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

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.

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.

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.