Biology subjects

Deming, Y.

Publications and source records attributed to Deming, Y..

7 recordsLinked to original sources

bioRxiv2025

Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology

The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimers disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology. In a cohort of 1,196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic analysis linked putative ImP producers to ADRD phenotypes. Genome-wide integrative analysis revealed a locus on chromosome 12 associated with both plasma ImP levels and AD risk in humans, supporting a host genetic contribution to ImP regulation and a causal role of this metabolite in AD. In mice, chronic ImP administration exacerbated AD-like pathology. Mechanistically, ImP impaired brain endothelial barrier and promoted tau hyperphosphorylation in primary neurons, an effect blocked by glycogen synthase kinase-3{beta} inhibition. Together, our study links ImP to hallmarks of neurodegeneration and suggest that targeting ImP may represent a potential strategy to modify ADRD risk.

pathology↗

bioRxiv2021

CSF metabolites associate with CSF tau and improve prediction of Alzheimer's disease status

INTRODUCTIONCerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) are biomarkers of Alzheimers disease (AD), yet much is unknown about AD-associated changes in tau metabolism and tau tangle etiology. METHODSWe assessed the variation of t-tau and p-tau explained by 38 previously identified CSF metabolites using linear regression models in middle-age controls from the Wisconsin Alzheimers Disease Research Center, and predicted AD/mild cognitive impairment (MCI) vs. an independent set of older controls using metabolites selected by the least absolute shrinkage and selection operator (LASSO). RESULTSThe 38 CSF metabolites explained 70.3% and 75.7% of the variance in t-tau and p-tau. Of these, 7 LASSO-selected metabolites improved the prediction ability of AD/MCI vs. older controls (AUC score increased from 0.92 to 0.97 and 0.78 to 0.93) compared to the base model. DISCUSSIONThese tau-correlated CSF metabolites increase AD/MCI prediction accuracy and may provide insight into tau tangle etiology.

molecular biology↗

bioRxiv2019

A/T/N polygenic risk score for cognitive decline in old age

INTRODUCTIONWe developed a novel polygenic risk score (PRS) based on the A/T/N (amyloid plaques (A), phosphorylated tau tangles (T), and neurodegeneration (N)) framework and compared a PRS based on clinical AD diagnosis to assess which was a better predictor of cognitive decline. METHODSWe used summary statistics from genome wide association studies of cerebrospinal fluid amyloid-{beta} (A{beta}42) and phosphorylated-tau (ptau181), left hippocampal volume (LHIPV), and late-onset AD dementia to calculate PRS for 1181 participants in the Alzheimers Disease Neuroimaging Initiative (ADNI). Individual PRS were averaged to generate a composite A/T/N PRS. We assessed the association of PRS with baseline and longitudinal cognitive composites of executive function and memory. RESULTSThe A/T/N PRS showed superior predictive performance on AD biomarkers and executive function decline compared to the clinical AD PRS. DISCUSSIONResults suggest that integration of genetic risk across AD biomarkers may improve prediction of disease progression. Research in ContextO_ST_ABSSystematic ReviewC_ST_ABSAuthors reviewed relevant literature using PubMed and Google Scholar. Key studies that generated and validated polygenic risk scores (PRS) for clinical and pathologic AD were cited. PRS scores have been increasingly used in the literature but clinical utility continues to be questioned. InterpretationIn the current research landscape concerning PRS clinical utility in the AD space, there is room for model improvement and our hypothesis was that a PRS with integrated risk for AD biomarkers could yield a better model for cognitive decline. Future DirectionsThis study serves as proof-of-concept that encourages future study of integrated PRS across disease markers and utility in taking an A/T/N (amyloidosis, tauopathy and neurodegeneration) focused approach to genetic risk for cognitive decline and AD.

genomics↗

bioRxiv2018

Biobank-wide association scan identifies risk factors for late-onset Alzheimer’s disease and endophenotypes

Rich data from large biobanks, coupled with increasingly accessible association statistics from genome-wide association studies (GWAS), provide great opportunities to dissect the complex relationships among human traits and diseases. We introduce BADGERS, a powerful method to perform polygenic score-based biobank-wide association scans. Compared to traditional approaches, BADGERS uses GWAS summary statistics as input and does not require multiple traits to be measured in the same cohort. We applied BADGERS to two independent datasets for late-onset Alzheimers disease (AD; N=61,212). Among 1,738 traits in the UK biobank, we identified 48 significant associations for AD. Family history, high cholesterol, and numerous traits related to intelligence and education showed strong and independent associations with AD. Further, we identified 41 significant associations for a variety of AD endophenotypes. While family history and high cholesterol were strongly associated with AD subgroups and pathologies, only intelligence and education-related traits predicted pre-clinical cognitive phenotypes. These results provide novel insights into the distinct biological processes underlying various risk factors for AD.

genetics↗

bioRxiv2018

The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in the cerebrospinal fluid (CSF) have been associated with Alzheimer disease (AD) status. TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may help reveal biological mechanisms underlying AD and identify novel therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 levels. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with higher CSF sTREM2 levels (rs1582763; P = 1.15x10-15) and replicated in independent datasets. The variants associated with increased levels of sTREM2 are also associated with reduced AD risk and delayed age-at-onset. Rs1582763 influences expression of MS4A4A and MS4A6A in multiple tissues, suggesting that one or both of these genes are important for regulating sTREM2. MS4A genes encode transmembrane proteins that may play a role in intracellular protein trafficking in microglia. We used human macrophages to begin to test the relationship between MS4A4A and TREM2 and found that they co-localize intracellularly and that antibody-mediated targeting of MS4A4A reduces sTREM2. Thus, genetic, molecular, and cellular findings suggest that MS4A4A regulates sTREM2. These findings also provide a mechanistic explanation of the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 is involved in sporadic AD risk in general, not only in TREM2 risk-variant carriers.

genomics↗

bioRxiv2018

Evaluation of gene-based family-based methods to detect novel genes associated with familial late onset Alzheimer disease

Gene-based tests to study the combined effect of rare variants towards a particular phenotype have been widely developed for case-control studies, but their evolution and adaptation for family-based studies, especially for complex incomplete families, has been slower. In this study, we have performed a practical examination of all the latest gene-based methods available for family-based study designs using both simulated and real datasets. We have examined the performance of several collapsing, variance-component and transmission disequilibrium tests across eight different software and twenty-two models utilizing a cohort of 285 families (N=1,235) with late-onset Alzheimer disease (LOAD). After a thorough examination of each of these tests, we propose a methodological approach to identify, with high confidence, genes associated with the studied phenotype with high confidence and we provide recommendations to select the best software and model for family-based gene-based analyses. Additionally, in our dataset, we identified PTK2B, a GWAS candidate gene for sporadic AD, along with six novel genes (CHRD, CLCN2, HDLBP, CPAMD8, NLRP9, MAS1L) as candidates genes for familial LOAD.

genetics↗

bioRxiv2017

A common haplotype lowers SPI1 (PU.1) expression in myeloid cells and delays age at onset for Alzheimer’s disease

In this study we used age at onset of Alzheimers disease (AD), cerebrospinal fluid (CSF) biomarkers, and cis-expression quantitative trait loci (cis-eQTL) datasets to identify candidate causal genes and mechanisms underlying AD GWAS loci. In a genome-wide survival analysis of 40,255 samples, eight of the previously reported AD risk loci are significantly (P < 5x10-8) or suggestively (P < 1x10-5) associated with age at onset-defined survival (AAOS) and a further fourteen novel loci reached suggestive significance. Using stratified LD score regression we demonstrated a significant enrichment of AD heritability in hematopoietic cells of the myeloid and B-lymphoid lineage. We then investigated the impact of these 22 AAOS-associated variants on CSF biomarkers and gene expression in cells of the myeloid lineage. In particular, the minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, shows association with higher age at onset of AD (P=8.40x10-6), higher CSF levels of A{beta}42 (P=1.2x10-4), and lower expression of SPI1 in monocytes (P=1.50x10-105) and macrophages (P=6.41x10-87). SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability is enriched within the SPI1 cistromes of monocytes and macrophages, implicating a myeloid PU.1 target gene network in the etiology of AD. Finally, experimentally altered PU.1 levels are correlated with phagocytic activity of BV2 mouse microglial cells and specific changes in the expression of multiple myeloid-expressed genes, including the mouse orthologs of AD-associated genes, APOE, CLU/APOJ, CD33, MS4A4A/MS4A6A, and TYROBP. Our results collectively suggest that lower SPI1 expression reduces AD risk by modulating myeloid cell gene expression and function.

neuroscience↗