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

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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.