A Comparative study on the Effectiveness of Augmented Reality on Denture Tooth Selection.

One of the most difficult aspects of providing removable dentures, for both the patient and the dentist, is the tooth selection process. The aim of this study was to assess the effectiveness of augmented reality (AR) on patient experience of the tooth selection process. MATERIALS AND METHODS: 3D scanning of upper anterior teeth of various shapes and sizes allowed for the creation of a virtual library that were subsequently used to programme an AR software application, 'ToothPick'. Seventeen participants were recruited to a comparative study at Leeds Dental Institute, over two clinical appointments, to trial the app and complete a 10-question survey to assess the efficacy of AR simulation. The sample size response generated outcome variables for 'perceived usefulness' and 'perceived ease of use' from the perspectives of the patient, dentist and technician. RESULTS: By the second appointment, 86% of participants preferred the app over the conventional methods for selection of denture teeth due to increased ease of use and accuracy that AR simulation had in replicating the wax try-in. CONCLUSION: The sample population favoured the adoption of AR technology to select denture teeth from the perspective of both the patient and the clinician.

Investigating the neuroimmunogenic architecture of schizophrenia.

The role of the immune system in schizophrenia remains controversial despite numerous studies to date. Most studies have profiled expression of select genes or proteins in peripheral blood, but none have focused on the expression of canonical pathways that mediate overall immune response. The current study used a systematic genetic approach to investigate the role of the immune system in a large sample of post-mortem brain of patients with schizophrenia: RNA sequencing was performed to assess the differential expression of 561 immune genes and 20 immune pathways in dorsolateral prefrontal cortex (DLPFC) (144 schizophrenia and 196 control subjects) and hippocampus (83 schizophrenia and 187 control subjects). The effect of RNA quality on gene expression was found to be highly correlated with the effect of diagnosis even after adjustment for observable RNA quality parameters (i.e. RNA integrity), thus this confounding relationship was statistically controlled using principal components derived from the gene expression matrix. In DLPFC, 23 immune genes were found to be differentially expressed (false discovery rate <0.05), of which seven genes replicated in both directionality and at nominal significance (P<0.05) in an independent post-mortem DLPFC data set (182 schizophrenia and 212 control subjects), although notably at least five of these genes have prominent roles in pathways other than immune function and overall the effect sizes were minimal (fold change <1.1). In the hippocampus, no individual immune genes were identified to be differentially expressed, and in both DLPFC and hippocampus none of the individual immune pathways were relatively differentially expressed. Further, genomic schizophrenia risk profiles scores were not correlated with the expression of individual immune pathways or differentially expressed genes. Overall, past reports claiming a primary pathogenic role of the immune system intrinsic to the brain in schizophrenia could not be confirmed.

GAD1 alternative transcripts and DNA methylation in human prefrontal cortex and hippocampus in brain development, schizophrenia.

Genetic variations and adverse environmental events in utero or shortly after birth can lead to abnormal brain development and increased risk of schizophrenia. γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain, plays a vital role in normal brain development. GABA synthesis is controlled by enzymes derived from two glutamic acid decarboxylase (GAD) genes, GAD1 and GAD2, both of which produce transcript isoforms. While the full-length GAD1 transcript (GAD67) has been implicated in the neuropathology of schizophrenia, the transcript structure of GAD1 in the human brain has not been fully characterized. In this study, with the use of RNA sequencing and PCR technologies, we report the discovery of 10 novel transcripts of GAD1 in the human brain. Expression levels of four novel GAD1 transcripts (8A, 8B, I80 and I86) showed a lifespan trajectory expression pattern that is anticorrelated with the expression of the full-length GAD1 transcript. In addition, methylation levels of two CpG loci within the putative GAD1 promoter were significantly associated with the schizophrenia-risk SNP rs3749034 and with the expression of GAD25 in dorsolateral prefrontal cortex (DLPFC). Moreover, schizophrenia patients who had completed suicide and/or were positive for nicotine exposure had significantly higher full-length GAD1 expression in the DLPFC. Alternative splicing of GAD1 and epigenetic state appear to play roles in the developmental profile of GAD1 expression and may contribute to GABA dysfunction in the PFC and hippocampus of patients with schizophrenia.

Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder.

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

Increasing BMI is associated with reduced expression of P-glycoprotein (ABCB1 gene) in the human brain with a stronger association in African Americans than Caucasians.

The efflux pump, p-glycoprotein, controls bioavailability and excretion of pharmaceutical compounds. In the blood-brain barrier, p-glycoprotein regulates the delivery of pharmaceutical substances to the brain, influencing efficacy and side effects for some drugs notably antipsychotics. Common side effects to antipsychotics include obesity and metabolic disease. Polymorphisms in the ABCB1 gene coding for p-glycoprotein are associated with more severe side effects to neuro-pharmaceuticals as well as weight gain, indicating a potential link between p-glycoprotein function and metabolic regulation. Using microarray data analysis from 145 neurologically sound adults, this study investigated the association between body mass index (BMI) and ABCB1 expression in the frontal cortex. Increasing BMI values were associated with a statistically significantly reduced expression of ABCB1. Investigation of DNA methylation patterns in a subgroup of 52 individuals found that the methylation/expression ratios of ABCB1 were unaffected by increasing BMI values. Interestingly, the effect of BMI on ABCB1 expression appeared stronger in African Americans than in Caucasians.

Surveys of Current Teaching and Practice for Impressions for Complete Dentures.

OBJECTIVES: The 3 objectives are to assess current preferences for impressions for complete dentures, audit practice and compare practice to current UK teaching. METHODS: Three surveys where undertaken; a survey of GDPs preferences, an audit of practice and a survey of teaching in UK dental schools. RESULTS: UK Universities advocate border moulded custom trays. In stated preferences, 99% of practitioners used custom trays for private practice; 67% for NHS work. In actual use, the audit found 91% practitioners in private practice used custom trays; in NHS practice 78% did so. The most widely taught materials were silicone (43%), alginate (29%), & zinc oxide eugenol paste (19%). In practitioners stated preferences, 97% of NHS and 53% of private dentists listed alginate as an option; however the audit showed only 74% (NHS) and 52% (private) actually used alginate, with 20% (NHS) and 48% (private) using silicone. CONCLUSIONS: Definitive impressions in custom trays are used by GDPs for both private and NHS work; they are universally taught at UK dental schools. Alginate is popular in NHS practice; however, silicone is more widely taught in UK Universities. The use of silicone materials for definitive impressions has increased since 1999. In UK private practice silicone usage is aligned in popularity with alginate.

A Systematic Review and Meta-Analysis of Baseline Ohip-Edent Scores.

BACKGROUND: OHIP-EDENT is widely used in the literature to assess Oral-Health-Related-Quality-of-Life (OHRQoL) for edentulous patients. However the normal variance and mean of the baseline OHIP scores has not been reported. It would facilitate critical appraisal of studies if we had knowledge of the normal variation and mean of baseline OHIP-EDENT scores. An established figure for baseline OHIP-EDENT, obtained from a meta-analysis, would simplify comparisons of studies and quantify variations in initial OHRQoL of the trial participants. OBJECTIVES: The aim of this study is to quantify a normal baseline value for pre-operative OHIP-EDENT scores by a systematic review and meta-analysis of the available literature. METHODS: A systematic literature review was carried. 83 papers were identified that included OHIP-EDENT values. After screening and eligibility assessment, 7 papers were selected and included in the meta-analysis. RESULTS: A meta-analysis for the 7 papers by a random-effect model yielded a mean baseline OHIP-EDENT score of 28.63 with a 95% Confidence intervals from 21.93 to 35.34. CONCLUSION: A pre-operative baseline OHIP-EDENT has been established by meta-analysis of published papers. This will facilitate the comparison of the initial OHRQoL of one study population to that found elsewhere in the published literature.

Neurexin 1 (NRXN1) splice isoform expression during human neocortical development and aging.

Neurexin 1 (NRXN1), a presynaptic cell adhesion molecule, is implicated in several neurodevelopmental disorders characterized by synaptic dysfunction including autism, intellectual disability and schizophrenia. To gain insight into NRXN1's involvement in human cortical development we used quantitative real-time PCR to examine the expression trajectories of NRXN1, and its predominant isoforms, NRXN1-α and NRXN1-ß, in prefrontal cortex from fetal stages to aging. In addition, we investigated whether prefrontal cortical expression levels of NRXN1 transcripts are altered in schizophrenia or bipolar disorder in comparison with non-psychiatric control subjects. We observed that all three NRXN1 transcripts were highly expressed during human fetal cortical development, markedly increasing with gestational age. In the postnatal dorsolateral prefrontal cortex, expression levels were negatively correlated with age, peaking at birth until ~3 years of age, after which levels declined markedly to be stable across the lifespan. NRXN1-ß expression was modestly but significantly elevated in the brains of patients with schizophrenia compared with non-psychiatric controls, whereas NRXN1-α expression was increased in bipolar disorder. These data provide novel evidence that NRXN1 expression is highest in human dorsolateral prefrontal cortex during critical developmental windows relevant to the onset and diagnosis of a range of neurodevelopmental disorders, and that NRXN1 expression may be differentially altered in neuropsychiatric disorders.

Experimental and Numerical Analysis of Initial Plasticity in P91 Steel Small Punch Creep Samples.

To date, the complex behaviour of small punch creep test (SPCT) specimens has not been completely understood, making the test hard to numerically model and the data difficult to interpret. This paper presents a novel numerical model able to generate results that match the experimental findings. For the first time, pre-strained uniaxial creep test data of a P91 steel at 600 ∘C have been implemented in a conveniently modified Liu and Murakami creep damage model in order to simulate the effects of the initial localised plasticity on the subsequent creep response of a small punch creep test specimen. Finite element (FE) results, in terms of creep displacement rate and time to failure, obtained by the modified Liu and Murakami model are in good agreement with experimental small punch creep test data. The rupture times obtained by the FE calculations which make use of the non-modified creep damage model are one order of magnitude shorter than those obtained by using the modified constitutive model. Although further investigation is needed, this novel approach has confirmed that the effects of initial localised plasticity, taking place in the early stages of small punch creep test, cannot be neglected. The new results, obtained by using the modified constitutive model, show a significant improvement with respect to those obtained by a 'state of the art' creep damage constitutive model (the Liu and Murakami constitutive model) both in terms of minimum load-line displacement rate and time to rupture. The new modelling method will potentially lead to improved capability for SPCT data interpretation.

Removable partial dentures: The clinical need for innovation.

STATEMENT OF PROBLEM: The number of partially dentate adults is increasing, and many patients will require replacement of missing teeth. Although current treatment options also include fixed partial dentures and implants, removable partial dentures (RPDs) can have advantages and are widely used in clinical practice. However, a significant need exists to advance materials and fabrication technologies because of the unwanted health consequences associated with current RPDs. PURPOSE: The purpose of this review was to assess the current state of and future need for prosthetics such as RPDs for patients with partial edentulism, highlight areas of weakness, and outline possible solutions to issues that affect patient satisfaction and the use of RPDs. MATERIAL AND METHODS: The data on treatment for partial edentulism were reviewed and summarized with a focus on currently available and future RPD designs, materials, means of production, and impact on oral health. Data on patient satisfaction and compliance with RPD treatment were also reviewed to assess patient-centered care. RESULTS: Design, materials, ease of repair, patient education, and follow-up for RPD treatment all had a significant impact on treatment success. Almost 40% of patients no longer use their RPD within 5 years because of factors such as sociodemographics, pain, and esthetics. Research on RPD-based treatment for partial edentulism for both disease-oriented and patient-centered outcomes is lacking. CONCLUSIONS: Future trials should evaluate new RPD materials and design technologies and include both long-term follow-up and health-related and patient-reported outcomes. Advances in materials and digital design/production along with patient education promise to further the application of RPDs and improve the quality of life for patients requiring RPDs.

Sex differences in glutamate receptor gene expression in major depression and suicide.

Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F21,59=2.32, P=0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups. These data reveal further evidence that, in addition to the NMDA receptor, the AMPA, kainate and the metabotropic GluRs may be targets for the development of rapidly acting antidepressant drugs.

Revisiting DARPP-32 in postmortem human brain: changes in schizophrenia and bipolar disorder and genetic associations with t-DARPP-32 expression.

Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32 or PPP1R1B) has been of interest in schizophrenia owing to its critical function in integrating dopaminergic and glutaminergic signaling. In a previous study, we identified single-nucleotide polymorphisms (SNPs) and a frequent haplotype associated with cognitive and imaging phenotypes that have been linked with schizophrenia, as well as with expression of prefrontal cortical DARPP-32 messenger RNA (mRNA) in a relatively small sample of postmortem brains. In this study, we examined the association of expression of two major DARPP-32 transcripts, full-length (FL-DARPP-32) and truncated (t-DARPP-32), with genetic variants of DARPP-32 in three brain regions receiving dopaminergic input and implicated in schizophrenia (the dorsolateral prefrontal cortex (DLPFC), hippocampus and caudate) in a much larger set of postmortem samples from patients with schizophrenia, bipolar disorder, major depression and normal controls (>700 subjects). We found that the expression of t-DARPP-32 was increased in the DLPFC of patients with schizophrenia and bipolar disorder, and was strongly associated with genotypes at SNPs (rs879606, rs90974 and rs3764352), as well as the previously identified 7-SNP haplotype related to cognitive functioning. The genetic variants that predicted worse cognitive performance were associated with higher t-DARPP-32 expression. Our results suggest that variation in PPP1R1B affects the abundance of the splice variant t-DARPP-32 mRNA and may reflect potential molecular mechanisms implicated in schizophrenia and affective disorders.

APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms.

The common APOE2 gene variant is neuroprotective against Alzheimer's disease (AD) and reduces risk by nearly 50%. However, the mechanisms by which APOE2 confers neuroprotection are largely unknown. Here we showed that ApoE protein abundance in human postmortem cortex follows an isoform-dependent pattern (E2>E3>E4). We also identified a unique downstream transcriptional profile determined by microarray and characterized by downregulation of long-term potentiation (LTP) related transcripts and upregulation of extracellular matrix (ECM)/integrin-related transcripts in E2 cases and corroborated this finding at the protein level by demonstrating increases in ECM collagens and laminins. In vivo studies of healthy older individuals demonstrated a unique and advantageous biomarker signature in E2 carriers. APOE2 also reduced the risk of mild cognitive impairment to AD conversion by half. Our findings suggest that ApoE2 protein abundance, coupled with its inability to bind to LDLRs, may act to increase amyloid-beta (Ab) clearance. In addition, increased ECM and reduced LTP-related expression results in diminished activity-dependent Ab secretion and/or excitotoxicity, and thus also promotes neuroprotection.

Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia and affective disorders, and associations with SNPs in postmortem brain.

Dopamine 2 receptor (DRD2) is of major interest to the pathophysiology of schizophrenia (SCZ) both as a target for antipsychotic drug action as well as a SCZ-associated risk gene. The dopamine 1 receptor (DRD1) is thought to mediate some of the cognitive deficits in SCZ, including impairment of working memory that relies on normal dorsolateral prefrontal cortex (DLPFC) function. To better understand the association of dopamine receptors with SCZ, we studied the expression of three DRD2 splice variants and the DRD1 transcript in DLPFC, hippocampus and caudate nucleus in a large cohort of subjects (~700), including patients with SCZ, affective disorders and nonpsychiatric controls (from 14th gestational week to 85 years of age), and examined genotype-expression associations of 278 single-nucleotide polymorphisms (SNPs) located in or near DRD2 and DRD1 genes. Expression of D2S mRNA and D2S/D2-long (D2L) ratio were significantly increased in DLPFC of patients with SCZ relative to controls (P<0.0001 and P<0.0001, respectively), whereas D2L, D2Longer and DRD1 were decreased (P<0.0001). Patients with affective disorders showed an opposite pattern: reduced expression of D2S (major depressive disorder, P<0.0001) and increased expression of D2L and DRD1 (bipolar disorder, P<0.0001). Moreover, SCZ-associated risk alleles at rs1079727, rs1076560 and rs2283265 predicted increased D2S/D2L expression ratio (P<0.05) in control individuals. Our data suggest that altered splicing of DRD2 and expression of DRD1 may constitute a pathophysiological mechanism in risk for SCZ and affective disorders. The association between SCZ risk-associated polymorphism and the ratio of D2S/D2L is consistent with this possibility.

Altered gene expression in the dorsolateral prefrontal cortex of individuals with schizophrenia.

The underlying pathology of schizophrenia (SZ) is likely as heterogeneous as its symptomatology. A variety of cortical and subcortical regions, including the prefrontal cortex, have been implicated in its pathology, and a number of genes have been identified as risk factors for disease development. We used in situ hybridization (ISH) to examine the expression of 58 genes in the dorsolateral prefrontal cortex (DLPFC, comprised of Brodmann areas 9 and 46) from 19 individuals with a premorbid diagnosis of SZ and 33 control individuals. Genes were selected based on: (1) previous identification as risk factors for SZ; (2) cell type markers or (3) laminar markers. Cell density and staining intensity were compared in the DLPFC, as well as separately in Brodmann areas 9 and 46. The expression patterns of a variety of genes, many of which are associated with the GABAergic system, were altered in SZ when compared with controls. Additional genes, including C8orf79 and NR4A2, showed alterations in cell density or staining intensity between the groups, highlighting the need for additional studies. Alterations were, with only a few exceptions, limited to Brodmann area 9, suggesting regional specificity of pathology in the DLPFC. Our results agree with previous studies on the GABAergic involvement in SZ, and suggest that areas 9 and 46 may be differentially affected in the disease. This study also highlights additional genes that may be altered in SZ, and indicates that these potentially interesting genes can be identified by ISH and high-throughput image analysis techniques.

Dentures for Randomised Controlled Trials.

Making complete dentures for dental research is difficult. The difficulty is not in the construction of dentures, but making sure the clinician is blind to the randomizations, and avoiding confounding variables. For research purposes it is essential that two sets of dentures are similar in every way, apart from the area to be investigated. A previous article showed how to duplicate a lower denture when it was articulated against a single upper denture. This paper describes the additional duplication of upper dentures. These additional problems presented the clinical and technical teams at the Leeds Dental Institute some challenges.

A Randomised Controlled Study Comparing the Anterior Mandibular Labio-Lingual Neutral Zone Position in Edentulous Subjects With and Without Their Maxillary Denture In-Situ.

Opinion is divided as to whether the neutral zone impression to determine the labio-lingual position of mandibular complete dentures requires the maxillary denture to remain in-situ or not. Two such neutral zone impressions were recorded for each of the 12 participants of this randomised controlled study. The presence of the maxillary denture made no statistically significant mean difference in labio-lingual position of the mandibular neutralzone. Within the confines of this research protocol there was no evidence that the shift in the labio-linguial position of the anterior mandibular neutral zone was consistently affected by the presence of a maxillary appliance.

A Randomised Controlled Trial of Postoperative Sensitivity after Class II Restoration with Bulk-Fill vs Conventional Composites.

INTRODUCTION: Bulk-fill composites may simplify posterior restorations, saving time and reducing technical complexity. Post-operative sensitivity is a risk of posterior composites; bulk-fill composites could mitigate this. This single centre, double-blinded, parallel groups randomised controlled trial compared postoperative sensitivity following restoration of class II carious lesions with bulk-fill or conventional, layered composite. NULL HYPOTHESIS: there will be no difference in post-operative sensitivity between the two materials. METHODS: Participants requiring class II restoration of posterior teeth were randomised to bulk-fill (FU) (Coltene Fill-UpTM) or conventional, layered (BE) (Coltene Brilliant Everglow) composite. Allocation was concealed during cavity preparation. Only the operating dentist knew allocation. The outcome was 24 h post-operative sensitivity. RESULTS: 41 patients were randomised (20/group). Two patients from FU group were excluded from analysis (factors unrelated to intervention). There was no difference in postoperative sensitivity at 24 h nor any time point. Only participant age and baseline sensitivity scores significantly impacted post-operative sensitivity. One restoration debonded in FU group at 10 days, with no other adverse effects. No difference in time taken to place restorations was seen. CONCLUSIONS: Within the study's limitations, post-operative sensitivity after class II posterior restorations was no different in bulk-fill restorations compared with conventional, incrementally cured composite.

Current challenges for 3D printing complete dentures: experiences from a multi-centre clinical trial.

Aims To develop an optimal clinical and laboratory protocol for the fabrication of 3D printing dentures.Design A prospective feasibility study across three UK dental schools.Material and methods Each patient received one conventional and one 3D-printed denture. Both dentures were constructed using the same impression, jaw registration and wax trial denture. Variables investigated included methods of digitisation of the impression and optional use of a 3D-printed baseplate for jaw registration.Results Clinicians strongly preferred 3D-printed baseplates. Patients felt that conventional and printed dentures were similar in retention and stability. More patients favoured conventional dentures over 3D-printed dentures in terms of comfort.Discussion It is feasible to combine conventional clinical work with digital techniques to produce 3D-printed dentures. 3D-printed baseplates offer a cost-effective alternative to conventional bases at the jaw registration stage. Challenges were faced in tooth positioning and managing occlusion, particularly where roots required adjustment.Conclusion 3D printing is suitable for producing baseplates for jaw registration blocks and wax trial insertions. It is feasible to produce 3D-printed dentures using conventional clinical techniques for impressions, jaw registration and wax trial insertion. The workflow used in this study for 3D-printed dentures is not superior to conventional dentures. Further work is required.

Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer's disease as based on APOE genotype.

Alzheimer's disease (AD) is a neurodegenerative condition characterized histopathologically by neuritic plaques and neurofibrillary tangles. The objective of this transcriptional profiling study was to identify both neurosusceptibility and intrinsic neuroprotective factors at the molecular level, not confounded by the downstream consequences of pathology. We thus studied post-mortem cortical tissue in 28 cases that were non-APOE4 carriers (called the APOE3 group) and 13 cases that were APOE4 carriers. As APOE genotype is the major genetic risk factor for late-onset AD, the former group was at low risk for development of the disease and the latter group was at high risk for the disease. Mean age at death was 42 years and none of the brains had histopathology diagnostic of AD at the time of death. We first derived interregional difference scores in expression between cortical tissue from a region relatively invulnerable to AD (primary somatosensory cortex, BA 1/2/3) and an area known to be susceptible to AD pathology (middle temporal gyrus, BA 21). We then contrasted the magnitude of these interregional differences in between-group comparisons of the APOE3 (low risk) and APOE4 (high risk) genotype groups. We identified 70 transcripts that differed significantly between the groups. These included EGFR, CNTFR, CASP6, GRIA2, CTNNB1, FKBPL, LGALS1 and PSMC5. Using real-time quantitative PCR, we validated these findings. In addition, we found regional differences in the expression of APOE itself. We also identified multiple Kyoto pathways that were disrupted in the APOE4 group, including those involved in mitochondrial function, calcium regulation and cell-cycle reentry. To determine the functional significance of our transcriptional findings, we used bioinformatics pathway analyses to demonstrate that the molecules listed above comprised a network of connections with each other, APOE, and APP and MAPT. Overall, our results indicated that the abnormalities that we observed in single transcripts and in signaling pathways were not the consequences of diagnostic plaque and tangle pathology, but preceded it and thus may be a causative link in the long molecular prodrome that results in clinical AD.