A precision medicine initiative for Alzheimer's disease: the road ahead to biomarker-guided integrative disease modeling

After intense scientific exploration and more than a decade of failed trials, Alzheimer’s disease (AD) remains a fatal global epidemic. A traditional research and drug development paradigm continues to target heterogeneous late-stage clinically phenotyped patients with single 'magic bullet' drugs. Here, we propose that it is time for a paradigm shift towards the implementation of precision medicine (PM) for enhanced risk screening, detection, treatment, and prevention of AD. The overarching structure of how PM for AD can be achieved will be provided through the convergence of breakthrough technological advances, including big data science, systems biology, genomic sequencing, blood-based biomarkers, integrated disease modeling and P4 medicine. It is hypothesized that deconstructing AD into multiple genetic and biological subsets existing within this heterogeneous target population will provide an effective PM strategy for treating individual patients with the specific agent(s) that are likely to work best based on the specific individual biological make-up. The Alzheimer’s Precision Medicine Initiative (APMI) is an international collaboration of leading interdisciplinary clinicians and scientists devoted towards the implementation of PM in Neurology, Psychiatry and Neuroscience. It is hypothesized that successful realization of PM in AD and other neurodegenerative diseases will result in breakthrough therapies, such as in oncology, with optimized safety profiles, better responder rates and treatment responses, particularly through biomarker-guided early preclinical disease-stage clinical trials

Resonant tunnelling features in the transport spectroscopy of quantum dots

We present a review of features due to resonant tunnelling in transport spectroscopy experiments on quantum dots and single donors. The review covers features attributable to intrinsic properties of the dot as well as extrinsic effects, with a focus on the most common operating conditions. We describe several phenomena that can lead to apparently identical signatures in a bias spectroscopy measurement, with the aim of providing experimental methods to distinguish between their different physical origins. The correct classification of the resonant tunnelling features is an essential requirement to understand the details of the confining potential or predict the performance of the dot for quantum information processing.Comment: 18 pages, 7 figures. Short review article submitted to Nanotechnology, special issue on 'Quantum Science and Technology at the Nanoscale

Relationship between 233 colorectal cancer risk loci and survival in 1926 patients with advanced disease

Background: Genome, transcriptome and methylome-wide association studies have identified single-nucleotide polymorphisms (SNPs) or genes at 258 loci associated with colorectal cancer (CRC) risk. We studied the relationship between these and patient outcome. // Methods: We studied 1926 unrelated patients with advanced CRC from COIN and COIN-B. Of 205 CRC-risk SNPs, 19 were directly genotyped and 162 were imputed, and of 53 risk genes, 52 were tested. An additive Cox model for overall survival was adjusted for known prognostic factors. For nominally significant SNPs or genes, we considered a recessive model with a Bonferroni corrected threshold of P = 2.1 × 10−4. We examined SNPs as expression quantitative trait loci (eQTL) and the relationship between gene expression in colorectal tumours and survival in 597 unrelated patients. // Results: Eleven SNPs or genes were nominally associated with survival under an additive model. Only rs117079142 mapping to UTP23 and EIF3H (Hazard Ratio [HR] = 2.79, 95% Confidence Intervals [CI] = 1.70–4.58, P = 4.7 × 10−5) and rs9924886 mapping to CDH1 and CDH3 (HR = 1.24, 95% CI = 1.12–1.38, P = 5.2 × 10−5) passed the multiple testing threshold under a recessive model. rs117079142 was an eQTL for UTP23 and rs9924886 for CDH1, CDH3 and ZFP90. Decreased CDH1 expression in CRCs was associated with worse survival (HR = 2.18, 95% CI = 1.3–3.5, P = 1.8 × 10−3). // Conclusion: rs117079142 and rs9924886 may represent potential prognostic biomarkers for CRC

Proton pump inhibitors and dementia risk: Evidence from a cohort study using linked routinely collected national health data in Wales, UK

Objectives: Proton pump inhibitors (PPIs) are commonly prescribed for prevention and treatment of gastrointestinal conditions or for gastroprotection from other drugs. Research suggests they are linked to increased dementia risk. We use linked national health data to examine the association between PPI use and the development of incident dementia. Methods and findings: A population-based study using electronic health-data from the Secure Anonymised Information Linkage (SAIL) Databank, Wales (UK) from 1999 to 2015. Of data available on 3,765,744 individuals, a cohort who had ever been prescribed a PPI was developed (n=183,968) for people aged 55 years and over and compared to non-PPI exposed individuals (131,110). Those with prior dementia, mild-cognitive-impairment or delirium codes were excluded. Confounding factors included comorbidities and/or drugs associated with them. Comorbidities might include head injury and some examples of medications include antidepressants, antiplatelets and anticoagulants. These commonly prescribed drugs were investigated as it was not feasible to explore all drugs in this study. The main outcome was a diagnosis of incident dementia. Cox proportional hazard regression modelling was used to calculate the Hazard ratio (HR) of developing dementia in PPI-exposed compared to unexposed individuals while controlling for potential confounders. The mean age of the PPI exposed individuals was 69.9 years and 39.8% male while the mean age of the unexposed individuals was 72.1 years and 41.1% male. The rate of PPI usage was 58.4% (183,968) and incident dementia rate was 11.8% (37,148/315,078). PPI use was associated with decreased dementia risk (HR: 0.67, 95% CI: 0.65 to 0.67, p<0.01). Conclusions: This study, using large-scale, multi-centre health-data was unable to confirm an association between PPI use and increased dementia risk. Previously reported links may be associated with confounders of people using PPI’s, such as increased risk of cardiovascular disease and/or depression and their associated medications which may be responsible for any increased risk of developing dementia

Coherent Electron-Phonon Coupling in Tailored Quantum Systems

The coupling between a two-level system and its environment leads to decoherence. Within the context of coherent manipulation of electronic or quasiparticle states in nanostructures, it is crucial to understand the sources of decoherence. Here, we study the effect of electron-phonon coupling in a graphene and an InAs nanowire double quantum dot. Our measurements reveal oscillations of the double quantum dot current periodic in energy detuning between the two levels. These periodic peaks are more pronounced in the nanowire than in graphene, and disappear when the temperature is increased. We attribute the oscillations to an interference effect between two alternative inelastic decay paths involving acoustic phonons present in these materials. This interpretation predicts the oscillations to wash out when temperature is increased, as observed experimentally.Comment: 11 pages, 4 figure

Path integral simulation of exchange interactions in CMOS spin qubits

The boom of semiconductor quantum computing platforms created a demand for computer-aided design and fabrication of quantum devices. Path integral Monte Carlo (PIMC) can have an important role in this effort because it intrinsically integrates strong quantum correlations that often appear in these multi-electron systems. In this paper we present a PIMC algorithm that estimates exchange interactions of three-dimensional electrically defined quantum dots. We apply this model to silicon metal-oxide-semiconductor (MOS) devices and we benchmark our method against well-tested full configuration interaction (FCI) simulations. As an application, we study the impact of a single charge trap on two exchanging dots, opening the possibility of using this code to test the tolerance to disorder of CMOS devices. This algorithm provides an accurate description of this system, setting up an initial step to integrate PIMC algorithms into development of semiconductor quantum computers.Comment: 10 pages , 5 figure