Biology subjects

Troakes, C.

Publications and source records attributed to Troakes, C..

17 recordsLinked to original sources

bioRxiv2026

Targeted single-nucleus sequencing of 39,800 neurons reveals extensive low-frequency somatic variants

Recent evidence implicates somatic mutations in disease-associated genes across multiple neurodegenerative disorders, including the identification of two somatic TARDBP variants as a putative cause of frontotemporal lobar degeneration with TDP-43 pathology type C (FTLD-TDP type C). However, these findings remain anecdotal. We performed single-nucleus amplicon sequencing of 39,800 neurons from the superior temporal gyrus of sporadic FTLD-TDP type C patients (34,738 neurons, 52 individuals) and non-demented controls (5,062 neurons, 26 individuals) using the Mission Bio Tapestri platform and investigated somatic variants in TARDBP and other FTLD-TDP-associated genes in a case-control setting. We uncovered an extensive landscape of ultra-low-frequency (<1%) somatic mutations across all analysed genes, including TARDBP. Rare somatic occurrences of known ALS/FTD-associated germline TARDBP variants, including p.N267S and p.M337V, were identified exclusively in patients. Among all targeted genes, TARDBP had the highest proportion of neurons harbouring a somatic variant, and this mutational burden was lower in individuals who died at an older age. Strikingly, the C-terminal domain of TDP-43, where most ALS/FTD germline pathogenic variants reside, exhibited a lower neuronal mutational burden than its other domains. This suggests that neurons harbouring damaging mutations may undergoprogressive loss prior to autopsy, leaving only rare survivors at frequencies too low to detect by bulk or small-scale single-cell approaches. Together, our findings provide an unprecedented resolution into the somatic mutational landscape of post-mitotic neurons in FTLD-TDP type C and reveal a gene-specific layer of neuronal mosaicism that current single-cell WGS studies fail to detect.

genetics↗

bioRxiv2026

Machine learning evaluation of gene expression-based ALS subtypes across brain and blood tissues

The clinical and molecular heterogeneity observed in amyotrophic lateral sclerosis (ALS) presents a challenge for diagnosis, prognosis, and treatment. RNA sequencing of post-mortem brain samples from ALS patients has identified several subtypes with distinct molecular signatures. We sought to evaluate these subtypes across diverse tissues and datasets and assess the feasibility of supervised machine learning models for sample classification. Unsupervised clustering and pathway analysis were performed to confirm the presence of ALS subtypes in motor cortex samples. Three machine learning strategies were then used to create models based on post-mortem motor cortex expression data of 112 people with ALS from the London Neurodegenerative Diseases Brain Bank. These models were subsequently improved through feature selection and evaluated in independent cohorts from motor cortex (n = 257, NYGC ALS Consortium) and blood (n = 96, Macquarie University Neurodegenerative Disease Biobank) samples. Multi-class linear discriminant analysis (LDA) models were then used for subtype classification. Clustering of ALS post-mortem motor cortex samples confirmed the presence of three subtypes: neuroinflammation (ALS-Neu), extracellular matrix organisation and muscle contraction (ALS-OxA), and synaptic and neuropeptide signalling (ALS-SNs). Among all machine learning strategies, random forests produced the most accurate and stable models for binary classification ([~]93% accuracy across the three subtypes). After feature selection, random forest models were able to classify samples from an independent post-mortem motor cortex cohort in their respective subtypes (AUC of [~]0.98 across the three subtypes). When these models were evaluated in blood using LDA, we found consistent clustering patterns, with samples aligning in the same subtype regions of the post-mortem motor cortex samples, with ALS-SNs being the subtype in which samples were classified with the highest confidence (LDA class probability [~]86%). Moreover, classification for this subtype improved when blood samples were collected closer to death. Our findings support the presence of three gene expression-based ALS subtypes in motor cortex samples and the utility of machine learning strategies for subtype classification. We also observed that the subtypes identified in the brain partially match those in the blood, with samples from the late stages of the disease more likely to be correctly predicted into the ALS-SNs cluster. This suggests a longitudinal effect in subtype identification that requires further investigation.

bioinformatics↗

bioRxiv2026

Why diabetes matters in dementia studies. Excluding diabetes status masks regional mitochondrial DNA copy number changes in human hippocampus, amygdala, and cerebellum in Alzheimers disease

STRUCTURED ABSTRACTO_ST_ABSINTRODUCTIONC_ST_ABSDiabetes is a major risk factor for Alzheimers disease (AD), and both diseases involve mitochondrial dysfunction. We hypothesised that AD is associated with reduced mitochondrial DNA copy number (mtDNA-CN) in vulnerable brain regions, and that diabetes modifies these changes. METHODSPost-mortem hippocampus, amygdala, and cerebellum samples (N=66-77) from non-cognitively impaired (NCI) and AD donors, with and without diabetes, were analysed. mtDNA-CN was quantified by absolute quantification. RESULTSOverall, mtDNA-CN was lower in AD. However, stratification by diabetes revealed opposite changes: non-diabetic AD cases showed reduced mtDNA-CN, whereas diabetic cases showed higher mtDNA-CN across all regions irrespective of cognitive status. DISCUSSIONThese findings confirm multiregional loss of mtDNA-CN in the AD brain, most evident in the absence of diabetes. The functional significance of higher mtDNA-CN in the diabetic brain remains unclear, but evidence that diabetes can mask effects has important implications for dementia studies.

neuroscience↗

bioRxiv2025

A validated panel of commercial antibodies for reliable detection of FET proteins.

The FET protein family comprises the highly conserved RNA-binding proteins FUS, EWS and TAF15 which are implicated in RNA metabolism and neurodegenerative diseases such as ALS and FTLD. Despite their structural similarity, reliable detection of individual FET proteins remains challenging due to antibody cross-reactivity and inconsistent localisation patterns reported in the literature. To address this, we systematically evaluated 23 commercially available antibodies for specificity and performance across western blotting, immunocytochemistry, and immunohistochemistry. Using single and double shRNA knockdowns in HeLa cells, we confirmed target engagement and identified antibodies which were specific as well as those with significant cross-reactivity. Immunofluorescence in rat primary neurons and HeLa cells showed antibody and cell type dependent variations in nuclear and cytoplasmic localisation; from these, we identified a subset that demonstrated high-quality, region-specific staining in postmortem human brain tissue. Our findings highlight substantial variability in antibody performance and underscore the need for rigorous validation to ensure reproducibility in FET protein research. We present a validated panel of antibodies suitable for diverse applications, providing a critical resource for studies of FET protein biology and pathology.

neuroscience↗

bioRxiv2025

CANVAS causing AAGGG repeat expansions cause tissue-specific reduction in RFC1 expression and increase sensitivity to DNA damage

Biallelic AAGGG expansions in Replication Factor Complex Subunit 1 (RFC1) are associated with cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and are increasingly recognised as a common cause of adult-onset ataxia and sensory neuropathy. However, the disease-causing mechanisms remain unclear. Here we leveraged in vitro assays, post-mortem brain tissue, patient-derived cell lines and a neuronal Drosophila model to demonstrate that AAGGG expansions are associated with tissue-specific reductions in the expression of RFC1 transcript, along with impaired RFC1 function and increased sensitivity to DNA damage from platinum-based drugs. CRISPR/Cas9 excision of the AAGGG repeat and flanking AluSx3 element normalized RFC1 expression in iPSC-derived neurons and rescued the DNA damage response, providing a framework for future therapeutic strategies. We also show that these biological findings are clinically relevant in heterozygous AAGGG expansion carriers, who display an increased risk and severity of neuropathy with platinum-based chemotherapy.

neuroscience↗

bioRxiv2025

Aberrant NSUN1 Activity Connects m5C RNA Modification to TDP-43 Neurotoxicity in ALS/FTD

In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the nuclear RNA-binding protein TDP-43 mislocalises to the cytoplasm and forms insoluble aggregates, but the mechanisms controlling this remain unclear. We define a native TDP-43 interactome in human SH-SY5Y cells and identify proteins linked to the 5-methylcytosine (m5C) RNA modification as highly enriched. Using a Drosophila model of TDP-43 pathology, we show that aberrant activity of m5C-RNA methyltransferases Nsun1 drives TDP-43-induced m5C-RNA hypermethylation, while Nsun1 downregulation alleviates TDP-43-induced degeneration, lifespan deficits, and cytoplasmic accumulation. In human cells, TDP-43 selectively interacts with NSUN1 isoform 3 independently of RNA. Furthermore, NSUN1 is nucleolar and TDP-43 is largely nucleoplasmic, yet they interact in both compartments, suggesting functional roles beyond their predominant localisations. In ALS/FTD post-mortem frontal cortex, NSUN1 isoform 3 persists, while the shorter isoform is reduced, suggesting that a pool of NSUN1 capable of contributing to pathological TDP-43 interactions remains in disease. These findings suggest that TDP-43 neurotoxicity is coupled to NSUN1 activation and m5C-RNA methylation, revealing a potential therapeutic axis in ALS/FTD. Summary blurbThe study shows that NSUN1-mediated m5C RNA methylation drives TDP-43 cytoplasmic accumulation and neurotoxicity, revealing a new pathway contributing to ALS/FTD pathogenesis.

cell biology↗

bioRxiv2023

Interaction of amisulpride with GLUT1 at the blood-brain barrier. Relevance to Alzheimer's disease

Blood-brain barrier (BBB) dysfunction may be involved in the increased sensitivity of Alzheimers disease (AD) patients to antipsychotics, including amisulpride. Studies indicate that antipsychotics interact with facilitated glucose transporters (GLUT), including GLUT1, and that GLUT1 BBB expression decreases in AD. We tested the hypotheses that amisulpride (charge: +1) interacts with GLUT1, and that BBB transport of amisulpride is compromised in AD. GLUT1 substrates and inhibitors, and GLUT-interacting antipsychotics were identified by literature review and their physicochemical characteristics summarised. Interactions between amisulpride, and GLUT1 were studied using in silico approaches and the human cerebral endothelial cell line, hCMEC/D3. Brain distribution of [3H]amisulpride was determined using in situ perfusion in wild type (WT) and 5xFamilial AD (5xFAD) mice. With transmission electron microscopy (TEM) we investigated brain capillary degeneration in WT and 5xFAD mice, and human samples. Western blots determined BBB transporter expression in mouse and human. Literature review revealed that, although D-glucose has no charge, charged molecules can interact with GLUT1. GLUT1 substrates are smaller (184.95{+/-}6.45g/mol) than inhibitors (325.50{+/-}14.40g/mol), and GLUT-interacting antipsychotics (369.38{+/-}16.04). Molecular docking showed beta-D-glucose (free energy binding: -15.39kcal/mol) and amisulpride (-29.04kcal/mol) interact with GLUT1. Amisulpride did not affect [14C]D-glucose accumulation in hCMEC/D3. 5xFAD mice showed increased brain [3H]amisulpride uptake, and no cerebrovascular space changes compared to WT. TEM revealed brain capillary degeneration in human AD. There was no significant effect of AD on mouse GLUT1 and P-gp BBB expression, and in human GLUT1 expression. In contrast, caudate P-glycoprotein expression was decreased in human AD capillaries versus controls. This study provides new details about the BBB transport of amisulpride, evidence that amisulpride interacts with GLUT1, and that BBB transporter expression is altered in AD. This suggests that antipsychotics exacerbate the cerebral hypometabolism in AD. Further research into the mechanism of amisulpride transport by GLUT1 is important for improving antipsychotics safety.

neuroscience↗

bioRxiv2021

Astrocytic C-X-C motif chemokine ligand-1 mediates β-amyloid-induced tau mislocalization and synaptotoxicity

BackgroundPathological interactions between {beta}-amyloid (A{beta}) and tau drive the synapse loss that underlies neural circuit disruption and cognitive decline in Alzheimers disease (AD). Reactive astrocytes, displaying altered functions, are also a prominent feature of AD brain. This large and heterogeneous population of cells are increasingly recognised as contributing to early phases of disease. However, the contribution of astrocytes to detrimental A{beta}-tau interactions in AD is not well understood. MethodsMouse and human astrocyte cultures were stimulated with concentrations and species of human A{beta} that mimic those in human AD brain. Astrocyte conditioned medium was collected and immunodepleted of A{beta} before being added to rodent or human neuron cultures. Cytokines, identified in unbiased screens were also applied to neurons, including following the pre-treatment of neurons with chemokine receptor antagonists. Tau mislocalisation, synaptic markers and dendritic spine numbers were measured in cultured neurons and organotypic brain slice cultures. ResultsConditioned medium from astrocytes stimulated with A{beta} induces tau mislocalisation and exaggerated synaptotoxicity that is recapitulated following spiking of neuron culture medium with recombinant C-X-C motif chemokine ligand-1 (CXCL1), a chemokine we show to be upregulated in Alzheimers disease brain. Antagonism of neuronal C-X-C motif chemokine receptor 2 (CXCR2) prevented tau mislocalisation and synaptotoxicity in response to CXCL1 and A{beta}-stimulated astrocyte secretions. ConclusionsOur data indicate that astrocytes exacerbate tau mislocalisation and the synaptotoxic effects of A{beta} via interactions of astrocytic CXCL1 and neuronal CXCR2 receptors, highlighting this chemokine-receptor pair as a novel target for therapeutic intervention in AD.

neuroscience↗

bioRxiv2021

TMCC2 Associates with Alzheimer's Disease Pathology

Transmembrane and Coiled-Coil 2 (TMCC2) is a protein that forms complexes with both apolipoprotein E (apoE) and the amyloid protein precursor (APP), two proteins central to the etiology of Alzheimers disease (AD). Here we have carried out the first investigation of TMCC2 expression in the human brain, where TMCC2 immunoreactivity is primarily neuronal. We also examined TMCC2 localization in late onset AD brains,early onset AD cases bearing a mutation in APP, and in Down syndrome cases. TMCC2 immunoreactivity is closely associated with APP immunoreactivity in both control and AD cases. In all AD cases examined, TMCC2 associated with dense core senile plaques and adjacent dystrophic neurites, but not with amyloid surrounding the core, nor with diffuse amyloid plaques or neurofibrillary tangles. In Down syndrome, we found dystrophic neurites in senile plaques that were positive for amyloid and TMCC2, but not for APP, in addition to the APP- and TMCC2-positive dense cores. Western blot analysis revealed TMCC2 exists as at least three protein isoforms. The relative abundance of the isoforms varies in the temporal gyrus and cerebellum, the relative proportions of which were influenced by APOE and/or dementia status. Taken together, these observations are consistent with the evolutionarily conserved interactions between APP and TMCC2 and suggest cooperation betweenTMCC2 and APP in the normal and AD brain. These findings thus support a role for TMCC2 as a mediator of the impact of apoE on AD pathogenesis.

neuroscience↗

bioRxiv2019

Schizophrenia risk from locus-specific human endogenous retroviruses

Schizophrenia genome-wide association studies highlight the substantial contribution of risk attributed to the non-coding genome where human endogenous retroviruses (HERVs) are encoded. These ancient viral elements have previously been overlooked in genetic and transcriptomic studies due to their poor annotation and repetitive nature. Using a new, comprehensive HERV annotation, we found that the fraction of the genome where HERVs are located (the retrogenome) is enriched for schizophrenia risk variants, and that there are 148 disparate HERVs involved in susceptibility. Analysis of RNA-sequencing data from the dorsolateral prefrontal cortex of 259 schizophrenia cases and 279 controls from the CommonMind Consortium showed that HERVs are actively expressed in the brain (n = 3,979), regulated in cis by common genetic variants (n = 1,759), and differentially expressed in patients (n = 81). Convergent analyses implicate LTR25_6q21 and ERVLE_8q24.3h as HERVs of etiological relevance to schizophrenia, which are co-regulated with genes involved in neuronal and mitochondrial function, respectively. Our findings provide a strong rationale for exploring the retrogenome and the expression of these locus-specific HERVs as novel risk factors for schizophrenia and potential diagnostic biomarkers and treatment targets.

neuroscience↗

bioRxiv2019

Mutations in the SPTLC1 gene are a cause of amyotrophic lateral sclerosis that may be amenable to serine supplementation

Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of childhood motor disorder with a heterogeneous clinical presentation. The underlying causes of this condition are poorly understood, hindering the development of effective therapies. In a whole-exome sequencing trio-family study of three unrelated juvenile patients diagnosed with ALS and failure to thrive, we identified de-novo mutations in SPTLC1 (p.Ala20Ser in two patients and p.Ser331Tyr) not present in their healthy parents or siblings. SPTLC1 encodes a subunit of the serine palmitoyltransferase complex, a key enzyme in sphingolipid biosynthesis. Mutations in this gene are known to cause hereditary sensory autonomic neuropathy, type 1A, with a characteristic increase in plasma levels of neurotoxic deoxymethyl-sphinganine. We found an increase of this metabolite in one of our patients carrying the p.Ala20Ser mutation. Treatment of one of the patients with high dose, oral L-serine led to an increase in body weight, suggesting that serine supplementation may be beneficial among patients carrying mutations in this gene.

genetics↗

bioRxiv2019

Loss of the Alzheimer’s-linked bridging integrator 1 (BIN1) protein affects synaptic structure and disrupts tau localisation and release

BackgroundPost-translational modifications of tau modify its interaction with binding partners and cause tau mislocalisation and altered tau function in Alzheimers disease (AD). The AD risk gene BIN1, is a binding partner for tau, however the mechanism by which BIN1 influences tau function is not fully understood. We hypothesised that BIN1 modulates AD risk by causing damaging tau mis-sorting to the synapse.\n\nMethodsTau and BIN1 levels, distribution and interactions were assessed in post-mortem control and AD brain and in primary neurons. In primary neurons, tau was further examined using structured illumination microscopy and immunoblotting following BIN1 knockdown, BIN1-tau interactions were examined using proximity ligation assays and tau release from neurons was measured by sensitive sandwich ELISA.\n\nResultsProline 216 in tau was identified as critical for tau interaction with the BIN1-SH3 domain, and tau phosphorylation at serine/threonine residues disrupted this interaction. Subcellular fractionation showed that BIN1 is lost from the cytoplasm of AD brain and this correlated with the mislocalisation of phosphorylated tau to synapses. Mimicking BIN1 loss in AD by knockdown of the protein in primary neurons altered the structure of dendritic spines, caused phosphorylated tau to mis-sort to synapses and reduced the physiological release of predominantly dephosphorylated tau.\n\nConclusionsThese data suggest that BIN1 loss in AD allows phosphorylated tau to be mis-sorted to synapses which likely alters the integrity of the post-synapse, alongside reducing the functionally important release of physiological forms of tau.

neuroscience↗

bioRxiv2019

Transcriptomic analysis of probable asymptomatic and symptomatic Alzheimer brains

Individuals with intact cognition and neuropathology consistent with Alzheimers disease (AD) are referred to as asymptomatic AD (AsymAD). These individuals are highly likely to develop AD, yet transcriptomic changes in the brain which might reveal mechanisms for their AD vulnerability are currently unknown. Entorhinal cortex, frontal cortex, temporal cortex and cerebellum tissue from 27 control, 33 AsymAD and 52 AD human brains were microarray expression profiled. Differential expression analysis identified a significant increase of transcriptomic activity in the frontal cortex of AsymAD subjects, suggesting fundamental changes in AD may initially begin within the frontal cortex region prior to AD diagnosis. Co-expression analysis identified an overactivation of the brain \"glutamate-glutamine cycle\", and disturbances in the brain energy pathways in both AsymAD and AD subjects, while connectivity of key hub genes in this network indicates a shift from an already increased cell proliferation in AsymAD subjects to stress response and removal of amyloidogenic proteins in AD subjects. This study provides new insight into the earliest biological changes occurring in the brain prior to the manifestation of clinical AD symptoms and provides new potential therapeutic targets for early disease intervention.

genetics↗

bioRxiv2018

Psychiatric risk gene NT5C2 regulates protein translation in human neural progenitor cells

Genome-wide significant variants associated with combined risk for major psychiatric disorders on chromosome 10q24 affect the expression of the cytosolic 5-nucleotidase II (NT5C2, cN-II) in population controls, implicating it as a psychiatric susceptibility gene. Risk alleles are associated with reduced expression of this gene in the developing and adult brain, but the resulting neurobiological risk mechanisms remain elusive. In this study, we provide further evidence for the association of NT5C2 with psychiatric disorders, and use a functional genetics approach to gain a deeper understanding of the function of this risk gene in the nervous system. NT5C2 expression was significantly reduced in the post-mortem brain of schizophrenia and bipolar disorder patients, and its protein predominately expressed in neurons within the adult brain. Using human neural progenitor cells (hNPCs), we found that NT5C2 expression peaked at the neural progenitor state, where the encoded protein was ubiquitously distributed through the cell. NT5C2 knockdown in hNPCs elicited transcriptomic changes associated with protein translation, that were accompanied by regulation of adenosine monophosphate-activated protein kinase (AMPK) signalling and ribosomal protein S6 (rpS6) activity. To identify the effect of reduced neuronal NT5C2 expression at a systems level, we knockdown its homologue, CG32549, in Drosophila melanogaster CNS. This elicited impaired climbing behaviour in the model organism. Collectively, our data implicate NT5C2 expression in risk for psychiatric disorders and in Drosophila melanogaster motility, and further suggest that risk is mediated via regulation of AMPK signalling and protein translation during early neurodevelopment.

neuroscience↗

bioRxiv2018

Heritability and genetic variance of dementia with Lewy bodies

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinsons disease (PD) or Alzheimers disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

neuroscience↗

bioRxiv2018

Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic forms of autism in postmortem human brain tissue.

Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behavior. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular etiology of ASD, we quantified genome-wide patterns of DNA methylation in 233 post-mortem tissues samples isolated from three brain regions (prefrontal cortex, temporal cortex and cerebellum) dissected from 43 ASD patients and 38 non-psychiatric control donors. We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the cerebellum. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically-defined subtype of ASD, were characterized by striking differences in DNA methylation across a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic signalling and neuronal regulation. Our study represents the first systematic analysis of DNA methylation associated with ASD across multiple brain regions, providing novel evidence for convergent molecular signatures associated with both idiopathic and syndromic autism.

genomics↗

bioRxiv2017

A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex

Alzheimers disease (AD) is a chronic neurodegenerative disorder characterized by the progressive accumulation of amyloid-{beta} (A{beta}) plaques and neurofibrillary tangles in the neocortex. Recent studies have implicated a role for regulatory genomic variation in AD progression, finding widespread evidence for altered DNA methylation associated with neuropathology. To date, however, no study has systematically examined other types of regulatory genomic modifications in AD. In this study, we quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) - a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding - in entorhinal cortex samples from AD cases and matched controls (n = 47) using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). Across ~182,000 robustly detected H3K27ac peak regions, we found widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (FDR < 0.05) between AD cases and controls. These differentially acetylated peaks are enriched in disease-specific biological pathways and include regions annotated to multiple genes directly involved in the progression of A{beta} and tau pathology (e.g. APP, PSEN1, PSEN2, MAPT), as well as genomic regions containing variants associated with sporadic late-onset AD. This is the first study of variable H3K27ac yet undertaken in AD and the largest study investigating this modification in the entorhinal cortex. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease, integrating our data with results obtained from genome-wide association studies as well as other epigenetic marks profiled on the same samples.

genomics↗