Nicola Voyle

Circulating Proteomic Signatures of Chronological Age

To elucidate the proteomic features of aging in plasma, the subproteome targeted by the SOMAscan assay was profiled in blood samples from 202 females from the TwinsUK cohort. Findings were replicated in 677 independent individuals from the AddNeuroMed, Alzheimer’s Research UK, and Dementia Case Registry cohorts. Results were further validated using RNAseq data from whole blood in TwinsUK and the most significant proteins were tested for association with aging-related phenotypes after adjustment for age. Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 (meta-analysis β [SE] = 0.013 [0.001], p = 3.66 × 10−46) and pleiotrophin (0.012 [0.005], p = 3.88 × 10−41). Chordin-like protein 1 was also significantly correlated with birthweight (0.06 [0.02], p = 0.005) and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK (0.71 [0.18], p = 9.9 × 10−5). Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and aging.

Blood Protein Markers of Neocortical Amyloid-β Burden: A Candidate Study Using SOMAscan Technology.

Abstract Background: Four previously reported studies have tested for association of blood proteins with neocortical amyloid-β burden (NAB). If shown to be robust, these proteins could have utility as a blood test for enrichment in clinical trials of Alzheimer’s disease (AD) therapeutics. Objective: This study aimed to investigate whether previously identified blood proteins also show evidence for association with NAB in serum samples from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL). The study considers candidate proteins seen in cohorts other than AIBL and candidates previously discovered in the AIBL cohort. Methods: Our study used the SOMAscan platform for protein quantification in blood serum. Linear and logistic regressions were used to model continuous NAB and dichotomized NAB respectively using single proteins as a predictor. Multiple protein models were built using stepwise regression techniques and support vectors machines. Age and APOE ɛ4 carriage were used as covariates for all analysis. Results: Of the 41 proteins previously reported, 15 AIBL candidates and 20 non-AIBL candidates were available for testing. Of these candidates, pancreatic polypeptide (PPY) and IgM showed a significant association with NAB. Notably, IgM was found to associate with continuous NAB across cognitively normal control subjects. Conclusions: We have further demonstrated the association of PPY and IgM with NAB, despite technical differences between studies. There are several reasons for a lack of significance for the other candidates including platform differences and the use of serum rather than plasma samples. To investigate the possibility of technical differences causing lack of replication, further studies are required.

Blood metabolite markers of neocortical amyloid-β burden: discovery and enrichment using candidate proteins.

We believe this is the first study to investigate associations between blood metabolites and neocortical amyloid burden (NAB) in the search for a blood-based biomarker for Alzheimers disease (AD). Further, we present the first multi-modal analysis of blood markers in this field. We used blood plasma samples from 91 subjects enrolled in the University of California, San Francisco Alzheimers Disease Research Centre. Non-targeted metabolomic analysis was used to look for associations with NAB using both single and multiple metabolic feature models. Five metabolic features identified subjects with high NAB, with 72% accuracy. We were able to putatively identify four metabolites from this panel and improve the model further by adding fibrinogen gamma chain protein measures (accuracy=79%). One of the five metabolic features was studied in the Alzheimers Disease Neuroimaging Initiative cohort, but results were inconclusive. If replicated in larger, independent studies, these metabolic features and proteins could form the basis of a blood test with potential for enrichment of amyloid pathology in anti-amyloid trials.

A pathway based classification method for analyzing gene expression for Alzheimer's disease diagnosis

Background: Recent studies indicate that gene expression levels in blood may be able to differentiate subjects with Alzheimer’s disease (AD) from normal elderly controls and mild cognitively impaired (MCI) subjects. However, there is limited replicability at the single marker level. A pathway-based interpretation of gene expression may prove more robust. Objectives: This study aimed to investigate whether a case/control classification model built on pathway level data was more robust than a gene level model and may consequently perform better in test data. The study used two batches of gene expression data from the AddNeuroMed (ANM) and Dementia Case Registry (DCR) cohorts. Methods: Our study used Illumina Human HT-12 Expression BeadChips to collect gene expression from blood samples. Random forest modeling with recursive feature elimination was used to predict case/control status. Age and APOE ɛ4 status were used as covariates for all analysis. Results: Gene and pathway level models performed similarly to each other and to a model based on demographic information only. Conclusions: Any potential increase in concordance from the novel pathway level approach used here has not lead to a greater predictive ability in these datasets. However, we have only tested one method for creating pathway level scores. Further, we have been able to benchmark pathways against genes in datasets that had been extensively harmonized. Further work should focus on the use of alternative methods for creating pathway level scores, in particular those that incorporate pathway topology, and the use of an endophenotype based approach.

Genetic meta-analysis identifies 10 novel loci and functional pathways for Alzheimer's disease risk

Late onset Alzheimer’s disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.

Genetic Risk as a Marker of Amyloid-β and Tau Burden in Cerebrospinal Fluid

Background: The search for a biomarker of Alzheimer’s disease (AD) pathology (amyloid-β (Aβ) and tau) is ongoing, with the best markers currently being measurements of Aβ and tau in cerebrospinal fluid (CSF) and via positron emission tomography (PET) scanning. These methods are relatively invasive, costly, and often have high screening failure rates. Consequently, research is aiming to elucidate blood biomarkers of Aβ and tau. Objective: This study aims to investigate a case/control polygenic risk score (PGRS) as a marker of tau and investigate blood markers of a combined Aβ and tau outcome for the first time. A sub-study also considers plasma tau as markers of Aβ and tau pathology in CSF. Methods: We used data from the EDAR*, DESCRIPA**, and Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts in a logistic regression analysis to investigate blood markers of Aβ and tau in CSF. In particular, we investigated the extent to which a case/control PGRS is predictive of CSF tau, CSF amyloid, and a combined amyloid and tau outcome. The predictive ability of models was compared to that of age, gender, and APOE genotype (‘basic model’). Results: In EDAR and DESCRIPA test data, inclusion of a case/control PGRS was no more predictive of Aβ, and a combined Aβ and tau endpoint than the basic models (accuracies of 66.0%, and 73.3% respectively). The tau model saw a small increase in accuracy compared to basic models (59.6%). ADNI 2 test data also showed a slight increase in accuracy for the Aβ model when compared to the basic models (61.4%). Conclusion: We see some evidence that a case/control PGRS is marginally more predictive of Aβ and tau pathology than the basic models. The search for predictive factors of Aβ and tau pathologies, above and beyond demographic information, is still ongoing. Better understanding of AD risk alleles, development of more sensitive assays, and studies of larger sample size are three avenues that may provide such factors. However, the clinical utility of possible predictors of brain Aβ and tau pathologies must also be investigated. *‘Beta amyloid oligomers in the early diagnosis of AD and as marker for treatment response’ **‘Development of screening guidelines and criteria for pre-dementia Alzheimer’s disease’

A Blood Test for Alzheimer’s Disease: Progress, Challenges, and Recommendations

Ever since the discovery of APOEɛ4 around 25 years ago, researchers have been excited about the potential of a blood test for Alzheimers disease (AD). Since then researchers have looked for genetic, protein, metabolite, and/or gene expression markers of AD and related phenotypes. However, no blood test for AD is yet being used in the clinical setting. We first review the trends and challenges in AD blood biomarker research, before giving our personal recommendations to help researchers overcome these challenges. While some degree of consistency and replication has been seen across independent studies, several high-profile studies have seemingly failed to replicate. Partly due to academic incentives, there is a reluctance in the field to report predictive ability, to publish negative findings, and to independently replicate the work of others. If this can be addressed, then we will know sooner whether a blood test for AD or related phenotypes with clinical utility can be developed.

24-MONTH AMYLOID PET RESULTS OF THE GANTENERUMAB HIGH-DOSE OPEN LABEL EXTENSION STUDIES

doses of LY3002813 resulted in significant reductions in florbetapir F18 tracer uptake on PET by 3 months, with further reduction with repeat dosing over time. For the initial dosing cohorts, reductions in florbetapir F18 at 3 months were -11.8 (SD 21.1) centiloids after a single dose of 10 mg/kg IV (n1⁄47); -39.0 (SD 18.1) centiloids after a single dose of 20mg/kg IV (n1⁄47); and -44.5 (SD 24.3) centiloids for 10mg/kg IVadministered every two weeks (n1⁄410). In patients with up to 72 weeks of follow-up after completion of treatment, the reduced post-treatment florbetapir F18 PET SUVr levels were maintained, without returning to pre-dose baseline levels. Conclusions: LY3002813 demonstrates significant, rapid and sustained reduction in cortical amyloid plaque in Alzheimer’s patients.

UPDATE ON THE SAFETY AND TOLERABILITY OF GANTENERUMAB IN THE ONGOING OPEN-LABEL EXTENSION (OLE) OF THE MARGUERITE ROAD STUDY IN PATIENTS WITH MILD ALZHEIMER’S DISEASE (AD) AFTER APPROXIMATELY TWO YEARS OF STUDY DURATION

dosing, patients were analyzed in three groups: the MRDB placebo cohort (MR-Pbo), theMRDB cohort pretreated with gantenerumab (MR-Gant) and a SR DB cohort combining patients originally assigned to placebo or gantenerumab (SR). Change from baseline OLE in amyloid burden was assessed via global and regional standard uptake value ratio (SUVR) analysis of florbetapir PET at months 12 and 24. Results: Preliminary analysis of 40 patients (MR-Pbo, 14; MR-Gant, 17; SR, 9) showed mean (SD) 12-month changes in absolute SUVR units of -0.24 (0.21), -0.27 (0.14), and -0.13 (0.16) in the MR-Pbo, MR-Gant, and SR groups, respectively. Reductions in amyloid burden and percent of patients below the amyloid positivity threshold using an updated data cut (May 30, 2018) will be reported. Approximately 37 patients (MR-Pbo 12; MR-Gant 12; SR 13) will have their OLE 24 month PET scan for this analysis, not accounting for patient drop-out. Conclusions:Updated findings are expected to confirm preliminary results and show continued reduction in amyloid burden with ongoing treatment up to 24 months. This work supports our planned Phase 3 program using high doses of gantenerumab. 1. Klein, CTAD 2017.

UPDATE ON THE SAFETY AND TOLERABILITY OF GANTENERUMAB IN THE ONGOING OPEN-LABEL EXTENSION OF THE SCARLET ROAD STUDY IN PATIENTS WITH PRODROMAL ALZHEIMER'S DISEASE AFTER APPROXIMATELY 2 YEARS OF STUDY DURATION

dosing, patients were analyzed in three groups: the MRDB placebo cohort (MR-Pbo), theMRDB cohort pretreated with gantenerumab (MR-Gant) and a SR DB cohort combining patients originally assigned to placebo or gantenerumab (SR). Change from baseline OLE in amyloid burden was assessed via global and regional standard uptake value ratio (SUVR) analysis of florbetapir PET at months 12 and 24. Results: Preliminary analysis of 40 patients (MR-Pbo, 14; MR-Gant, 17; SR, 9) showed mean (SD) 12-month changes in absolute SUVR units of -0.24 (0.21), -0.27 (0.14), and -0.13 (0.16) in the MR-Pbo, MR-Gant, and SR groups, respectively. Reductions in amyloid burden and percent of patients below the amyloid positivity threshold using an updated data cut (May 30, 2018) will be reported. Approximately 37 patients (MR-Pbo 12; MR-Gant 12; SR 13) will have their OLE 24 month PET scan for this analysis, not accounting for patient drop-out. Conclusions:Updated findings are expected to confirm preliminary results and show continued reduction in amyloid burden with ongoing treatment up to 24 months. This work supports our planned Phase 3 program using high doses of gantenerumab. 1. Klein, CTAD 2017.