The mechanisms and consequences of plaque removal following Abeta immunotherapy in human Alzheimer's disease

Lead Research Organisation: University of Southampton
Department Name: Unlisted

Abstract

Alzheimer’s disease (AD) is the commonest cause of dementia in old age. In AD a protein known as amyloid-beta (A?) accumulates in the brain regions critical for learning and memory.
Recently in animal studies immunization with A? has been shown to result in removal of A? from the brain associated with improvement in brain function. Some preliminary results of the initial human clinical trials suggested a slower cognitive deterioration in patients with an appropriate immune response.
The precise mechanism by which the activated immune system removes Ab is as yet unclear. Furthermore, some patients developed cerebral inflammatory complications, halting the clinical trials. Access to post mortem brain tissue from patients participating in the clinical trial of Ab immunotherapy puts us in a unique position to address important questions. We aim to clarify: (i) the mechanism(s) of Ab plaque removal (ii) if plaque removal can take place without the unwanted side effects of severe cerebral inflammation and (iii) the consequences of Ab removal on the other features of AD pathology.
This information is important in order to inform the second generation of trials of Ab immunotherapy which are already underway.

Technical Summary

Immunization with amyloid beta-peptide (Abeta) has been proposed as a novel treatment for Alzheimer‘s disease (AD). Experimental models and human clinical trials have shown that Abeta accumulation in the brain, a key feature of the disease, can be reversed by immunotherapy. However, the precise mechanism by which the activated immune system removes Abeta and the consequences this has on the brain are as yet unclear. Furthermore, some patients developed meningoencephalitis, halting the clinical trials. Access to post mortem brain tissue from patients in the first trial of Abeta immunotherapy puts me in a unique position to address important questions. I aim to clarify: (i) the mechanism of plaque removal (ii) whether plaque removal can take place without a severe and unacceptable meningoencephalitis and (iii) the consequences of Abeta removal on other features of AD pathology such as tau pathology, synaptic loss and cerebral amyloid angiopathy. Post-mortem brain tissues from 5 immunized patients are already available with their clinical data. Twenty additional immunized patients have given ante-mortem consent to post-mortem neuropathological examinations and 20 unimmunized AD controls from the Neuropathology archive, Southampton General Hospital, will be used as controls. The specific questions will be addressed using immunohistological techniques with sections of frontal and temporal lobes (usually severely affected in unimmunized AD). The midbrain will also be included in this study as a region relatively unaffected by Abeta pathology to assess whether the cerebral inflammation is localised to the vicinity of plaque-containing areas or whether it is a global event throughout the brain. In addition, within the immunized cases, areas devoid of plaques will be compared with areas containing residual plaques. All immunostaining will be assessed by computerized image analysis and multilabel confocal microscopy when appropriate. This information from the first human trl is important in order to inform the second generation of trials of Abeta immunotherapy in AD which are currently being planned or are already underway.

Publications

10 25 50
 
Description Advise on Federal Drug Administration
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
Impact A taskforce convened to advise the Federal Drug Administration on the design of early (pre-dementia) Alzheimer's disease studies, citesour research as evidence as to why it is necessary to start therapies before the onset of clinical dementia in order for it to have any positive effect. Report of the task force on designing clinical trials in early (predementia) AD.
 
Description Forbes
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Financial analysis states that the huge financial losses by pharmaceutical companies in these failed trials could have been prevented if they had not ignored our findings (Sadeghi-Nejad N. The lessons of failure: what we can learn from Bapineuzumab's blow up. Forbes magazine 8/7/12)
 
Description Lancet paper
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
 
Description MRC Department of Health
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact Shaping Research policy on Dementia Research Strategy accross the UK
 
Description Meeting with the Prime Minister
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
Impact Southampton's research programme has contributed to increasing UK government awareness about the importance of funding further research into Alzheimer's. The charity Alzheimer's Research Trust organised for the Southampton team to present their findings in the House of Lords, and at a face-to-face meeting with the then-Prime Minister Gordon Brown at 10 Downing Street in 2008. Both events were followed a year later by a ministerial summit on dementia on November 15, 2009 at which Prof Holmes chaired round table discussions. This meeting led to the formation of the ministerial advisory group on dementia research. Subsequently, in March 2012, Prime Minister David Cameron announced a doubling of funding for Alzheimer's disease to £66 million by 2015 and early detection screening.
 
Description Practitioners
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Inform general practitioners on advance in new treatments for Alzheimer's disease
 
Description Recommendations from the US Alzheimer's Association to the NIH
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact The pathological "side effects" we have identified are relevant to current immunotherapy trials, indicating that at least in a proportion of patients removing amyloid from the brain has complications mainly related to changes in the cerebral vasculature (increased cerebral amyloid angiopathy) that need to be surmounted. Our advisory roles to the pharmaceutical industry have led to the inclusion of methods to monitor and interpret effects and side effects encountered in the current clinical trials.This led directly to a policy change by the US Food and Drug Administration in 2012 to implement advisory measures for the safe monitoring of patients receiving immunotherapy treatments for Alzheimer's (1). These recommendations include: reducing the dose of amyloid-modifying drugs in clinical participants who develop amyloid-related imaging abnormalities (ARIA), increasing the monitoring of study participants in Phase I and early Phase II studies to gain further knowledge about the mechanisms underlying micro haemorrhages, and updating reporting standards for MRIs used to evaluate and monitor for ARIA. (1) USA Alzheimer's Association. Key Alzheimer drug development stakeholders join forces to establish clinical trial safeguards and accelerate discovery. http://www.alz.org/documents_custom/final_aria_news_release_071211_alz-dem_jrnl.pdf. Jul 2011.
 
Description ART Major Research Grant
Amount £67,310 (GBP)
Funding ID ART-PG2006-4 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2006 
End 08/2010
 
Description ART extension grant
Amount £49,996 (GBP)
Funding ID ART/PG2006/4 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2010 
End 09/2011
 
Description ARUK major grant
Amount £316,261 (GBP)
Funding ID ARUK-PG2012-8 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 12/2016
 
Description ARUK scholarship
Amount £86,034 (GBP)
Funding ID ART-PhD2011-22 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2012 
End 04/2015
 
Description FP7 people 2013 Marie Curie Intra European Fellowship
Amount € 221,606 (EUR)
Funding ID AlzProtAgeing n° 627152 
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 03/2014 
End 02/2016
 
Description National Institutes of Health (US)
Amount £14,000 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 08/2009 
End 07/2014
 
Description Philippe Chatrier
Amount € 30,000 (EUR)
Organisation Philippe Chatrier Foundation 
Sector Charity/Non Profit
Country France
Start 03/2013 
End 02/2014
 
Description The Gerald Kerkut Trust PhD
Amount £70,254 (GBP)
Organisation The Gerald Kerkut Charitable Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 09/2015
 
Title Immunised AD brain tissues 
Description The study has made use of cohort of AD patients actively immunised with Abeta42. The clinical follow-up and collection and assessment of post-mortem brain tissues was funded by the Alzheimer's Research Trust (Network Cooperation - ART/NPCG2003B) 
Type Of Material Biological samples 
Year Produced 2007 
Provided To Others? Yes  
Impact We are studying the pathological and clinical effects of the Abeta42 immunisation on the Alzheimer's disease (AD). Our findings are influencing the interpretation of the current generation of Abeta immunisation trials in AD. PMID 18640458 
URL http://europepmc.org/abstract/MED/18640458
 
Description Dr Claire Paquet 
Organisation Lariboisière Hospital
Department Alzheimer Centre
Country France 
Sector Hospitals 
PI Contribution - Access to the immunised AD cases. - Scientific and technical contribution. - Collaborator on the grant ART-PhD2011-22
Collaborator Contribution Scientific contribution on PKR a pro-apoptotic marker in chronic neurodegenerative diseases.
Impact - 2 papers under review, 1 paper in preparation - Collaborator on the ARUK PhD scholarship
Start Year 2011
 
Description Dr Guillaume Dorothee 
Organisation National Institute of Health and Medical Research (INSERM)
Department INSERM U938 (Research Centre St. Antoine)
Country France 
Sector Academic/University 
PI Contribution Collaboration on Neuroinflammation in Tauopathies (ARUK-PG2018A-012) To perform and bring expertise on the human studies
Collaborator Contribution To perform the experimental studies and bring expertise on adaptive immunity
Impact Multi-disciplinary expertise including in neuroimmunology, neuropathology and neurodegenerative diseases. Invitation to participate to a workshop at the International meeting NeuroFrance 2019.
Start Year 2018
 
Description Prof Clive Holmes 
Organisation University of Southampton
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution - Involved in the clinico-neuropathological follow up of the AD patients actively immunised by Abeta42 (AN1792). - co-applicant in the project to explore Systemic and central inflammation in Dementia with Lewy Bodies - co-supervisor - Dr Jay Amin Clinical Fellow
Collaborator Contribution - Acted as the chief investigator for the clinical part of the study, performed the clinical assessment. - Bring the clinical expertise essentiel to the work - Co-applicant on other grants
Impact See publications
Start Year 2006
 
Description Prof Jacques Hugon 
Organisation Lariboisière Hospital
Department Alzheimer Centre
Country France 
Sector Hospitals 
PI Contribution - Access to immunised AD cases - We have been successful in obtaining funding to investigate whether a group of proteins (metaflammasome) known to be associated with the risk factors identified in AD (diabetes, hyperlipidaemia) are responsible for the chronic inflammation and thus the neuronal damage. This project is funded by the ARUK to support a PhD student.
Collaborator Contribution Co-supervision of Mariko Taga, the ARUK scholarship student.
Impact - 2 papers under review, 3 papers in preparation - The outputs/outcomes are expected in 2015
Start Year 2011
 
Description Prof James Nicoll 
Organisation University Hospital Southampton NHS Foundation Trust
Department Department of Cellular Pathology
Country United Kingdom 
Sector Academic/University 
PI Contribution - Involved in the clinico-neuropathological follow-up of the AD patients actively immunised against Abeta42 (AN1792).
Collaborator Contribution - Bring the human neuropathology expertise, essentiel to the work - Co-applicant on other grants - Co-supervisor Mariko Taga (ART-PhD2011-22)
Impact See all publications
Start Year 2006
 
Description Prof James Nicoll 
Organisation University of Southampton
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution - Involved in the clinico-neuropathological follow-up of the AD patients actively immunised against Abeta42 (AN1792).
Collaborator Contribution - Bring the human neuropathology expertise, essentiel to the work - Co-applicant on other grants - Co-supervisor Mariko Taga (ART-PhD2011-22)
Impact See all publications
Start Year 2006
 
Description Prof Seth Love 
Organisation University of Bristol
Department Neuropathology
Country United Kingdom 
Sector Multiple 
PI Contribution - Access to the immunised AD cases
Collaborator Contribution - Access to the South West Dementia Brain Bank - Significant input into my research - Co-applicant on 3 grants.
Impact See publications
Start Year 2007
 
Description ARUK lab tour 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 20 persons selected by the ARUK attended the lab tour.

One of the persons is funding our ARUK PhD scholarship.
Year(s) Of Engagement Activity 2012
 
Description Alzheimer's Research UK Public event 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The event included hands-on presentations by researchers and clinicians, including postgraduate students and EXR, within and outside the South Coast network. The interactive booths are always particularly well received by the public.

Members of the public have requested to receive further information from upcoming events and the ARUK.
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013
 
Description Alzheimer's Research UK Reception 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact A joint presentation of Profs Clive Holmes and James Nicoll on the possibility of a vaccine for Alzheimer's disease. 50 parliamentarians

This presentation raised the awareness of the current clinical trials regarding Alzheimer's disease and preceded a series of parliamentary questions on dementia research.
Year(s) Of Engagement Activity 2007
 
Description Alzheimer's Research UK Westminster Reception 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Around 70 persons including scientists, health professionals and members of the public attended the event.

This event has raised the awareness of the major challenge poses by dementia and the research strategy highlighted by ARUK.
Year(s) Of Engagement Activity 2010,2013
 
Description Alzheimer's Society 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact To present the current treatments and research carry on at the University of Southampton on Alzheimer's disease and related dementias. 20 "lay" persons attended the meeting

This event has raised the awareness of the problems associated with dementia in terms of costs, care
Year(s) Of Engagement Activity 2007,2008
 
Description GP meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Health professionals
Results and Impact To present the current treatments on Alzheimer's disease 20 GPs

To update the GPs on current research and new treatment approaches on the Alzheimer's disease
Year(s) Of Engagement Activity 2009
 
Description Neuroscience Information Day 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The University of Southampton in conjunction with the Alzheimer's Society and the Alzheimer's Research Trust, highlighted the research into the condition that is being carried out within the University 60 "lay" persons attended the seminar

Over half of those who attending said they had come because they wanted help with understanding the illness, and subsequent feedback showed that over 98% of delegates felt that the conference had fulfilled their reason for attending.
Year(s) Of Engagement Activity 2007,2008,2010
 
Description Slide scanner lab visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact We hosted a visit for Mr Richmond, the executor of Jean Richardson's will, who provided the fund allocated to the purchase of the slide scanner. The visit included a tour of the Biomedical Imaging Facility, a demonstration of the slide scanner and a short presentation how the equipment will improve our research via a summary of the ongoing studies in dementia in Southampton.
Year(s) Of Engagement Activity 2017
 
Description Southampton Neuroscience Group (SoNG) outreach events 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Outreach activities performed under the SoNG umbrella including:
- Pint of Science Festival - beautiful mind
- Annual outreach event for 6th form students
Year(s) Of Engagement Activity 2013,2014,2015,2016
 
Description University of the 3rd Age 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Invitation to deliver a lecture on Dementia.
Year(s) Of Engagement Activity 2017
 
Description Wellcome Trust funded Exsite programme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Participation to a workshop on human brain for students from the science department of Peter Symonds 6th form college
Year(s) Of Engagement Activity 2016