New insights into the genetic etiology of Alzheimer’s disease and related dementias

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<br/>genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found...

Mapping the genetic landscape of early-onset Alzheimer’s disease in a cohort of 36 families

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...

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

Alzheimer’s disease (AD), the leading cause of dementia, has an estimated<br/>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...

SnpXplorer: A web application to explore human SNP-associations and annotate SNP-sets

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...

Polygenic Risk Score of Longevity Predicts Longer Survival across an Age Continuum

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 (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with...

Genetics Contributes to Concomitant Pathology and Clinical Presentation in Dementia with Lewy Bodies

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...

The Effect of Alzheimer’s Disease-Associated Genetic Variants on Longevity

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...

SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network

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,...

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy...

Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease

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...

EIF2AK3 variants in Dutch patients with Alzheimer's disease

Next-generation sequencing has contributed to our understanding of the genetics of Alzheimer's disease (AD) and has explained a substantial part of the missing heritability of familial AD. We sequenced 19 exomes from 8 Dutch families with a high AD burden and identified EIF2AK3, encoding for protein kinase RNA-like endoplasmic reticulum...

A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer’s disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven...

A genome-wide association study identifies genetic loci associated with specific lobar brain volumes

Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial...

Centenarian controls increase variant effect sizes by an average twofold in an extreme case–extreme control analysis of Alzheimer’s disease

The detection of genetic loci associated with Alzheimer’s disease (AD) requires large numbers of cases and controls because variant effect sizes are mostly small. We hypothesized that variant effect sizes should increase when individuals who represent the extreme ends of a disease spectrum are considered, as their genomes are assumed to be...

Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: A clinical interpretation strategy

Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1...

Heritability of the shape of subcortical brain structures in the general population

The volumes of subcortical brain structures are highly heritable, but genetic underpinnings of their shape remain relatively obscure. Here we determine the relative contribution of genetic factors to individual variation in the shape of seven bilateral subcortical structures: the nucleus accumbens, amygdala, caudate, hippocampus, pallidum,...