Sven J van der Lee

Sven J van der Lee
Amsterdam University Medical Center | VUmc · Alzheimer Centre VUmc

MD, PhD.

About

240
Publications
60,128
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13,070
Citations
Citations since 2016
210 Research Items
12862 Citations
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201620172018201920202021202205001,0001,5002,0002,500

Publications

Publications (240)
Article
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Background Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer’s disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau le...
Article
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Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing d...
Preprint
Dementia is multifactorial with Alzheimer (AD) and vascular (VaD) pathologies making the largest contributions. Genome-wide association studies (GWAS) have identified over 70 genetic risk loci for AD but the genomic determinants of other dementias, including VaD remain understudied. We hypothesize that common forms of dementia will share genetic ri...
Preprint
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INTRODUCTION: Both Alzheimer's disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be discovered is debated. Variability in the estimation of SNP-based heritability could explain the differences in reported heritability. METHODS: We comput...
Article
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Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, i...
Article
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Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1,...
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Background: Many families with clinical early-onset Alzheimer's disease (EOAD) remain genetically unexplained. A combination of genetic factors is not standardly investigated. In addition to monogenic causes, we evaluated the possible polygenic architecture in a large series of families, to assess if genetic testing of familial EOAD could be expan...
Article
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The original article [1] contained an error in co-author, Lars Bertram’s affiliation which has since been corrected.
Article
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 ris...
Article
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We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12–16% of EA variance and contributes to risk predi...
Article
Full-text available
Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 ris...
Preprint
Full-text available
Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, i...
Article
Full-text available
Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer’s disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in cognitively hea...
Article
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Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling...
Article
The reported sex distribution differs between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that have resulted in variable findings. Our aim was to determine the sex distribution in a large international retrospective cohort o...
Article
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Background: Damaging rare variants in the TREM2, SORL1 and ABCA7 genes have been associated with an increased risk of developing Alzheimer's Disease (AD) with odds ratios that were not observed since the identification of the main AD genetic risk factor, the APOE-ε4 allele. Here, we aimed to identify additional AD-associated genes by investigating...
Article
Background: Neuronal dysfunction is central to the clinical manifestation of Alzheimer's disease (AD). However, genome-wide studies also suggest important roles for non-neuronal brain cell-types such as microglia and astrocytes. Our objective was to study whether brain cell type-specific polygenic risk scores (PGRS) for AD, including single nucleo...
Article
Background: Dementia in families can be caused by one genetic variant. Identifying these so-called monogenic causes of dementia is important, because it explains the origin of dementia in families and raises the possibility of predictive testing for relatives. Still, we do not know how frequent these monogenic causes are, due to strict selection c...
Article
Background: Several collaborative genome-wide-association studies (GWAS) have characterized the genetic landscape of Alzheimer's disease (AD), which now counts >70 single-nucleotide polymorphisms (SNPs) associated with AD-risk. Method: We linked these SNPs to their affected biological pathways, and combined the effect of multiple SNPs into pathw...
Article
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Background: Reported sex distributions differ between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that has resulted in varying demographics. Objective: Our aim was to determine the sex distribution of sporadic and genetic...
Article
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Introduction: We investigated relationships among genetic determinants of Alzheimer's disease (AD), amyloid/tau/neurodegenaration (ATN) biomarkers, and risk of dementia. Methods: We studied cognitively normal individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort and SCIENCe project. We examined associations betwe...
Article
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Abstract Genetic factors play a major role in frontotemporal dementia (FTD). The majority of FTD cannot be genetically explained yet and it is likely that there are still FTD risk loci to be discovered. Common variants have been identified with genome-wide association studies (GWAS), but these studies have not systematically searched for rare varia...
Article
Brain-derived neurotrophic factor (BNDF) plays a role in synapse integrity. We investigated in 398 cognitively normal adults (60±8y, 41%F, MMSE=28±1) the joint association of the Val66Met polymorphism of the BDNF gene (Met+/-) and plasma BDNF levels and abnormal CSF amyloid-beta (A+/-) with cognitive decline and dementia risk. Age-, sex- and educat...
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Background: Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity. Objective: We tested if genetic variants in part explain the heterogeneity in DLB. Methods: We tested the effects of variants previously associated with DLB (near APOE, GBA, and...
Article
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Dysfunction of the endolysosomal-autophagy network is emerging as an important pathogenic process in Alzheimer’s disease. Mutations in the sorting receptor-encoding gene SORL1 cause autosomal-dominant Alzheimer’s disease, and SORL1 variants increase risk for late-onset AD. To understand the contribution of SORL1 mutations to AD pathogenesis, we ana...
Article
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Genetic association studies are frequently used to study the genetic basis of numerous human phenotypes. However, the rapid interrogation of how well a certain genomic region associates across traits as well as the interpretation of genetic associations is often complex and requires the integration of multiple sources of annotation, which involves...
Article
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Introduction: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures. Methods: We included 12,369 non-demented participants from eight population-based studies....
Article
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A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22613-2
Preprint
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Risk for late-onset Alzheimer's disease (LOAD) is driven by multiple loci primarily identified by genome-wide association studies, many of which are common variants with minor allele frequencies (MAF)>0.01. To identify additional common and rare LOAD risk variants, we performed a GWAS on 25,170 LOAD subjects and 41,052 cognitively normal controls i...
Preprint
Full-text available
The genetics underlying human longevity is influenced by the genetic risk to develop -or escape- age-related diseases. As Alzheimer's disease (AD) represents one of the most common conditions at old age, an interplay between genetic factors for AD and longevity is expected. We explored this interplay by studying the prevalence of 38 AD-associated s...
Article
Full-text available
Introduction: Studies examining the effect of polygenic risk scores (PRS) for Alzheimer's disease (AD) and apolipoprotein E (APOE) genotype on incident dementia in very old individuals are lacking. Methods: A population-based sample of 2052 individuals ages 70 to 111, from Sweden, was followed in relation to dementia. AD-PRSs including 39, 57, 1...
Article
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Background: Right temporal variant frontotemporal dementia (rtvFTD) has been generally considered as a right sided variant of semantic variant primary progressive aphasia (svPPA), which is a genetically sporadic disorder. Recently, we have shown that rtvFTD has a unique clinical syndrome compared to svPPA and behavioral variant frontotemporal deme...
Article
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Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical Aβ deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque's association with clinical disease and perform in-depth immunohistochemical and m...
Article
Recent meta‐analyses of genome‐wide association studies (GWAS) have identified ∼30 susceptibility LOAD loci in addition to APOE, however the majority are common variants (minor allele frequency (MAF)>0.02). We used the dense, high‐resolution Haplotype Reference Consortium (HRC) r1.1 reference panel (64,976 haplotypes/39,235,157 SNPs), which allows...
Article
Previous studies showed that in preclinical AD, the Brain‐derived neurotrophic factor (BNDF) Val66Met polymorphism Met was related to faster decline in episodic memory. We aimed to assess the joint associations of BDNF Val66Met polymorphism and amyloid positivity with decline over time in the main cognitive domains, and with risk of incident dement...
Article
Interest in Apolipoprotein E (ApoE) genetic testing for Alzheimer’s disease dementia (AD) is increasing. Even though ApoE‐status is more often being disclosed to cognitively normal adults in clinical trials and services like 23andMe are growing, disclosure in the context of individualized risk profiling is not yet common practice. Our objective was...
Article
The combined effect of common genetic variants (SNPs) into polygenic risk scores (AD‐PRS) have been shown to have a strong influence on incident AD between ages 60 and 95 years, especially in carriers of the APOE ϵ4 genotype. However, few studies have investigated the effect of AD‐PRS on incident dementia in the general population and among the old...
Article
Assuming measurable biological properties to be more strongly related to the underlying Alzheimer’s disease (AD) pathogenesis than the diagnostic classification, we studied the genetics of AD‐relevant protein levels in cerebrospinal fluid (CSF). Initiated by the European Alzheimer’s disease DNA biobank (EADB), we established the largest collaborati...
Article
Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD‐pathways: immune response, β‐amyloid metabolism, endocytosis, cholesterol/lipid metabolism and angiogenesis. The extent to which these pathways are involved in the resilience against AD have thus far been poorly addressed. Here, we inve...
Article
The majority of individuals with subjective cognitive decline (SCD) is worried well, but in some the subjective experience of cognitive decline herald’s incipient neurodegenerative disease. Understanding the determinants of disease in SCD is important to separate wheat from chaff. Here we studied APOE and a polygenic risk score for Alzheimer’s dise...
Article
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Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic-risk-scores (PRS) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cogni...
Preprint
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Genetic association studies are largely used to study the genetic basis of numerous traits. However, the interpretation of genetic associations is often complex and requires the integration of multiple sources of annotation. We developed snpXplorer , a web-server application for exploring SNP-association statistics across human traits and functiona...
Preprint
Full-text available
Deciphering the genetic landscape of Alzheimer’s disease (AD) is essential to define the pathophysiological pathways involved and to successfully translate genomics to potential tailored medical care. To generate the most complete knowledge of the AD genetics, we developed through the European Alzheimer’s Disease BioBank (EADB) consortium a discove...
Article
Background: Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other g...
Article
Full-text available
Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each...
Article
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Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individua...
Article
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Objective: To identify common genetic variants associated with the presence of brain microbleeds (BMB). Methods: We performed genome-wide association studies in 11 population-based cohort studies and 3 case-control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMB were...
Article
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The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to sel...
Preprint
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The genetic component of Alzheimers disease (AD) has been mainly assessed using Genome Wide Association Studies (GWAS), which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals —16,036 AD cases and 16,522 controls— in a two-stage an...
Article
Full-text available
A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R wit...
Article
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The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
Preprint
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Mammalian prions are lethal pathogens composed of fibrillar assemblies of misfolded prion protein. Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the gene that encodes prion protein ( PRNP ) are strong risk factors for sCJD, but althou...
Article
Objectives The objectives of this study were to investigate the effect of genetic and social factors on depressive symptoms and depression over time and to test whether social factors moderate the relationship between depressive symptoms and its underlying genetics in later life. Methods The study included 2279 participants with a mean follow-up o...
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Importance Some individuals who reach ages beyond 100 years in good cognitive health may be resilient against risk factors associated with cognitive decline. Exploring the processes underlying resilience may contribute to the development of therapeutic strategies that help to maintain cognitive health while aging. Objective To identify individuals...
Preprint
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BACKGROUND: Disentangling the genetic constellation underlying Alzheimer's disease (AD) is important. Doing so allows us to identify biological pathways underlying AD, point towards novel drug targets and use the variants for individualised risk predictions in disease modifying or prevention trials. In the present work we report on the largest geno...
Article
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Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK...