March 2014 Issue 131

alzheimers.org.uk/research Research newsletter Quality Research in Dementia Focus: Reducing the risk of dementia | Newly funded research February/M...
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Research newsletter Quality Research in Dementia

Focus: Reducing the risk of dementia | Newly funded research

February/March 2014 Issue 131

Notes from the editor

A Happy New Year from all of us in Alzheimer’s Society’s Research team. We have already had a busy start to the year, following on from a very busy pre-Christmas period with the G8 summit on dementia research.

On the cover

We have been using the momentum that came out of the summit to advance several important projects.

Discovery programme, in collaboration with the Alzheimer’s Drug Discovery Foundation (see page 11).

In late January we launched our Dementia Research Leaders programme, which aims to increase the number of researchers working in the field of dementia as well as to retain high quality researchers. You can read more about this on page 11.

We continue in our ambition to fund high-quality research into cause, cure, care and prevention for all forms of dementia. Now is an exciting time for dementia research, and as the dust settles after the G8 summit we must not let the commitments that were made at it be forgotten.

We have also announced an exciting new call for funding applications as part of our Drug

Sharing data saves lives campaign

Images representing a healthy diet and exercise. This newsletter looks in focus at the latest research, including some funded by Alzheimer’s Society, into the factors that may reduce the risk of developing dementia (see pages 8-10).

You may have heard in the news, and received a leaflet through your door if you live in England, about NHS England’s plans to provide data from individuals’ health records for research through a programme called Care.data. This aims to use the wealth of information within people’s NHS records to support research that will lead to better patient care.

Contents

Researchers in academia and the pharmaceutical industry will be able to access data from health records that has been stripped of information that identifies patients individually. Patients will be given the right to object to their data being stored within a central repository and accessed in this way.

2 Notes from the editor 3 Research in the press 4-6 Newly funded research: PhD studentships 7 Newly funded research: Clinical training fellowship 7 Recently completed research 8-10 Focus: Risk reduction and public health 11 Research funding news

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Alzheimer’s Society is supporting this project as a member of the Association of Medical Research Charities, which launched the Sharing data save lives campaign alongside the Medical Research Council and Wellcome Trust.

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Research in the press cautioned on drawing too firm conclusions from the results. ‘It is surprising to see that older women with both naturally high oestrogen levels and diabetes were so much more likely to develop dementia in this study. However as this only applied to 10 women, we need to conduct much larger studies before reaching any conclusions. An overview of research stories that have made the national press and how we commented on them.

A study by researchers at the French National Institute of Health and Medical Research (Inserm) has linked high oestrogen levels in older women who also have diabetes with a 14-fold increase in the risk of developing dementia. Researchers measured levels of blood oestrogen in 5,644 women aged 65 years or above who didn’t have dementia. They were assessed four years later for dementia and common dementia risk factors, including diabetes and high blood pressure. Comparing 132 women with dementia to 543 without it, those with both very low and very high levels of natural oestrogen were twice as likely to develop the condition when compared to those with normal oestrogen levels. But in the 10 women with diabetes and high oestrogen, this risk was 14 times greater than for those with diabetes and normal hormone levels. Dr Doug Brown, Director of Research and Development, February/March 2014

‘Although it’s very difficult to do anything about lowering your oestrogen levels, we do know that people can take steps to reduce their chance of developing diabetes. Adopting a healthy diet and taking regular exercise might be the key to helping prevent both diabetes and dementia.’

A study by University College London researchers has found excessive alcohol consumption to be associated with faster cognitive ageing in men. The researchers found no differences in memory and cognitive function between men who were alcohol abstainers, quitters or light to moderate drinkers. However consumption of more than four and a half units of alcohol a day was associated with faster decline in all of the cognitive functions that were measured when compared with light to moderate consumption. The findings are less clear in women. Data was collected from 5,054 men and 2,099 women aged between 44 and 69 from the Whitehall II civil service cohort study. Alcohol consumption was assessed three times in the 10 years preceding the first cognitive assessment, and a further two

cognitive assessments were made five and 10 years after. Dr Alison Cook, Director of External Affairs, said, ‘We’ve known for some time that drinking excessive amounts of alcohol is bad for your brain. This study shows that drinking more than four and a half units of alcohol a day makes your brain age faster, which increases your risk of developing dementia.’

A new study from scientists at Ohio State University has claimed that a 15-minute self-test conducted at home can indicate early signs of cognitive decline. The team hope that the test will help to give doctors a baseline of cognitive function so that progressive changes may be tracked over time, with the results shared with physicians to help them spot early symptoms of dementia. Asking more than 1,000 people aged 50 and older to take the Self-Administered Gerocognitive Exam (SAGE) test, researchers found that 28 per cent had mild cognitive impairment. Doug Brown said, ‘This is an interesting development, but currently home tests are not a reliable way of diagnosing Alzheimer’s disease or other forms of dementia. Dementia and mild cognitive impairment are difficult to diagnose, and we need to continue to fund more research into tests like this and other ways that may help improve the accuracy and ease of diagnosis.’

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Newly funded research: PhD studentships Understanding how genes related to the immune system contribute to Alzheimer’s disease Dr Angela Hodges, Institute of Psychiatry, King’s College London Mutations in two genes relating to the immune system – TREM2 and CSF1R – have been found to increase the risk of people developing Alzheimer’s disease. This project will use information about changes to these genes and knowledge about their function to understand what goes wrong and how this increases risk for Alzheimer’s. The researchers will create cells within the lab with each of the

identified changes on these genes. The effects of their over- and under-production in cells and their impact on things likely to contribute to Alzheimer’s will be compared, and the aspects of cell function that are affected will be assessed. The researchers will also test the ability of normal cells and changed cells to respond to things required for the normal function of these genes and they will measure the impact.

They will then test whether the effects they have measured are also altered in the brains and blood of people who have changes in these genes which cause or contribute to their Alzheimer’s disease. A better understanding of what these genes do is not only vital for the families who have an altered version of the gene but is also likely to be relevant to all people who develop Alzheimer’s disease and related dementias.

How are the connections between brain cells affected in inherited Alzheimer’s disease? Dr Richard Wade-Martins, University of Oxford A new technique allows researchers to create induced pluripotent stem cells (iPSCs) from the skin cells of people with familial Alzheimer’s disease. This project will use these stem cells to grow neurones in the lab and investigate how connections between them are affected by the presence of amyloid plaques. The researchers will then use drugs to alter the amount of amyloid produced by these cells or to stop tau from being affected by amyloid.

hallmarks of Alzheimer’s disease have on communication and connections between neurones. Neurones connect at junctions called synapses, the healthy functioning of which are crucial for cognitive function. Better understanding of how synapses are affected in Alzheimer’s is crucial for the development of drugs to prevent this damage and so stop the deterioration in cognitive functions.

The connections between neurones are called synapses. The below image is of a synapse seen through a microscope. Dr Wade-Martins’ PhD student will use stem cells to investigate how synapses are effected during Alzheimer’s disease.

This will help our understanding about the effect that the

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alzheimers.org.uk/research

How does tau affect the connections between brain cells? Dr Tara Spires-Jones, University of Edinburgh The healthy functioning of synapses, the connections between neurones, is essential for memory and learning. The loss of synapses is a strong predictor of dementia in people with Alzheimer’s disease prior to the death of the neurones themselves. In this project the researchers will ask whether tau phosphorylation – the process that leads to tau tangles – causes synapse death and they will investigate why this might be the case. One factor leading from tau to synapse loss may be problems with moving mitochondria to synapses.

Mitochondria are the ‘batteries’ of all cells, using oxygen and sugars to make energy. The proper distribution of mitochondria throughout the cell is essential to maintaining cellular health. This is a particularly important in neurones because they have high energy demands in comparison to cells elsewhere in the body. The long branches of neurones that carry signals from one part of the brain to another or from the brain all the way to the bottom of the spinal cord present unique challenges to cellular transport.

Tau is normally bound to structures that act as the skeleton of the cells, called microtubules, which form the ‘tracks’ for this transport throughout the cell. In Alzheimer’s, these tracks are disrupted as tau detaches and forms into tangles. Previous work has shown that the transport of mitochondria in neurones is disrupted by tau in Alzheimer’s models. What is not known is how this affects synapses. Finding out why synapses die during Alzheimer’s disease is an essential step towards developing treatments for the disease.

Investigating a way to clear tau tangles, a hallmark of Alzheimer’s disease Dr Jacqueline van der Spuy, University College London Researchers have discovered that a protein called NUB1 reduces the accumulation of tau tangles in brain cells grown in the lab, and that their accumulation is much worsened following the loss of this protein. NUB1 may therefore protect cells against the damaging effects of tau tangle accumulation. NUB1 has been implicated in several neurodegenerative diseases, including Parkinson’s disease, dementia with Lewy bodies, Huntington’s disease and Alzheimer’s disease. There is mounting evidence that this

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protein is neuroprotective in several of these disorders and that the increase of NUB1 could be a viable strategy for new treatments. The researchers want to understand how tau tangles are cleared by NUB1 and how it may prevent the abnormal tangle prone form of tau from forming. A better understanding of the functions of NUB1 will give us clues as to how these discoveries can be harnessed to develop new types of treatments for Alzheimer’s disease.

Tau is a protein that forms part of the ‘skeleton’ of neurones. During Alzheimer’s disease, it starts to break down and form ‘tangles’ within cells. These cause disruption to the cells’ activity, including the connections between cells (see Dr Tara SpiresJones’ PhD project, above), which leads to cell death, resulting in dementia. (Image by Patho)

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Understanding Alzheimer’s disease by investigating the disease in people with Down’s syndrome Professor Elizabeth Fisher, University College London People with Down’s syndrome have a greatly increased risk of developing Alzheimer’s disease, often early-onset. People usually have 23 pairs of chromosomes, but people with Down’s syndrome have three copies of chromosome 21. The gene amyloid precursor protein (APP) is present on chromosome 21 and plays a key role in the development of amyloid plaques and so the development of

Alzheimer’s. It is thought that having three ‘doses’ of the APP gene explains some of the increased risk of developing Alzheimer’s disease in people with Down’s syndrome. This project will investigate other genes present on chromosome 21 that are important for controlling the activity of APP, and so the production of amyloid-beta. By understanding what other genes

play a role in producing amyloid-beta, the researchers hope to understand more about the development of Alzheimer’s and identify potential targets for future treatments. This will benefit people with both Down’s syndrome and Alzheimer’s as well as the wider community with Alzheimer’s disease.

Improving diagnosis of a type of frontotemporal dementia using brain scans Professor Nick Fox, University College London Frontotemporal dementia is the second most common cause of dementia in people under the age of 65. The most common form of frontotemporal dementia results in predominantly frontal lobe damage and initial changes in personality and behaviour. This is the behavioural variant of frontotemporal dementia, and its particular signs and symptoms depend on what parts of the frontal lobes are most affected.

A characteristic feature of people with the behavioural variant of frontotemporal dementia is brain atrophy (loss of brain volume resulting from the damage and death of neurones). This is accompanied by deficits in the main functions and behaviours served by these brain regions. The variability that is such a feature of frontotemporal dementia is also expressed in the pattern of the brain regions involved.

There are no disease-modifying treatments for the behavioural variant of frontotemporal dementia and, unlike Alzheimer’s disease, there are also no specific symptomatic treatments. As a result people are often given antipsychotic medication.

It is uncertain whether patterns of atrophy are best viewed as a feature of all people with the behavioural variant of frontotemporal dementia, or whether distinct patterns and subtypes can be reliably identified.

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The overall objective of the project is to investigate brain imaging and behavioural symptoms in a large group of people with the behavioural variant of frontotemporal dementia in order to better understand the nature and different expressions of this complex, variable and devastating disease and to develop non-invasive markers for future clinical trials.

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Newly funded research: Clinical training fellowship Exploring the experiences of diagnostic imaging for people with dementia Emily Lewis, Radiographer, University of Bradford Many aspects of patients’ experiences of X-ray departments are different from those in other hospital departments (for example, relatives are not allowed in the room with patients) and the healthcare professionals involved need to be particularly task-focused. No research has been done that looks at the experiences of people with dementia and their carers in this setting. The researcher would like to understand the experiences of

people with dementia and their carers when they have an X-ray or scan and how these may be improved. She also wants to understand more about radiographers’ attitudes and approaches to working with people with dementia in order to improve practice. By conducting interviews with people with dementia who have experience of radiography in addition to focus groups with people affected by dementia and with radiographers, the researcher

hopes to develop best practice guidelines to be used by radiography departments. The findings of this study will help to improve standards of radiography practice and the experiences of people with dementia and their carers within the X-ray department. The study will provide the first ever guidance and recommendations for radiographers about taking X-rays and scans of people with dementia.

Recently completed research: Investigating the translational control of genes involved in Alzheimer’s disease Dr Keith Spriggs supervised Alex Hughes during her PhD studentship at the University of Nottingham Genes do not always act in isolation – they often respond to signals to ‘switch on’ or become more or less active. This enables the activity of a gene to respond to its environment and the demands of the cell. This project investigated the ways in which genes associated with Alzheimer’s disease are regulated. Understanding what signals regulate these genes is critical to knowing more about why they are associated with Alzheimer’s and identifying potential avenues for new treatments to be developed.

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Some of these genes may lead to neurodegeneration while others may be neuroprotective. More knowledge of both will lead to deeper understanding of the underlying changes that occur in the brain during the development of Alzheimer’s disease. As a result of this project, the researchers have been able to show that a number of genes associated with Alzheimer’s are controlled using similar mechanisms. The activity of these genes is also increased in response to cellular stresses, such as oxidative stress, that have been

proposed as risk factors for Alzheimer’s disease. They have also learned something about the way a protein that clears amyloid deposits, called neprilysin, is regulated differently depending on the conditions within the cell. This will allow the researchers to work towards finding ways to increase the amount of neprilysin within neurones in people with Alzheimer’s, independently of the potentially ‘stressed’ conditions of these cells.

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Focus: Risk reduction and public health We often read about things that may either increase or decrease our risk of developing conditions including dementia. However we don’t yet have a good understanding of the factors that can really make a difference to our risk of developing dementia and the evidence we do have may not be conclusive. The most robust evidence is about factors related to a generally healthy lifestyle, such as regular exercise and a healthy diet.

PREVENT research programme Dr Craig Ritchie and Katie Wells, Imperial College London It is becoming increasingly clear that many of the changes in the brain that lead to dementia start decades before symptoms develop. We need to know how to identify these changes in people in middle age and how to stop them from progressing. We may be able to stop progression by removing risks or with more specific interventions such as drugs, special diets or cognitive training. The PREVENT research programme will establish a cohort of individuals aged 40–59 to explore differences in their brains and cognitive function. People will be categorised initially as high, mid or low risk based on their family history and

ApoE status (a well known risk gene). One of the main aims of the study is to identify the earliest signs of changes in the brain while people are still in good health. We will look at biological indicators including markers in blood, saliva, urine and spinal fluid as well as direct imaging of the brain’s structure and function. We will then see how changes in all of these markers develop over two years and work out if there are other risks, in addition to family history and ApoE status, that predict these changes. The project involves collaboration between many different universities and health trusts, each providing different areas of expertise.

The hope for this programme’s future development would be to continue following up these individuals in a long-term observational study. This would allow us to explore the interaction between changes in biological indicators and cognitive changes. The establishment of mid-life cognitive and biological indicators of dementia risk will also provide an opportunity to propose prevention strategies. These may include early treatment of problems known to increase risk and increasing activities that stimulate brain function.

Research publication summary: Healthy lifestyles reduce the incidence of chronic diseases and dementia: Evidence from the Caerphilly cohort study A study in Caerphilly, south Wales followed 2,235 men for 35 years to better understand the effects of lifestyle factors on health in later life. The study is the longest of its kind into the influence of environmental factors on chronic disease. Page 8

The study, funded by the Medical Research Council, Alzheimer's Society and British Heart Foundation, identifies five healthy behaviours as integral to reducing risk – taking regular exercise, not smoking, maintaining low bodyweight and having a healthy diet and a low alcohol intake.

The people who consistently followed four or five of these behaviours experienced 60 per cent less dementia and cognitive decline compared with people who followed none, with exercise being the strongest mitigating factor. There were also 70 per cent fewer instances of alzheimers.org.uk/research

diabetes, heart disease and stroke in this group. The level of risk reduction was surprising and provides promising potential avenues for future public health messaging. The principle investigator, Professor Peter Elwood from Cardiff University’s School of Medicine, said, ‘What the research shows is that following a healthy lifestyle confers surprisingly large benefits to health –

healthy behaviours have a far more beneficial effect than any medical treatment or preventative procedure. ‘If the men had been urged to adopt just one additional healthy behaviour at the start of the study 35 years ago and if only half of them complied, then during the ensuing 35 years there would have been a 13 per cent reduction in dementia, a 12 per cent drop in diabetes, 6 per cent less vascular disease and a 5 per cent reduction in deaths.’

Recent surveys indicate that fewer than 1 per cent of people in Wales follow a completely healthy lifestyle based on the five recommended behaviours, while 5 per cent follow none.

Reference: Elwood P et al (2013). Healthy lifestyles reduce the incidence of chronic diseases and dementia: Evidence from the Caerphilly cohort study, PLOS One, PMID: 24349147.

Flavonoids in the diet: Could they help to prevent Alzheimer’s disease? Carla Cox, PhD student, University of Bath Despite all the resources aimed at developing new drugs for Alzheimer’s disease over the last two decades, there are no treatments available that are able to alter the progression of the disease. This has caused scientists to look at other ways to reduce the number of people who develop Alzheimer’s. Like other diseases affecting mostly older people, such as cancer and type 2 diabetes, environment and lifestyle are thought to have an impact on the likelihood of developing Alzheimer’s disease. Population studies carried out all over the world have suggested that increased intake of certain fruits, vegetables and drinks may delay the onset of Alzheimer’s, but the particular components of these foods that convey the benefit have not been identified. My PhD project, jointly funded by the Medical Research Council and Alzheimer’s Society, has been to look at the effect of flavonoids on the production of

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amyloid-beta – the major protein component of the amyloid plaques seen in the brains of people with Alzheimer’s. Flavonoids are particularly abundant in fruits, vegetables, green tea and red wine, making them a likely source of the effects seen in population studies. In my project I have used mouse brain cells grown in the lab, which are very similar to human brain cells, and measured changes in APP protein, the precursor of amyloid-beta, after different flavonoids have been fed into their growth medium. This allowed me to identify a subfamily of flavonoids, called flavanols, that reduced amyloid-beta production in the healthy brain cells. We then went on to investigate how they were acting. Although we were not able to establish the exact mechanism, they appeared to target a protein responsible for breaking down APP to produce amyloid-beta. If we can understand how flavonoids are acting, we may then develop

them into more effective treatments for the prevention of Alzheimer’s disease. This work has been exciting as it strengthens the link between diet and dementia, however much more research is required to elucidate the role that flavonoids play in reducing the risk of Alzheimer’s disease. Until that time, your ‘five a day’ may be helping you to maintain a healthy mind as well as a healthy body.

Carla Cox is a PhD student, supervised by Dr Rob Williams at the University of Bath. She is currently writing up her project results in her PhD thesis.

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Risk reduction and public health Research publication summary: Preventing Alzheimer’s disease-related grey matter atrophy by B-vitamin treatment Professor A David Smith, OPTIMA, University of Oxford Beyond the age of 50 our brains shrink by about 0.5 per cent each year, which is equivalent to the loss of about a teaspoonful of brain tissue a year. It is not certain that this loss of brain tissue matters very much, though it could explain some of the decline in cognitive abilities with older age. In some older people who have minor memory problems – mild cognitive impairment – the brain shrinks twice as fast. This shrinkage does not take place in all regions of the brain, but is limited to certain areas that are known to be important for normal cognitive function. One of these is the medial temporal lobe, which includes the hippocampus, a very small part of the brain that is crucial for normal memory function. The shrinkage of this part of the brain correlates with a decline in performance on memory tests and, if it continues, it may lead to Alzheimer’s disease. Several modifiable factors have been associated with brain shrinkage, especially of the

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medial temporal lobe. One of these less prominent factors is raised levels of an amino acid called homocysteine in the blood. Homocysteine levels are influenced by lifestyle but they mainly reflect the body’s B vitamin status. Even if your diet is good, your B vitamin intake will still influence the blood homocysteine level. It has been found that relatively high doses of B vitamins (folic acid and vitamins B6 and B12) are needed to get a really low homocysteine level. We carried out a randomised clinical trial called VITACOG that aimed to see if lowering homocysteine by giving B vitamins would slow the rate of shrinkage of the brain in 200 people who have mild cognitive impairment. Over two years, the B vitamin treatment slowed the rate of shrinkage by 30 per cent on average and by more than 50 per cent in people whose starting level of homocysteine was high. In those with high homocysteine the B vitamin treatment also slowed down cognitive decline, in particular memory decline. We

found that the medial temporal lobe and other areas that are damaged in Alzheimer’s disease were markedly protected. The VITACOG trial proves the principle that it is possible to modify the disease process. However this was a small trial and only a special subgroup benefitted – people with high homocysteine levels. We need to carry out a much larger trial in which B vitamins are given to people with mild cognitive impairment who have high homocysteine levels to see whether the treatment slows, or even prevents, the conversion to dementia.

Reference: Douaud G et al (2013). Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment, Proc Natl Acad Sci USA, PMID: 23690582.

alzheimers.org.uk/research

Research funding news Dementia Research Leaders programme A crucial aspect of making progress in dementia research is to ensure that the very best researchers are working in the field and to encourage more to do so. This includes lab scientists, but also healthcare professionals who would like to improve care for people with dementia. We have set up the Dementia Research Leaders programme to provide advice, information about opportunities for funding from us and others, and many other resources to help researchers with their careers. The programme encompasses some of our existing grants as well as new. To find out more about the programme, please see alzheimers.org.uk/researchleaders

The Dementia Research Leaders website is a resource for early career researchers. It has videos, funding opportunities and links to useful information.

ADDF funding We have secured a joint funding agreement as part of our Drug Discovery programme with the Alzheimer’s Drug Discovery Foundation (ADDF), which funds international research. The initiative will support lab-based work and clinical trials to either repurpose existing drugs or reposition drugs in development for other conditions and which may be useful for dementia. Each grant may be worth up to £1 million and to qualify for Alzheimer’s Society funding at least one research partner must be based in the UK.

Drug Discovery video As more work is funded through the Drug Discovery programme – the liraglutide trial for Alzheimer’s disease, the vascular dementia trial and now the ADDF partnership – we have created a video to help explain it. A scene from the Drug Discovery video narrated by our Ambassador Fiona Phillips.

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To find out more about the programme and to watch the video, visit alzheimers.org.uk/ drugdiscovery

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The Research Network

Research team contacts

People with dementia and their carers are integral to our grants programme. We believe that they make a unique and valuable contribution to our work. Their knowledge and passion ensures our research funding is allocated to projects that address the real needs and concerns of people with dementia and their carers.

Research Engagement Manager Matt Murray T 020 7423 3603 E [email protected]

Research Network volunteers: set our research priorities prioritise and comment on grant applications sit on grant selection panels monitor ongoing projects funded by Alzheimer’s Society • tell others about the results of research. • • • •

If you have been a carer for someone with dementia or you have dementia and are interested in joining the Research Network, please contact Becky Driscoll, the Research Engagement Officer and request an application form, or apply online at alzheimers.org.uk/researchnetwork If you are not a carer or a person with dementia, but you would like to learn more about our research and keep up to date, you are welcome to become a Friend of Research. Just fill in the form on the website (above) and you’ll receive a regular copy of the Research newsletter and information on all our research events.

Research Engagement Officer (first point of contact for the Research Network and Friends of Research) Becky Driscoll T 020 7423 5153 E [email protected] Director of Research and Development Dr Doug Brown Research Communications Officer Jess Smith T 020 7423 5143 E [email protected] Website alzheimers.org.uk/research Email [email protected] Fundraising enquiries Customer Care T 0845 306 0898 E [email protected]

Sunrise Senior Living is generously sponsoring the Research Network. Alzheimer’s Society maintains editorial independence over this content. For more information please visit www.sunrise-care.co.uk General enquiries: [email protected] Alzheimer’s Society website: alzheimers.org.uk Registered charity no. 296645. A company limited by guarantee and registered in England no. 2115499. Alzheimer’s Society operates in England, Wales and Northern Ireland