abstract

Due to increased life expectancy, the number of people suffering from dementia is growing. Alzheimer's disease (AD), the most common form of dementia, is still incurable. Clinical trials with Amyloid ß (Aß) plaques as clearing targets have failed to show major improvements, resulting in pharmaceutical companies, such as Pfizer, to reduce investments into AD treatments. This emphasizes that studies on other mechanisms related to underlying pathophysiology of the disease are urgently needed. Moreover, although Aß is an early biomarker for AD, it does not have any prognostic value to predict age at onset (AAO) or rate of cognitive decline. The aim of this project is to identify genetic determinants of rate of cognitive decline, in a combined genomics and transcriptomics investigation of altered functional connectivity in the default mode network (DMN). Altered functional connectivity in the DMN, caused by synaptic degeneration, has previously been linked with cognitive decline in the context of AD. We will select a series of post-mortem brain tissue from AD patients and controls, and perform RNA sequencing on brain regions of the DMN. Differential expression analysis will identify transcripts that are differentially regulated between AD patients and cognitively unimpaired individuals, as well as between fast and slow decliners. In a next step, we will perform eQTL analyses to identify genetic variants that drive these differences at transcript level, and we will perform genotype-phenotype correlation analyses in larger cohorts of AD and MCI patients and control individuals. Genetic modifiers that are also associated with onset age and rate of decline will be used to construct a polygenic risk score (PRS) that can predict AAO and rate of decline. Predictive ability of this PRS will be tested in the EADB MCI cohort.Outcomes of this project will provide an insight into the processes contributing to network disruption, possibly delivering new druggable targets as well as prognostic markers for early diagnosis of AD.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

• VIB CMN - Genetics of Alzheimer’s Disease

Project type(s)

• Research Project

Abstract

Due to increased life expectancy, the number of people suffering from dementia is growing. Alzheimer's disease (AD), the most common form of dementia, is still incurable. Clinical trials with amyloid B (AB plaques as clearing targets have failed to show major improvements, resulting in pharmaceutical companies, such as Pfizer, to reduce investments into AD treatments. This emphasizes that studies on other mechanisms related to underlying pathophysiology of the disease are urgently needed. Moreover, although AB is an early biomarker for AD, it does not have any prognostic value to predict age at onset (AAO) or rate of cognitive decline. We hope to provide proof that altered functional connectivity in the default mode network (DMN), caused by synaptic degeneration, is linked with cognitive decline. This hypothesis will be challenged by studying DMN brain regions with a combined genomics and transcriptomics approach in order to find clear underlying genetic modifiers of altered gene expression. These modifiers will allow construction of a polygenic risk score (PRS) that can predict AAO and rate of decline. Outcomes of this PhD project will provide an insight into the processes contributing to network disruption, possibly delivering new druggable targets as well as prognostic markers for early diagnosis of AD.

Researcher(s)

• Promoter: Sleegers Kristel
• Fellow: Duchateau Lena

Research team(s)

Project type(s)

• Research Project

Abstract

Evidence accumulates that predicted loss-of-function mutations in the Alzheimer risk gene ABCA7 are 4 — 5 times more frequent among Alzheimer's disease (AD) patients than cognitively healthy individuals. Two striking characteristics of ABCA7 mutation carriers are -on the one hand- an increased proportion of familial disease, and -on the other hand- wide spread in onset age and incomplete penetrance. Thus, while these mutations might be clinically relevant given their relatively high frequency and significant effect on personal as well as familial disease risk, reduced penetrance currently hinders implementation of genetic screening for ABCA7 mutations in clinical practice. In a pilot experiment using third generation cDNA sequencing, we identified potential rescue mechanisms at transcript level that may explain reduced penetrance of these mutations. Here, we propose to perform long-read cDNA sequencing analyses on different tissues of a large series of mutation carriers, and correlate mutation-rescue events with parameters of disease severity. We have an unprecedented repository containing 104 ABCA7 PTC mutation carriers, putting us in a unique position to conduct this project. The outcomes of this project will be important for informed decision making on diagnostic screening of ABCA7 in AD. The insights gained through nature's own rescue experiments at transcript level will provide a window onto pharmaceutical intervention strategies for this genetic subtype of AD.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

• VIB CMN - Genetics of Alzheimer’s Disease

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is an incapacitating, incurable disease characterized by a progressive loss of cognitive functions. It has a long disease course and ultimately requires fulltime medical care. Aside from drugs that temporarily relieve symptoms, no treatment exists for AD. More than 35 million people are living with dementia worldwide. With the growing proportion of people > 65 years, and the high costs associated with care for AD patients, the future impact of AD on society and public health is of great concern. Owing to technological progress and global collaborative research in the field of AD genetics, our understanding of the genetic foundations of AD is rapidly expanding. Genome-wide association studies (GWAS) have resulted in an explosion of new insights in the pathways underlying AD. At least twenty novel genetic risk loci have now been identified in addition to APOE ε4. GWAS have proven to be an excellent tool to locate new AD risk loci, but they are typically not sufficient to detect the actual risk variant(s) in the locus, let alone their downstream effects. Identification of the true risk alleles, however, is key in understanding the molecular mechanisms through which risk genes are involved in AD. Due to their location in a functional domain, or their mutation mechanism, these variants may shed light on the mechanism through which a gene is involved in AD, providing anchor points for downstream research. Epidemiological estimates of new risk genes, as well as genetic risk profiling become more precise once the true underlying genetic risk factors are known. The aim of this project is to discover these true genetic risk factors, using a well-characterized, longitudinal study cohort supported by a biobank holding a range of biomaterials, ascertained from a population characterized by large sibships and limited migration, creating founder effects that facilitate detection of otherwise rare genetic variants. We will make use of advanced genomic technologies, testing targeted hypotheses and integrating RNA sequencing. We will explore the clinical as well as scientific potential of genetic risk profiles for AD. We will investigate the clinical impact of rare variants of intermediate-to-high penetrance to evaluate if and how the knowledge of carrier status of such a variant can be used in genetic risk prediction and genetic subtyping, as a stepping-stone towards a precision medicine-based approach to AD care.

Researcher(s)

• Promoter: Sleegers Kristel
• Fellow: Sleegers Kristel

Research team(s)

• VIB CMN - Genetics of Alzheimer’s Disease

Project type(s)

• Research Project

Abstract

Alzheimer dementia (AD) is a major health care problem. Given the multifactorial nature of AD, there is a growing incentive towards precision medicine in AD care. This requires the ability to distinguish between molecular subtypes of AD, but risk factors for AD risk are still insufficiently characterized. In a targeted re-sequening study on Belgian AD patients and control individuals, we discovered rare predicted loss-of-function mutations in the AD risk gene ABCA7 that contribute notably to familial clustering of AD. One mutation was particularly frequent in Belgium, and segregated with disease in a family with autosomal dominant pattern of inheritance. Increased familial clustering, even resembling autosomal dominant inheritance, suggests that ABCA7 loss-of-function represents a genetic subtype of AD that holds promise for precision medicine. Before this knowledge can be translated into genetic subtyping, however, critical questions need to be addressed. For example, what is the penetrance of these mutations, and what is the recurrence risk for relatives? Are all predicted loss-of-function mutations in ABCA7 equally pathogenic? How much do these variants contribute to the occurrence of AD? The key aim of this project is to get a better understanding of the role of ABCA7 mutations in familial clustering of AD, with the ultimate goal to assess if and how the knowledge of carrier status of such a variant can be used in genetic subtyping and risk prediction. In this project, we will extend our discovery study by targeted re-sequencing of ABCA7 in individuals from Belgium and Europe, to obtain a comprehensive catalogue of ABCA7 variants involved in AD pathogenesis and assess the extent of the contribution of ABCA7 loss-of-function to the occurrence of AD in the population. We will follow this up by RNA sequencing of mutation carriers to investigate the effect of predicted loss-of-function mutations at the transcript level, and correlate outcomes with clinical phenotype. This will provide a framework to distinguish between pathogenic and neutral ABCA7 variants, a prerequisite for genetic subtyping. Finally, we will perform a genotype-first approach on identified mutation carriers, to investigate mutation penetrance, familial clustering and clinically detectable phenotypes. Ultimately, the project will give insight in the relevance, possibility and desirability of genetic subtyping of ABCA7 loss-of-function mutations.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is an important threat to both personal and publich health. Familial clustering of AD has long been known, and in the past few decades, important progress has been made in unraveling the genetics of AD. For patients and their relatives today, the most tangible benefit of this progress is the ability to genetically diagnose or predict the disease. Nevertheless, this only applies to a minority of families, in which a mutation in APP, PSEN1 or PSEN2 has been identified that causes a rare autosomal dominant form of AD. For the majority of patients, the disease has a complex genetic background, which cannot be readily translated into accurate risk prediction. Remarkable in this light is our recent observation that rare predicted loss-of-function mutations in the AD risk gene ABCA7 are associated with autosomal dominant pattern of inheritance of AD. Multiplex AD families segregating such rare variants represent a distinct subgroup in which some of the benefits of genetic testing may hold true. The key aim of this PhD project is to get a better understanding of the role of these rare risk variants in familial clustering of AD, with the ultimate goal to assess if and how the knowledge of carrier status of such a variant can be used in genetic risk prediction. A variety of state-of-the-art approaches will be used to address this aim. Molecular characterization of rare variants through RNA sequencing analysis of lymphoblast cell lines and brain will contribute to a better understanding of the impact of the mutations, as well as a delineation of neutral and pathogenic variants. Genetic-epidemiological characterization through DNA sequencing on additional cohorts will shed further light on the frequency and penetrance of these mutations. The mode of action and causes of phenotypic heterogeneity will be investigated in derivatives of induced pluripotent stem cells of mutation carriers. Finally, this patient-derived model will be used to investigate the potential of compounds to modify the effect of the mutation, eventually enabling targeted treatment. This PhD project covers an uncharted but promising territory in the battle against AD, particularly considering the increasing focus in this battle on patient stratification, early detection and precision medicine.

Researcher(s)

• Promoter: Sleegers Kristel
• Fellow: Küçükali Fahri

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is the predominant form of dementia and one of the principal challenges in modern medicine. In 2015, an estimated 46.8 million people suffer from dementia with a global cost of US$ 818 billion. Due to our worldwide aging society, the number of patients is projected to double every 20 years, posing a tremendous burden on patients, society and economy. Finding a cure is paramount to avoid this calamity, but AD clinical trials to date have met with limited success. Focusing treatment on patients with overt symptomatology, which already endured decades of neurodegenerative decay, and an underestimation of the multifactorial etiology of AD, are thought to be the main reasons for this struggle. Several paradigm shifts may improve the clinical trial success rate, including: (1) Expanding our knowledge of the AD pathomechanisms to identify novel drug targets, (2) developing better biomarkers for early detection of the disease, and (3) treating patients according to the affected pathomechanism and finding means to determine the underlying etiology. The aim of this PhD project is to contribute to this transformation: (1) through analysis of common, rare and structural variants in AD susceptibility loci, identified through genome-wide association studies (GWAS). GWAS only provide information on associated SNPs that are in linkage disequilibrium with functional variants and it is therefore often unknown which genes and/or mechanisms are involved in the disease process. These loci will be elucidated with novel "third-generation" Oxford Nanopore sequencing technology, and promising variants will be validated and genotyped on our entire Belgian study population of more than 3000 individuals with the use of targeted resequencing on an Illumina sequencing platform. This innovative mix of next-generation sequencing will be fast, inexpensive, and enables unprecedented studying of (structural) variants in the entire loci. When feasible within the workplan, the downstream mechanisms of identified variants can be studied with the use of our in-house RNA-seq dataset and biobank, and through collaborations. As a result, novel insights in AD pathomechanisms and potential targets are provided, which in long-term can lead to a cure. (2) The previously identified variants will be included in genetic risk profiles, which will improve the existing risk scores that are based on indirectly associated GWAS SNPs. In addition, novel weighting approaches will be used and epistasis between variants and genes will be assessed. These profiles will be evaluated on prodromal cohorts, which allow further association with molecular and clinical (endo)phenotypes. (3) In addition to genetic risk scores, which represent the overall risk of developing AD, we will generate network-based genetic profiles based on biological pathways to distinguish individuals based on their underlying disease etiology. Through alignment with electronic health records and post-hoc analysis of clinical trials, their utility will be assessed in prediction of susceptibility to treatment. This PhD project has the following deliverables: (1) novel insights into the genes and pathways causing AD and (2) genetic profiles to serve as biomarkers for (subforms of) AD, along with a genotyping assay for immediate application in pre-selection of clinical trial participants. In the long term, this project can contribute to the discovery of a treatment for AD and the developed profiles may be used in personalized medicine.

Researcher(s)

• Promoter: Sleegers Kristel
• Fellow: De Roeck Arne

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims to study the biological mechanisms acting on onset age modification by focusing on the identification of genes influencing the onset age using the latest molecular genetics technologies. This research will generate valuable novel insights to develop disease-delaying therapies for FTLD and related neurodegenerative disorders.

Researcher(s)

• Promoter: Cruts Marc
• Co-promoter: Sleegers Kristel
• Co-promoter: Van Broeckhoven Christine

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand SAO. UA provides SAO research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer dementia (AD) is a very common, incurable disease. Because of changing demographics, the prevalence of AD increases rapidly. Recently, nine novel genes were identified that contribute to the risk to develop AD, and due to large scale international collaborations, several more are in the pipeline. This PhD project aims to identify the genetic polymorphisms in these genes that cause the increase in AD risk. To this end, next generation sequencing will be performed on a study population that counts >2200 patients and control individuals. Once the true genetic risk factors have been identified, a translational characterization will be performed, including genotype-phenotype correlation studies on existing and novel phenotypes, to enable translation of findings into progress in the treatment of and care for AD patients.

Researcher(s)

• Promoter: Sleegers Kristel
• Fellow: Verheijen Jan

Research team(s)

Project type(s)

• Research Project

Abstract

Advances in medical research require an increasing quantity and detail of human health data to answer increasingly complex and detailed research questions. At the same time, huge volumes of human health data are being collected and electronically stored, but such data sources are typically fragmented in a variety of environments and systems and often used in isolation. Hence, the full potential of the available human health data is yet to be realized. Additionally, privacy, legal and ethical issues are not always properly covered. The IMI-funded European Medical Information Framework (EMIF) project aims to create an environment that allows for efficient re-use of existing health data. The project includes two specific disease oriented research topics, one of which is Alzheimer's disease (EMIF-AD). The overall aim of EMIF-AD is to build an information framework for studies on neurodegeneration to discover and validate predictive and prognostic AD biomarkers for the facilitation of drug development and trial design in pre-dementia AD. In this setting, we will perform massive parallel amplicon-based sequencing of causal and susceptibility genes on a cohort of 1000 carefully selected European individuals in the prodromal stages of AD (asymptomatic with biomarker signs of AD, subjective cognitive impairment or mild cognitive impairment), and use these data in advanced genetic risk profiling and genotype-phenotype correlation studies, to explore the potential of genetic risk profiling in identification of high risk individuals during an optimal therapeutic window of opportunity. In addition, our genetic data on this cohort will be aligned with other types of –omics data, clinical, neuropsychological, biochemical and neuroimaging markers of disease in an integrated data analysis.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

AgedBrainSYSBIO is a 4-year collaborative project funded by the EC under the 7th Framework Programme (FP7), which addresses the basis of brain ageing by studying the pathways through which the ageing phenotype develops in normal and in neurodegenerative conditions. Novel pathways and their evolutionary properties will be modeled and experimentally tested in order to identify druggable targets, eventually providing new diagnostic tools and drug discovery programs that will directly benefit ageing populations. In this context we perform massive parallel resequencing of known and novel risk genes for Alzheimer Disease (AD) in a patient-control design, to identify true susceptibility alleles that may pinpoint alterations of protein-protein interactions. This genetic effort may provide the AgedBrainSYSBIO partners candidates, for mouse and drosophila models, to explore the functional pathways that are involved in pathogenesis of AD. We will use a targeted resequencing approach, based on MASTR and on HaloPlex enrichment technology. Bioinformatics analysis will be performed, followed by statistical analysis of common and rare genetic variants. In addition, we contribute to AgedBrainSYSBIO by providing biomaterials for transcriptomic analysis, and for the induction of pluripotent stem cells to generate patient-derived neurons to model functional pathways and protein interactions in subregions of neurons.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

BioAdaptAD is a Transformational Medical Research consortium project coordinated by Janssen Pharmaceuticals (module 1 (R&D)) and academic partners at the University of Antwerp, the KU Leuven and the VIB (module 2, strategic basic research). The project is focusing on development and implementation of multiple adaptive clinical trials for Alzheimer dementia (AD) and strategic basic research on biomarkers that will enable adaptive trials as decision making tools. Module 2 has an exclusive focus on the pre-dementia stage of mild cognitive impairment (MCI), and will address the question which MCI patients are most likely to convert to AD, i.e. are most likely to show an increase in amyloid deposition, and which in vivo methods are optimally suited to detect or predict this conversion. Defining these methods will enable adaptive clinical trials, and will catalyze the paradigm shift from 'diagnose and treat' to 'predict and prevent' once effective treatments are available. Our contribution specifically aims to identify a set of genetic markers which can predict risk of AD in the MCI phase, to enable intervention early in the natural course of disease. The predictive value of genetic markers will be tested by massive parallel amplicon-based resequencing of selected genes using the MASTR technology in a prospective cohort of MCI patients, including biochemical analyses of CSF and extensive neuroimaging, to study genotype-phenotype correlations. Data will be analyzed with an established bioinformatics and statistical pipelines, and replicated in existing AD and MCI cohorts.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

We aim to establish an integrated network to identify genes and proteins involved in neurodegenerative disorders, determine their biological functions, establish their role in the pathophysiological processes, identify modifiers of the function by genetic screens, The network meets the prerequisites for such a project: frontline research in functional genomics related to human health, creating synergies with and between research efforts, teaming up with clinical groups through translational research for providing novel avenues for diagnosis, prevention, treatment and providing training and mobility to improve the skills of our young researchers.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Cruts Marc
• Co-promoter: Sleegers Kristel
• Co-promoter: Theuns Jessie
• Co-promoter: van der Zee Julie

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand USAMRAA. UA provides USAMRAA research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer's disease and related neurodegenerative brain diseases are strongly disabling and ultimately fatal. Due to changing demographics and in the current absence of a cure, these diseases pose a considerable threat to both personal and public health. This project proposes to come to a better understanding of these genetically complex diseases, and to translate this knowledge into useful tools for molecular diagnostics and risk prediction. To achieve this goal, the project is built on three pillars, a powerful well-documented study population, advanced molecular genetic techniques including next generation sequencing and genome-wide copy number variation detection, and state-of-the-art genetic epidemiological data analysis. Findings will be translated into markers for early diagnosis and molecular profiling, eventually enabling personalized causal treatment of these conditions.

Researcher(s)

• Promoter: Sleegers Kristel
• Fellow: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is the most common form of dementia. By pooling many study populations and thus increasing statistical power, recent international genome wide association studies have uncovered 10 novel genes associated with Alzheimer's risk (CLU, CR1, PICALM, BIN1, ABCA7, CD2AP, CD33, EPHA1, MS4A4E and MS4A6A). The principal aim of this project is to identify and extensively investigate novel genetic risk variants that might explain pieces of the missing heritability of AD. We will use next-generation sequencing technology to investigate the entire novel AD genes, including up- and downstream regulatory regions, in our prospective Flanders-Belgian study population (currently 1263AD patients and 1029 control individuals). The genetic follow-up of these AD genes consists of 5 tiers: Identification of a common genetic variant that explains the observed association between the gene and AD, in a high-density SNP-based analysis of the Flanders-Belgian AD study population. Exploration of the presence of both rare variants and structural variations in the novel AD genes. We will also investigate the possibility of genetic interactions between different genes because of the complexity of late onset AD. Further we will perform genotype-phenotype correlation studies with phenotypes ranging from biomarker profiles in CSF, plasma or serum to clinical phenotypes. Lastly we will investigate the functional effect of the associated variations.

Researcher(s)

• Promoter: Sleegers Kristel
• Co-promoter: Van Broeckhoven Christine
• Fellow: Cuyvers Elise

Research team(s)

Project type(s)

• Research Project

Abstract

Mutations in the gene progranulin (GRN) are an important cause of familial frontotemporal lobar degeneration (FTLD). A striking feature is the wide variability of onset age in mutation carriers, which can span 40 years within one family. This points towards the existence of one or multiple potent modifiers of the onset of disease. Insight into these modifying factors may provide inroads for development of therapy that can delay or even prevent the disease. In this project we will follow a family-based approach to discover genetic modifiers of onset age of GRN-related neurodegeneration. In an extended Belgian pedigree segregating FTLD we identified a GRN null mutation. This pedigree offers a powerful setting for this onset age analysis, including 226 clinically well documented individuals spanning at least 7 generations amongst whom 42 patients (onset age ranging from 45 to 76 years) and numerous at risk mutation carriers. Segregation analyses suggest one major quantitative trait locus (QTL) affecting onset age in this pedigree. We will employ a combination of methods to identify the genetic modifier, starting from a genome-wide linkage analysis for censored traits, SNP fine-mapping and next generation sequencing. Comparative brain transcriptomics and serum proteomics have been performed on a number of relatives, facilitating identification of the genetic modifying factor.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

Early-onset Alzheimer's disease (AD) is a fatal neurodegenerative dementia occurring in mid-life (onset of disease between 30 and 65 years) that is severely disruptive for patients and their relatives. An estimated 3000 to 11000 people have early-onset AD in Belgium. Early-onset AD has a strong genetic component, but the majority of the genetic etiology is still unresolved, as mutations in the known dementia genes and the genetic risk conferred by APOE ε4 do not explain more than 10-20% of the occurrence of early-onset AD. The aim of this project is to further unravel the genetic etiology of early-onset AD beyond pathogenic mutations in the known dementia genes by combining a well-documented homogeneous study population with the newest technologies in molecular genetics, to come to a fuller understanding of the pathogenesis of AD. We will employ family-based studies to identify novel pathogenic mutations and rare variants, and we will perform population based whole genome studies to identify potential recessive causes of disease, as well as common genetic risk factors, rare variants and modifying factors. Promising genetic variants will be followed up by functional characterization, genotype-phenotype correlation studies and translation into biomarkers.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Cruts Marc
• Co-promoter: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer dementia (AD) is a common, incurable disorder. Because of changing demographics, the prevalence of AD increases rapidly. This project aims to advance understanding of the genetic etiology of AD, amongst others in explorative association studies of genes in their biological networks, and ultra-high throughput sequencing to characterize allelic heterogeneity. In addition to AD we will also study the phenotype mild cognitive impairment to detect genetic factors that play a role early in the pathological cascade. In addition we propose an integrated approach of genetics and proteomics. By performing these analyses on the same individuals, we can examine if 'prognostic' genes can also affect easily measurable quantitative biomarkers such as differences in protein expression.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is a common, incurable neurodegenerative dementia with a complex pattern of inheritance. Current known genetic factors only explain a proportion of the substantial heritability of AD, and recently performed genome-wide association studies have not yet unequivocally identified novel loci that can account for the unexplained gap in the heritability. With this project we propose a genome-wide survey of structural genetic variation, in particular copy-number variation (CNVs), to identify common or rare CNVs, or both, that might underlie the susceptibility to AD and account for part of the as yet unexplained heritability of this disease. Both rare and common CNVs will be examined in a carefully selected group of 175 Belgian AD patients enriched for genetic factors (positive family history and/or early disease onset). Candidate CNVs will be further explored in a targeted analysis on a larger group of patients and controls, totaling >1700 individuals.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims to contribute to a better understanding of the genetic etiology of complex forms of Alzheimer dementia by means of genetic-epidemiological and molecular genetic techniques. This will help in identifying molecular mechanisms that can serve as targets for early detection, prevention and treatment of this common and incurable disease. High-throughput association studies (both genome-wide and focused on biological pathways) and intermediary or endophenotypes will be performed in a well-characterized study population with sufficient statistical power. Translation of findings to prodromal stages of AD will point out which factors are already of relevance early in the pathological cascade. These factors might find use as early predictors. Pathway analysis will identify subgroups with an increased epidemiological risk profile. In addition, we will assess if these prognostic markers affect easily measurable quantitative traits, e.g. in an integrated study of genome wide genotype data and differential protein expression in a proteomics study. If a correlation can be demonstrated, this trait can be used as a biomarker specific to the disease process. In addition we aim to identify genetic factors that modify onset age, to find novel targets for treatment, to delay or prevent the pathological cascade.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Fellow: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is the most common form of dementia in the elderly. In the majority of AD patients the molecular cause of neurodegeneration is so far unknown. Once AD appears it can be considered as an end point of several disease processes which impedes the research of the exact etiology. Intermediate phenotypes such as the episodic memory, which change early in the pathological process are more directly under influence of the underlying genetic factors and can therefore support the genetic research of AD. By a molecular genetic approach this project will contribute to the research of the neurodegenerative process in AD and will therefore lead to a better understanding of the etiology of dementia. Genetic association studies on selected candidate genes as well as genomic association studies will be performed in a large and well characterized Belgian AD population. The role of the identified AD risk genes in the conversion of "Mild Cognitive Impairment (MCI)" to AD will be further investigated in MCI patients. Results from the AD research will also be analyzed in a group of healthy individuals coming from a Swedish memory population. Additionally we will identify novel biomarkers in plasma or cerebrospinal fluid using amyloid beta quantifications and proteomics profiling experiments. When genetic informative multiplex families are available, genomic linkage studies will be carried out.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Sleegers Kristel
• Fellow: Bettens Karolien

Research team(s)

Project type(s)

• Research Project

Abstract

In 2006 we discovered a new cause for frontotemporal lobar degeneration. Mutations in the gene progranulin cause the disease in 1 of 10 patients, and we could also demonstrate a role of progranulin genetic variability in other neurodegenerative diseases. This cause of neurodegeneration differs markedly from other well-known causes, such as amyloid deposits in the brain. Based on signs and symptoms, however, no distinction can be made between these causes during life. The ability to clinically distinguish between the different causes of neurodegeneration is important, especially once treatment options become available that target the specific underlying causes. Therefore we developed an ELISA that can rapidly detect this cause of neurodegeneration, by measuring the amount of circulating progranulin. People carrying a progranulin null mutation causing dementia have a ~50% reduction in progranulin, and this test can detect this with 100% accuracy. It can already detect it preceding any clinical symptoms, indicating the predictive potential of this biomarker assay. In 2009 we received the Santkin Award of the National Alzheimer League, Belgium, for this work.

Researcher(s)

• Promoter: Cruts Marc
• Co-promoter: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to identify risk factors for Alzheimer dementia (AD), through studying the endophenotype Aß1-42 (in plasma). The use of Aß1-42 as outcome variable allows direct evaluation of the role of associated candidate genes in the amyloid cascade. Insight in the genetic variation of plasma Aß1-42 levels will in the long run contribute to targeted development of therapeutic and preventative strategies.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is the most common form of dementia in the elderly. In the majority of AD patients the molecular cause of neurodegeneration is so far unknown. Once AD appears it can be considered as an end point of several disease processes which impedes the research of the exact etiology. Intermediate phenotypes such as the episodic memory, which change early in the pathological process are more directly under influence of the underlying genetic factors and can therefore support the genetic research of AD. By a molecular genetic approach this project will contribute to the research of the neurodegenerative process in AD and will therefore lead to a better understanding of the etiology of dementia. Genetic association studies on selected candidate genes as well as genomic association studies will be performed in a large and well characterized Belgian AD population. The role of the identified AD risk genes in the conversion of "Mild Cognitive Impairment (MCI)" to AD will be further investigated in MCI patients. Results from the AD research will also be analyzed in a group of healthy individuals coming from a Swedish memory population. Additionally we will identify novel biomarkers in plasma or cerebrospinal fluid using amyloid beta quantifications and proteomics profiling experiments. When genetic informative multiplex families are available, genomic linkage studies will be carried out.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Sleegers Kristel
• Fellow: Bettens Karolien

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to contribute to further unravel the etiology and epidemiology of AD and neurodegeneration, using molecular genetics as a tool. We will go through following steps to achieve this: (1) Genetic characterisation and expansion of a Belgian AD patient population. We will perform a mutation analysis of the known dementia genes and an APOE genotyping. Multiplex families and patient-triads will be collected starting from this population. (2) Identification of new causal AD genes, using the positional cloning strategy in collected multiplex families. (3) Identification of new AD risk genes in the patient-triads by use of association studies. We will use family-based (in patient-triads) as well as classical patient/control association studies. (4) Determination of the Ab42/Ab40 ratio in plasma, to identify non-symptomatic at risk individuals and to use as co-variant in association studies.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Sleegers Kristel
• Fellow: Brouwers Nathalie

Research team(s)

Project type(s)

• Research Project

Abstract

Recently we identified mutations in the gene coding for the growth factor progranulin (PGRN) that cause frontotemporal dementia (FTD) in ~10% of FTD-patients. One mutation that eliminates 50% of the protein segregates in an extended Belgian founder family in which we currently have knowledge of 41 patients. The age at onset in this family is highly variable, which suggests that other genetic factors are modulating age at onset. The size of this family gives us a world-wide unique opportunity to identify these factors. This in turn may increase our knowledge of mechanisms that may delay or possibly even prevent development of this devastating disease.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is characterized by a progressive deterioration of cognition, of which loss memory for specific personal events is the most prominent. The pathological process leading to AD is already taking place years before the disease becomes evident. In this stage people may show signs of mild cognitive impairment. We aim to find genetic factors that may affect the risk to get AD, and we want to study if these genetic risk factors already differentiate between good and poor memory performance before the disease becomes evident. Knowledge about genes implicated in AD and memory will clarify which molecular processes are crucial in the development of AD, which will help setting the targets for future development of medicine. Further, we want to examine correlations between newly identified genetic risk factors, poor memory performance or AD, and changes in biomarkers, such as brain volume or activity on MRI scans, or composition of cerebrospinal fluid. If we are able to identify genetic factors that cause AD and are correlated with specific biomarker profiles, this might help in future research to determine risk profiles for prevention strategies.

Researcher(s)

• Promoter: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is characterized by a progressive deterioration of cognition, of which loss of memory for specific personal events is the most prominent. The pathological process leading to AD is already taking place years before the disease becomes evident. In this stage people may show signs of mild cognitive impairment. We aim to find genetic factors that may affect the risk to get AD, and we want to study if these genetic risk factors already differentiate between good and poor memory performance before the disease becomes evident. Knowledge about genes implicated in AD and memory will clarify which molecular processes are crucial in the development of AD, which will help setting the targets for future development of medicine. Further, we want to examine correlations between newly identified genetic risk factors, poor memory performance or AD, and changes in biomarkers, such as brain volume or activity on MRI scans, or composition of cerebrospinal fluid. If we are able to identify genetic factors that increase risk of AD and are correlated with specific biomarker profiles, this might help in future research to determine risk profiles for prevention strategies.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Fellow: Sleegers Kristel

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to contribute to further unravel the etiology and epidemiology of AD and neurodegeneration, using molecular genetics as a tool. We will go through following steps to achieve this: (1) Genetic characterisation and expansion of a Belgian AD patient population. We will perform a mutation analysis of the known dementia genes and an APOE genotyping. Multiplex families and patient-triads will be collected starting from this population. (2) Identification of new causal AD genes, using the positional cloning strategy in collected multiplex families. (3) Identification of new AD risk genes in the patient-triads by use of association studies. We will use family-based (in patient-triads) as well as classical patient/control association studies. (4) Determination of the Ab42/Ab40 ratio in plasma, to identify non-symptomatic at risk individuals and to use as co-variant in association studies.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Sleegers Kristel
• Fellow: Brouwers Nathalie

Research team(s)

Project type(s)

• Research Project