The complex genetic architecture of Alzheimer's disease: novel insights and future directions

EBioMedicine, Journal Year: 2023, Volume and Issue: 90, P. 104511 - 104511

Published: March 10, 2023

Language: Английский

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Towards a future where Alzheimer’s disease pathology is stopped before the onset of dementia

Nature Aging, Journal Year: 2023, Volume and Issue: 3(5), P. 494 - 505

Published: May 18, 2023

Language: Английский

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A global view of the genetic basis of Alzheimer disease

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(5), P. 261 - 277

Published: April 6, 2023

Language: Английский

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Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer’s disease

Journal of Neurology Neurosurgery & Psychiatry, Journal Year: 2023, Volume and Issue: 94(11), P. 954 - 961

Published: June 22, 2023

Alzheimer's disease (AD) is the leading cause of dementia. Currently, there are no effective disease-modifying treatments for AD. Mendelian randomisation (MR) has been widely used to repurpose licensed drugs and discover novel therapeutic targets. Thus, we aimed identify targets AD analyse their pathophysiological mechanisms potential side effects.A two-sample MR integrating identified druggable genes was performed estimate causal effects blood brain expression quantitative trait loci (eQTLs) on A repeat study conducted using different eQTL data sources validate genes. Using markers with available genome-wide association studies data, evaluated relationship between established explore possible mechanisms. Finally, treatment were assessed a phenome-wide MR.Overall, 5883 unique aggregated; 33 in at least one dataset (brain or blood), 5 validated dataset. Among them, three prior (epoxide hydrolase 2 (EPHX2), SERPINB1 SIGLEC11) reached significant levels both tissues. EPHX2 may mediate pathogenesis by affecting entire hippocampal volume. Further analysis revealed targeting EPHX2, SIGLEC11.This provides genetic evidence supporting benefits treatment, which will be useful prioritising drug development.

Language: Английский

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Step by step: towards a better understanding of the genetic architecture of Alzheimer’s disease

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(7), P. 2716 - 2727

Published: May 2, 2023

Alzheimer's disease (AD) is considered to have a large genetic component. Our knowledge of this component has progressed over the last 10 years, thanks notably advent genome-wide association studies and establishment consortia that make it possible analyze hundreds thousands cases controls. The characterization dozens chromosomal regions associated with risk developing AD (in some loci) causal genes responsible for observed signal confirmed involvement major pathophysiological pathways (such as amyloid precursor protein metabolism) opened up new perspectives central role microglia inflammation). Furthermore, large-scale sequencing projects are starting reveal impact rare variants - even in like APOE on risk. This increasingly comprehensive now being disseminated through translational research; particular, development risk/polygenic scores helping identify subpopulations more at or less AD. Although difficult assess efforts still needed comprehensively characterize AD, several lines research can be improved initiated. Ultimately, genetics combination other biomarkers) might help redefine boundaries relationships between various neurodegenerative diseases.

Language: Английский

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Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Jan. 3, 2024

Abstract Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well Alzheimer’s disease (AD) pathogenesis. We previously reported the MS4A locus key modulator for soluble TREM2 (sTREM2) cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed largest genome-wide association study (GWAS) identified four loci CSF sTREM2 3,350 individuals European ancestry. Through multi-ethnic fine mapping, two independent missense variants (p.M178V MS4A4A p.A112T MS4A6A ) that drive showed an epistatic effect levels AD risk. The chr 6 contains rare (rs75932628 p.R47H, P =7.16×10 -19 ; rs142232675 p.D87N, =2.71×10 -10 associated with third TGFBR2 RBMS3 gene region (rs73823326, =3.86×10 -9 included regulatory variant microglia-specific chromatin loop promoter . Using cell-based assays demonstrate overexpression knock-down TGFBR2, but not RBMS3, leads to significant changes sTREM2. last is located APOE (rs11666329, =2.52×10 -8 ), demonstrated this signal was genotype. This colocalized cis-eQTL NECTIN2 brain cortex cis-pQTL CSF. Overexpression led increase supporting findings. our knowledge, date aimed at identifying provided insights into loci, well-known risk genes, modulators involved biology.

Language: Английский

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Cerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 1, 2024

Cerebrospinal fluid (CSF) biomarkers reflect brain pathophysiology and are used extensively in translational research as well clinical practice for diagnosis of neurological diseases, e.g., Alzheimer's disease (AD). However, CSF biomarker concentrations may be influenced by non-disease related inter-individual variability. Here we use a data-driven approach to demonstrate the existence variability mean standardized protein levels. We show that these differences cause many commonly reported highly correlated, thereby producing misleading results if not accounted for. To adjust this variability, identified evaluated high-performing reference proteins which improved diagnostic accuracy key AD biomarkers. Our method attenuates risk false positive findings, improves sensitivity specificity biomarkers, with broad implications both practice.

Language: Английский

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Alzheimer Disease and Epilepsy

Neurology, Journal Year: 2023, Volume and Issue: 101(4)

Published: May 24, 2023

Observational studies suggested a bidirectional relationship between Alzheimer disease (AD) and epilepsies. However, it remains debated whether in which direction causal association exists. This study aims to explore the genetic predisposition AD, CSF biomarkers of AD (β-amyloid [Aβ] 42 phosphorylated tau [pTau]), epilepsies with 2-sample, Mendelian randomization (MR) method.Genetic instruments were obtained from large-scale genome-wide meta-analysis (Ncase/proxy = 111,326, Ncontrol 677,663), (Aβ42 pTau, N 13,116), epilepsy (Ncase 15,212, 29,677) European ancestry. Epilepsy phenotypes included all epilepsy, generalized focal childhood absence juvenile myoclonic tonic-clonic seizures, hippocampal sclerosis (focal HS), lesion-negative epilepsy. Main analyses performed using summary data-based MR. Sensitivity inverse variance weighted, MR pleiotropy residual sum outlier, MR-Egger, weighted mode, median.For forward analysis, was associated an increased risk (odds ratio [OR] 1.053, 95% CI 1.002-1.105, p 0.038) HS (OR 1.013, 1.004-1.022, 0.004). These associations consistent across sensitivity replicated separate set another study. For reverse there suggestive effect on 3.994, 1.172-13.613, 0.027). In addition, genetically predicted lower Aβ42 (β 0.090, 0.022-0.158, 0.010).This supports link amyloid pathology, also indicates close HS. More effort should be made screen seizure unravel its clinical implications, role as putative modifiable factor.

Language: Английский

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Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer’s disease

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: June 9, 2023

The integration of quantitative trait loci (QTL) with disease genome-wide association studies (GWAS) has proven successful at prioritizing candidate genes disease-associated loci. QTL mapping mainly been focused on multi-tissue expression or plasma protein (pQTL). Here we generated the largest-to-date cerebrospinal fluid (CSF) pQTL atlas by analyzing 7,028 proteins in 3,107 samples. We identified 3,373 independent study-wide associations for 1,961 proteins, including 2,448 novel pQTLs which 1,585 are unique to CSF, demonstrating genetic regulation CSF proteome. In addition established chr6p22.2-21.32 HLA region, pleiotropic regions chr3q28 near

Language: Английский

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The Alzheimer’s disease risk gene BIN1 regulates activity-dependent gene expression in human-induced glutamatergic neurons

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(9), P. 2634 - 2646

Published: March 22, 2024

Bridging Integrator 1 (BIN1) is the second most important Alzheimer's disease (AD) risk gene, but its physiological roles in neurons and contribution to brain pathology remain largely elusive. In this work, we show that BIN1 plays a critical role regulation of calcium homeostasis, electrical activity, gene expression glutamatergic neurons. Using single-cell RNA-sequencing on cerebral organoids generated from isogenic wild type (WT), heterozygous (HET) homozygous knockout (KO) human-induced pluripotent stem cells (hiPSCs), mainly expressed by oligodendrocytes neurons, like human brain. Both HET KO specific transcriptional alterations, associated with ion transport synapses We then demonstrate cell-autonomously regulates using novel protocol generate pure culture hiPSC-derived induced (hiNs). system, also key neuronal transients activity via interaction L-type voltage-gated channel Cav

Language: Английский

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