LonDownsPREVENT: A longitudinal study of the mechanisms of cerebral amyloid angiopathy and neurodegeneration in Down syndrome to inform AD prevention

Lead Research Organisation: King's College London
Department Name: Forensic and Neurodevelopmental Science

Abstract

This project will explore changes in the blood and brain that happen as people with Down syndrome (DS) get older. People with DS are at ultra-high risk of developing Alzheimer's disease (AD), because differences in their genes lead to excess production of a protein called 'amyloid', which can eventually clump together in the brain in plaques. These plaques are a hallmark of Alzheimer's disease and are found in all adults with DS by their mid-30s. Amyloid protein can also enter the blood vessels in the brain, called cerebral amyloid angiopathy (CAA) and can cause brain bleeding and strokes. We are interested in the mechanisms that link these two forms of amyloid deposits with damage to the brain (neurodegeneration) and subsequent decline in abilities in people with DS. Because people with DS have this excess of amyloid, but a lower risk of other health problems that can affect the blood vessels and cause dementia, such as smoking or high blood pressure, they are an important population for understanding how amyloid deposits eventually lead to AD.

Despite these known risks, people with DS have historically been excluded from prevention or treatment trials, for ethical and logistical reasons. As all adults with DS will have the hallmark plaques of AD, and most will go on to develop clinical dementia, we argue that there is an ethical imperative to research into ways to treat, or even prevent, this increasing health burden. To develop these much-needed clinical trials in the DS population, we require sound data showing how different biomarkers, which can include proteins like amyloid measured by blood samples, or MRI scans of brain structure, change over time in adults with DS, and how these changes relate to the clinical progression of dementia.

In our previous work, we recruited a group of around 450 adults with DS who are keen to be involved in research, and have developed a battery of sensitive cognitive tests that can be used to track decline in this population. We also found that a blood-based protein called 'neurofilament light' (NfL) can provide an important biomarker of neurodegeneration in adults with DS. For the current study, we want to see how different blood based biomarkers (including measures of NfL and amyloid) and changes in the structure and blood flow of the brain measured through magnetic resonance imaging (MRI) scans are related to CAA and the clinical symptoms of AD in DS.

We plan to see 80 adults with DS aged 35-54 who do not yet have a diagnosis of dementia three times, at 12-month intervals. At each time point, participants will provide blood samples, have an MRI scan and complete cognitive tests that will assess their abilities, including IQ, memory, reaction time and verbal skills. We will also collect information from caregivers regarding changes in everyday skills, personality and behaviour. We will then explore how each of these measures changes over time and use data models to show the order that changes in different biomarkers and brain structure happen, and how these changes are related to the clinical symptoms of dementia. We will also complete the same tests once in a group of 40 younger adults with DS aged 18-30 to act as a control group who will not be showing the same degree of amyloid burden as the older adults.

This project will provide essential information about changes in the brain that happen with AD in people with DS, and will provide important data to allow the development of future clinical trials. We hope to unpick some of the mechanisms that lead to AD, which will be of importance not only for people with DS, but for all people who develop AD.

Technical Summary

The proposed research focuses uniquely on the earliest stages of AD in DS, a population with ultra-high genetic risk for dementia (>90% at age 65), to understand the mechanisms leading to CAA and neurodegeneration in patients with "pure" amyloid-driven pathology. We will conduct a longitudinal study with sequential MRI imaging (3 timepoints 12 months apart) in 80 DS participants with AD pathology but without dementia diagnoses aged 35 - 54 years (i.e. in preclinical and prodromal stages of AD), as well as baseline assessments in a younger, healthy DS group aged 18-30 (n = 40). Participants will complete clinical assessments using our validated, sensitive tools and donate blood samples for DNA analysis (APOE and DS subtype) and plasma biomarkers (Neurofilament light (NfL), Abeta-42,40 and Tau using ultrasensitive SIMOA assays). Using MRI, we aim to deliver critical data on 1) cerebrovascular alterations using structural MRI markers of CAA (e.g. cerebral microbleeds, cSS) and to quantify cerebral blood flow (arterial spin labeling), and 2) AD progression using both diffusion MRI (microstructural changes) as early marker of AD, and structural MRI (macroscopic changes and cortical atrophy). At the plasma biomarker level, this will allow us to explore hypotheses related to the sequence of events leading to amyloid-induced CAA, using Abeta 42/40 ratio as marker of amyloid deposition, Tau for neuronal response and NfL as marker of neurodegeneration. At the imaging level, we will consider the role of cerebral blood flow alterations and changes in MRI diffusion as early surrogate markers for cognitive decline, with atrophy developing subsequently. DS individuals are typically excluded from clinical trials of new amyloid-targeting treatment to prevent or delay AD because of a lack of biomarker and progression data and concern about safety. We will deliver longitudinal, multimodal data to describe the parameters of AD progression which can then be used to plan such trials.

Planned Impact

The work set out in this proposal will result in several outputs, with clear impact at the academic, clinical and patient levels:
1. Cross-sectional and longitudinal multi-modal observational data on preclinical and prodromal features of AD in DS (from month 18)
2. Associated biobank(s) of DS plasma samples (from month 18)
3. Comparison of AD features and progression on MRI and biomarkers in DS and sAD (from month 18)
4. Longitudinal data on AD mechanisms in DS using MRI and plasma biomarkers (from month 30)
5. DNA and SNP data to expand the data available to the Horizon21 Down syndrome genomic consortium (from month 18)
6. Progression models of AD in DS (from month 30)
7. Modelling of aspects of clinical trial design(s) suitable for AD prevention trials in DS (from month 30)

Impact at the academic level:
By studying DS, an ultra-high risk group for amyloid-associated AD, we will deliver progression models that will improve understanding of the mechanisms leading to neurodegeneration and dementia. The data generated as part of this project will benefit the wider research community, including researchers (basic and clinical) in the AD and DS fields and associated disciplines by contributing to current models of AD, and by generating new hypotheses that can be pursued in future research. Improved understanding of the mechanisms of progression may also help to identify new treatment targets. The project will also facilitate sharing of techniques, skills and biobanks, and our data and bioresources will (in due course) be available to other AD researchers. Given the relative rarity of such DS resources, it will open up new avenues for research.

Impact at the clinical and patient level:
DS is the most common cause of intellectual disability, as well as the most common genetic cause of Alzheimer's disease world-wide. This exceptionally high neuropathological burden means that AD is now the main cause of death in adults with DS. It is also costly on a personal and caregiver level and for the NHS. Impacts at the clinical level are expected to include data on MRI and plasma biomarkers of AD progression during the preclinical and prodromal stages that will inform diagnosis and disease monitoring, and help to provide more refined estimates of prognosis. A better understanding of the cerebrovascular alterations associated with amyloid deposition may lead to the identification of potential treatment and prevention strategies, not only for individuals with Down syndrome, but also for other patient groups at risk for AD. Impacts for patients include the availability of better information for carers and individuals with DS who are at risk of AD, particularly on the cerebrovascular complications of AD. Ultimately, the data generated by this proposed study will enable clinical trials of treatments to prevent or delay AD in DS individuals. The results of such trials will not only benefit DS individuals, but also other high-risk patient groups.

Publications

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Antonarakis SE (2020) Down syndrome. in Nature reviews. Disease primers

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Aschenbrenner AJ (2021) Markers of early changes in cognition across cohorts of adults with Down syndrome at risk of Alzheimer's disease. in Alzheimer's & dementia (Amsterdam, Netherlands)

 
Description COVID-19 vaccination prioritisation for people with Down syndrome
Geographic Reach Multiple continents/international 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact Based upon our recommendation, most people with Down syndrome now have access to COVID-19 vaccination and we have subsequently demonstrated that vaccination is safe, and also resulted in a significant decrease in mortality following infection
URL https://www.t21rs.org/covid_vaccination/
 
Description Clinical and trial outcome measures for dementia in individuals with Down syndrome
Amount £180,000 (GBP)
Organisation LuMind Research Down Syndrome Foundation 
Sector Charity/Non Profit
Country United States
Start 08/2018 
End 12/2020
 
Description Horizon21: Clinical and trial outcome measures for dementia in individuals with Down syndrome
Amount £44,965 (GBP)
Organisation Jerome Foundation 
Sector Charity/Non Profit
Country United States
Start 02/2019 
End 01/2021
 
Description Multi-professional Clinical Training Partnership - Aarsland, D., Sleeman, K., Strydom, A.
Amount £225,000 (GBP)
Organisation Alzheimer's Society 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2019 
End 12/2021
 
Description GO-DS21 
Organisation EU Health Programme
Country European Union (EU) 
Sector Public 
PI Contribution The work on HEROES led to the formation of a subsequent collaboration, including most of the HEROES partners with addition of new partners. This is called GO-DS21 and led to a successful application to teh EU's Horizon2020 programme.
Collaborator Contribution See above
Impact Multi-disciplinary collaboration; impacts to follow
Start Year 2020
 
Description COVID and Down Syndrome Webinar 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact An update on the Trisomy 21 Research Society COVID and Down Syndrome Survey and discussed the DSMIG-USA Vaccination Position Statement.
Year(s) Of Engagement Activity 2021
URL https://www.youtube.com/watch?v=9WKB90zua-o
 
Description COVID-19 is 10 times deadlier for people with Down syndrome, raising calls for early vaccination 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Impact of Covid-19 on down syndrome patients
Year(s) Of Engagement Activity 2020
URL https://www.science.org/content/article/covid-19-10-times-deadlier-people-down-syndrome-raising-call...
 
Description Covid-19 and Down Syndrome on-line survey: results and perspective 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact EDSA (European Down syndrome association) - Organized webinar with Dr. Andre Strydom and Prof. Mara Dierssen about Covid-19 and Down Syndrome.
Year(s) Of Engagement Activity 2020
URL https://www.youtube.com/watch?v=97-UyBUbkaQ
 
Description International study finds increased mortality in adults with Down syndrome 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Research led by King's College London in collaboration with the Centre for Genomic Regulation (CRG) and the Trisomy 21 Research Society (T21RS) finds increased COVID-19 mortality among adults with Down syndrome compared to the general population, emphasizing the need to prioritise vaccinations for those with the genetic disorder.

https://thedaily.case.edu/international-study-finds-increased-covid-19-mortality-among-adults-with-down-syndrome/

https://news.emory.edu/stories/2021/02/coronavirus_inreased_mortality_down_syndrome/index.html
Year(s) Of Engagement Activity 2021
URL https://eu.usatoday.com/story/news/2021/03/08/covid-19-vaccine-many-adults-down-syndrome-cant-get-sh...
 
Description Keynote at Trisomy 21 Research Society international conference 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keynote speaker at Trisomy 21 Research Society international conference
Year(s) Of Engagement Activity 2019
URL https://www.t21rs.org/news-meetings
 
Description LDID SIG chair 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I am the founding chair of the London Dementia in Intellectual Disabilities Special Interest Group, which has membership from clinicians across London. It is a forum for regular discussion and dissemination of research results related to the treatment and management of Dementia in individuals with Down Syndrome (DS) or other Intellectual Disabilities (ID).

We have formed a new research collaboration to collect anonymised clinical data from dementia assessments on adults with DS and ID, which will be used to seek answers to clinically driven research questions.
We have also developed generic care pathway guides which can be used by clinicians to improve services, and are in the process of organising a conference in 2012 that will be used as platform for a Intellectual Disabilities Dementia Care Alliance.
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015,2016,2017,2018,2019,2020
URL https://www.kcl.ac.uk/ioppn/depts/fans/research/dementia-in-intellectual-disabilities-special-intere...
 
Description Medical vulnerability of individuals with Down syndrome to severe COVID-19-data from the Trisomy 21 Research Society and the UK ISARIC4C survey 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Researcher chat via facebook organised by a family organisation to support uptake of covid vaccination for people with Down syndrome
Year(s) Of Engagement Activity 2021
 
Description The COVID-19 pandemic should be last orders for poor care of people with neurodevelopmental disorders 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Editorial - Explored whether the needs of individuals with neurodevelopmental disorders have been overlooked during the COVID-19 pandemic and set out the issues that
need to be considered in response to future health crises and pandemics.
Year(s) Of Engagement Activity 2021
URL https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/covid19-pandemic-s...
 
Description The Down Syndrome Medical Interest Group Annual Winter Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact The impact of COVID-19 on children & adults with Down Syndrome
Year(s) Of Engagement Activity 2020
 
Description World Down Syndrome day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Talking about research to people with Down syndrome and their carers
Year(s) Of Engagement Activity 2019,2020,2021