Nicholas J. Ashton

Plasma proteins predict conversion to dementia from prodromal disease

The study aimed to validate previously discovered plasma biomarkers associated with AD, using a design based on imaging measures as surrogate for disease severity and assess their prognostic value in predicting conversion to dementia.

Blood protein predictors of brain amyloid for enrichment in clinical trials

Measures of neocortical amyloid burden (NAB) identify individuals who are at substantially greater risk of developing Alzheimers disease (AD). Blood‐based biomarkers predicting NAB would have great utility for the enrichment of AD clinical trials, including large‐scale prevention trials.

Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly

Increasingly, clinical trials for Alzheimers disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p <  0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q <  0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature.

Plasma protein biomarkers of Alzheimer’s disease endophenotypes in asymptomatic older twins: early cognitive decline and regional brain volumes

There is great interest in blood-based markers of Alzheimer’s disease (AD), especially in its pre-symptomatic stages. Therefore, we aimed to identify plasma proteins whose levels associate with potential markers of pre-symptomatic AD. We also aimed to characterise confounding by genetics and the effect of genetics on blood proteins in general. Panel-based proteomics was performed using SOMAscan on plasma samples from TwinsUK subjects who are asymptomatic for AD, measuring the level of 1129 proteins. Protein levels were compared with 10-year change in CANTAB-paired associates learning (PAL; n=195), and regional brain volumes (n=34). Replication of proteins associated with regional brain volumes was performed in 254 individuals from the AddNeuroMed cohort. Across all the proteins measured, genetic factors were found to explain ~26% of the variability in blood protein levels on average. The plasma level of the mitogen-activated protein kinase (MAPK) MAPKAPK5 protein was found to positively associate with the 10-year change in CANTAB-PAL in both the individual and twin difference context. The plasma level of protein MAP2K4 was found to suggestively associate negatively (Q<0.1) with the volume of the left entorhinal cortex. Future studies will be needed to assess the specificity of MAPKAPK5 and MAP2K4 to eventual conversion to AD.

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.

Finding a pathological diagnosis for Alzheimer's disease: Are inflammatory molecules the answer?

Conventional diagnostic tools for Alzheimers disease (AD) are currently based on a number of clinical criteria, and a definitive diagnosis still relies on pathological evaluation at autopsy. Moreover, neurodegenerative changes are believed to begin years before clinical presentation. There is therefore an essential need for a reliable AD biomarker to aid in the identification of preclinical disease, early diagnosis, prediction of disease progression and treatment response. There is mounting evidence that chronic inflammatory processes play a fundamental role in the progression of neuropathological changes in AD. Clinical and experimental evidence supports the involvement of inflammatory changes in the early stages of AD, even before the appearance of amyloid deposits. Therefore biomarkers that reflect the inflammatory process in AD hold promise. Tests based on these should preferably be reliable, noninvasive and costeffective, which has led to an increasing focus on the use of blood‐based biomarkers. This review considers the current progress in AD inflammatory biomarker research followed by a detailed analysis of two leading putative inflammatory biomarkers: α‐2‐macroglobulin and clusterin.

Plasma REST: a novel candidate biomarker of Alzheimer’s disease is modified by psychological intervention in an at-risk population

The repressor element 1-silencing transcription (REST) factor is a key regulator of the aging brain’s stress response. It is reduced in conditions of stress and Alzheimer’s disease (AD), which suggests that increasing REST may be neuroprotective. REST can be measured peripherally in blood plasma. Our study aimed to (1) examine plasma REST levels in relation to clinical and biological markers of neurodegeneration and (2) alter plasma REST levels through a stress-reduction intervention—mindfulness training. In study 1, REST levels were compared across the following four well-characterized groups: healthy elderly (n=65), mild cognitive impairment who remained stable (stable MCI, n=36), MCI who later converted to dementia (converter MCI, n=29) and AD (n=65) from the AddNeuroMed cohort. REST levels declined with increasing severity of risk and impairment (healthy elderly>stable MCI>converter MCI>AD, F=6.35, P<0.001). REST levels were also positively associated with magnetic resonance imaging-based hippocampal and entorhinal atrophy and other putative blood-based biomarkers of AD (Ps<0.05). In study 2, REST was measured in 81 older adults with psychiatric risk factors for AD before and after a mindfulness-based stress reduction intervention or an education-based placebo intervention. Mindfulness-based training caused an increase in REST compared with the placebo intervention (F=8.57, P=0.006), and increased REST was associated with a reduction in psychiatric symptoms associated with stress and AD risk (Ps<0.02). Our data confirm plasma REST associations with clinical severity and neurodegeneration, and originally, that REST is modifiable by a psychological intervention with clinical benefit.

Investigation of REST protein in healthy elderly and Alzheimer's disease using a blood-based approach

P3-086 INVESTIGATIONOF REST PROTEIN IN HEALTHY ELDERLYAND ALZHEIMER’S DISEASE USING A BLOOD-BASED APPROACH Natalie L. Marchant, Nicholas J. Ashton, Abdul Hye, Simon Lovestone, IOPPN, King’s College London, London, United Kingdom; NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, United Kingdom; King’s College London, London, United Kingdom; University of Oxford, Oxford, United Kingdom. Contact e-mail: natalie.marchant@kcl.ac.uk

Update on biomarkers for amyloid pathology in Alzheimer's disease

At the center of Alzheimers disease pathogenesis is the aberrant aggregation of amyloid-β (Aβ) into oligomers, fibrils and plaques. Effective monitoring of Aβ deposition directly in patients is essential to assist anti-Aβ therapeutics in target engagement and participant selection. In the advent of approved anti-Aβ therapeutics, biomarkers will become of fundamental importance in initiating treatments having disease modifying effects at the earliest stage. Two well-established Aβ biomarkers are widely utilized: Aβ-binding ligands for positron emission tomography and immunoassays to measure Aβ42 in cerebrospinal fluid. In this review, we will discuss the current clinical, diagnostic and research state of biomarkers for Aβ pathology. Furthermore, we will explore the current application of blood-based markers to assess Aβ pathology.

PLASMA PRIMARY FATTY AMIDES ASSOCIATE TO CSF AMYLOID LEVELS AND ALZHEIMER’S DISEASE PROGRESSION IN THE EMIF-AD BIOMARKER DISCOVERY COHORT

with albumin ratio (r1⁄40.28, p1⁄40.006). We observed no independent effects, but a synergistic effect of IL-6 and albumin ratio on Aß (Z1⁄4-2.72, p1⁄40.006). The JN-analyses showed that the association between albumin ratio and Aßwas significant for IL-6 levels 3.48 pg/ml. We found no direct relation between the albumin ratio and p-Tau levels (p1⁄40.91), but mediation analyses indicated that the mediation of Aß,on the association between BBB dysfuction and p-Tau, was contingent on elevated IL-6 levels (indirect effect for IL-6: mean-1s (b1⁄40.026, Z1⁄40.075, p1⁄40.94), mean (b1⁄41.16, Z1⁄41.64, p1⁄40.09), mean+1s (b1⁄43.51, Z1⁄40.197, p1⁄40.049)). There is a negative relationship between Aß and pTau (p<0.001). Conclusions: The results suggest a link between BBB-dysfunction and markers of neurodegeneration via Aßmediated mechanisms in the presence of elevated IL-6 levels, indicating that inflammation and BBB-dysfunction, in addition to Aß are important components in the path to neurodegeneration. These results fit with autopsy studies reporting a common cooccurrence of Aß and vascular pathology in AD-type dementia.