Genetic architecture of common non-Alzheimer's disease dementias.
Ontology highlight
ABSTRACT:
SUBMITTER: Guerreiro R
PROVIDER: S-EPMC8207829 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Age-related hearing loss was recently established as the largest modifiable risk factor for Alzheimer's disease (AD), however, the reasons for this link remain unclear. We investigate shared underlying genetic associations using results from recent large genome-wide association studies (GWAS) on adult hearing difficulty and AD. Genetic correlation and Mendelian randomization (MR) analysis do not support a genetic correlation between the disorders, but suggest a direct causal link from AD genetic risk to hearing difficulty, driven by APOE. Systematic MR analyses on the effect of other traits revealed shared effects of glutamine, gamma-glutamylglutamine, and citrate levels on reduced risk of both hearing difficulty and AD. In addition, pathway analysis on GWAS risk variants suggests shared function in neuronal signalling pathways as well as etiology of diabetes and cardiovascular disease. However, after multiple testing corrections, neither analysis led to statistically significant associations. Altogether, our genetic-driven analysis suggests hearing difficulty and AD are linked by a shared vulnerability in molecular pathways rather than by a shared genetic architecture.
| S-EPMC8298411 | biostudies-literature
Project description:Advances in genetic and genomic technologies over the last thirty years have greatly enhanced our knowledge concerning the genetic architecture of Alzheimer's disease (AD). Several genes including APP, PSEN1, PSEN2, and APOE have been shown to exhibit large effects on disease susceptibility, with the remaining risk loci having much smaller effects on AD risk. Notably, common genetic variants impacting AD are not randomly distributed across the genome. Instead, these variants are enriched within regulatory elements active in human myeloid cells, and to a lesser extent liver cells, implicating these cell and tissue types as critical to disease etiology. Integrative approaches are emerging as highly effective for identifying the specific target genes through which AD risk variants act and will likely yield important insights related to potential therapeutic targets in the coming years. In the future, additional consideration of sex- and ethnicity-specific contributions to risk as well as the contribution of complex gene-gene and gene-environment interactions will likely be necessary to further improve our understanding of AD genetic architecture.
| S-EPMC7409822 | biostudies-literature
Project description:Proton pump inhibitors (PPIs) are among the most prescribed medications. Previous epidemiological studies have presented contradictory results about PPIs and the risk of dementia. Our objective was to investigate the association between the use of PPIs and an increasing risk of incident AD or non-AD dementias. A community-based retrospective cohort study was conducted based on the data available from 1st January 2002 to 31st December 2015 in the Catalan health service (CatSalut) system. This cohort included all PPI users (N?=?36,360) and non-users (N?=?99,362). A lag window of 5 years was considered between the beginning of the PPI treatment and the diagnosis of dementia. PPI use was not associated with the risk of AD (adjusted odds ratio (OR) 1.06) (95% CI 0.93-1.21; p?=?0.408). A weakly but significantly increased risk of non-AD dementias was observed among PPI users (adjusted OR 1.20, 95% CI 1.05-1.37; p?=?0.007). A higher dose of PPIs was not associated with an increased risk of either AD or non-AD dementias (OR 1.20; 95% CI 0.91-1.61 and OR 0.95; 95% CI 0.74-1.22, respectively). Regarding the number of PPIs used, we observed an increased risk of AD (OR 1.47; 95% CI 1.18-1.83) and non-AD dementias (OR 1.38; 95% CI 1.12-1.70) in users of two types of PPIs compared with those who used only one type. We did not find a higher incidence of AD among PPI users, but a weak increase in the risk of non-AD dementias among PPI users was observed.
| S-EPMC7713356 | biostudies-literature
Project description: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 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
| S-EPMC9005347 | biostudies-literature
Project description:BackgroundGenome-wide association studies (GWAS) have indicated moderate genetic overlap between Alzheimer's disease (AD) and related dementias (ADRD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), neurodegenerative disorders traditionally considered etiologically distinct. However, the specific genetic variants and loci underlying this overlap remain almost entirely unknown.MethodsWe leveraged state-of-the-art GWAS for ADRD, PD, and ALS. For each pair of disorders, we examined each of the GWAS hits for one disorder and tested whether they were also significant for the other disorder, applying Bonferroni correction for the number of variants tested. This approach rigorously controls the family-wise error rate for both disorders, analogously to genome-wide significance.ResultsEleven loci with GWAS hits for one disorder were also associated with one or both of the other disorders: one with all three disorders (the MAPT/KANSL1 locus), five with ADRD and PD (near LCORL, CLU, SETD1A/KAT8, WWOX, and GRN), three with ADRD and ALS (near GPX3, HS3ST5/HDAC2/MARCKS, and TSPOAP1), and two with PD and ALS (near GAK/TMEM175 and NEK1). Two of these loci (LCORL and NEK1) were associated with an increased risk of one disorder but decreased risk of another. Colocalization analysis supported a shared causal variant between ADRD and PD at the CLU, WWOX, and LCORL loci, between ADRD and ALS at the TSPOAP1 locus, and between PD and ALS at the NEK1 and GAK/TMEM175 loci. To address the concern that ADRD is an imperfect proxy for AD and that the ADRD and PD GWAS have overlapping participants (nearly all of which are from the UK Biobank), we confirmed that all our ADRD associations had nearly identical odds ratios in an AD GWAS that excluded the UK Biobank, and all but one remained nominally significant (p < 0.05) for AD.ConclusionsIn one of the most comprehensive investigations to date of pleiotropy between neurodegenerative disorders, we identify eleven genetic risk loci shared among ADRD, PD, and ALS. These loci support lysosomal/autophagic dysfunction (GAK/TMEM175, GRN, KANSL1), neuroinflammation/immunity (TSPOAP1), oxidative stress (GPX3, KANSL1), and the DNA damage response (NEK1) as transdiagnostic processes underlying multiple neurodegenerative disorders.
| S-EPMC10273745 | biostudies-literature
Project description:BackgroundThe hippocampus is a heterogeneous structure, comprising histologically and functionally distinguishable hippocampal subfields. The volume reductions in hippocampal subfields have been demonstrated to be linked with Alzheimer's disease (AD). The aim of our study is to investigate the hippocampal subfields' genetic architecture based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set.MethodsAfter preprocessing the downloaded genetic variants and imaging data from the ADNI database, a co-sparse reduced rank regression model was applied to analyze the genetic architecture of hippocampal subfields volumes. Homology modeling, docking, molecular dynamics simulations, and Co-IP experiments for protein-protein interactions were used to verify the function of target protein on hippocampal subfields successively. After that, the association analysis between the candidated genes on the hippocampal subfields volume and clinical scales were performed.ResultsThe results of the association analysis revealed five unique genetic variants (e.g., ubiquitin-specific protease 10 [USP10]) changed in nine hippocampal subfields (e.g., the granule cell and molecular layer of the dentate gyrus [GC-ML-DG]). Among five genetic variants, USP10 had the strongest interaction effect with BACE1, which affected hippocampal subfields verified by MD and Co-IP experiments. The results of association analysis between the candidated genes on the hippocampal subfields volume and clinical scales showed that candidated genes influenced the volume and function of hippocampal subfields.ConclusionsCurrent evidence suggests that hippocampal subfields have partly distinct genetic architecture and may improve the sensitivity of the detection of AD.
| S-EPMC10915996 | biostudies-literature
Project description:The severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and the сoronavirus disease 2019 (COVID-19) have become a global health threat. At the height of the pandemic, major efforts were focused on reducing COVID-19-associated morbidity and mortality. Now is the time to study the long-term effects of the pandemic, particularly cognitive impairment associated with long COVID. In recent years much attention has been paid to the possible relationship between COVID-19 and Alzheimer's disease, which is considered a main cause of age-related cognitive impairment. Genetic predisposition was shown for both COVID-19 and Alzheimer's disease. However, the analysis of the similarity of the genetic architecture of these diseases is usually limited to indicating a positive genetic correlation between them. In this review, we have described intrinsic linkages between COVID-19 and Alzheimer's disease, pointed out shared susceptibility genes that were previously identified in genome-wide association studies of both COVID-19 and Alzheimer's disease, and highlighted a panel of SNPs that includes candidate genetic risk markers of the long COVID-associated cognitive impairment.
| S-EPMC10625425 | biostudies-literature
Project description:The National Alzheimer's Project Act, signed into law in 2011, mandates a National Plan to Address Alzheimer's Disease that is updated annually. In the Plan, the term Alzheimer disease includes not only Alzheimer disease (AD) proper, but also several specified related dementias, namely, frontotemporal, Lewy body, vascular, and mixed dementia. In response to a specific action item in the 2012 National Plan, the National Institute of Neurological Disorders and Stroke, in collaboration with the National Institute on Aging, convened panels of experts and conducted a 2-day public conference to develop research priorities and timelines for addressing Alzheimer disease-related dementias (ADRD) in 5 topic areas: multiple etiology dementias, health disparities, Lewy body dementias including dementia with Lewy bodies and Parkinson disease dementia, frontotemporal dementia and related tauopathies, and vascular contributions to ADRD. By design, the product was up to 8 prioritized research recommendations in each topic area including estimated timelines from when work on a recommendation is started to completion or to full implementation of an ongoing activity, and recognition of shared research themes across recommendations. These included increased education and training of both researchers and health care professionals, addressing health disparities, fundamental neurobiology research, advanced diagnostics, collaborative biosample repositories, and a focus on developing effective interventions to prevent or treat ADRD by the year 2025 as targeted by the National Plan.
| S-EPMC4155046 | biostudies-literature
Project description: Not available
| S-EPMC9727773 | biostudies-literature
Project description:Despite the enormous burden of Alzheimer's disease and related dementias (ADRD) on patients, caregivers, and society, only a few treatments with limited efficacy are currently available. While drug development conventionally focuses on disease-associated proteins, RNA has recently been shown to be druggable for therapeutic purposes as well. Approximately 70% of the human genome is transcribed into non-protein-coding RNAs (ncRNAs) such as microRNAs, long ncRNAs, and circular RNAs, which can adopt diverse structures and cellular functions. Many ncRNAs are specifically enriched in the central nervous system, and their dysregulation is implicated in ADRD pathogenesis, making them attractive therapeutic targets. In this review, we first detail why targeting ncRNAs with small molecules is a promising therapeutic strategy for ADRD. We then outline the process from discovery to validation of small molecules targeting ncRNAs in preclinical studies, with special emphasis on primary high-throughput screens for identifying lead compounds. Screening strategies for specific ncRNAs will also be included as examples. Key challenges-including selecting appropriate ncRNA targets, lack of specificity of small molecules, and general low success rate of neurological drugs and how they may be overcome-will be discussed throughout the review.
| S-EPMC8701955 | biostudies-literature