Alzheimer's disease
Neurodegenerative diseases such as Alzheimer’s are set to become a ‘silent epidemic’, placing a major healthcare burden on countries with aging populations.
Researchers at Oxford are working to better understand the molecular and genetic mechanisms of Alzheimer’s disease in order to enable early diagnosis and detection. They are uncovering previously unknown viral and genetic risk factors and discovering uniquely human traits of neurodegenerative diseases.
Our experts are translating these understandings into exciting drug discovery trials and innovative therapies, in the hope of developing preventative treatments and slowing the cognitive decline of those affected by Alzheimer’s disease.
Identifying Alzheimer’s
What is Alzheimer’s disease?
Alzheimer’s disease is a progressive neurodegenerative condition, where symptoms develop gradually over many years.
Eventually Alzheimer’s disease causes so much damage to the brain that the person develops dementia. Alzheimer’s is the most common cause of dementia in the UK, making up 60% of diagnoses.
The disease is characterised by the abnormal build-up of amyloid and tau proteins in the brain, which can occur years before clinical symptoms such as memory loss are detected.
Tau:
Tau proteins are found on the inside of neurons’ axons, or nerve fibres, and help to maintain their correct structure. In some forms of dementia, including Alzheimer’s disease, tau proteins become damaged and detach from their axons. Now moving freely inside the neuron, the abnormal tau proteins clump together to form neurofibrillary tangles
Amyloid:
Amyloid begins life as amyloid precursor protein which is a common, normal protein in the central nervous system. Amyloid-beta is dangerous because it clumps together, eventually accumulating into bulky amyloid plaques. These clumps cause a variety of chemical reactions around neurons that damage and destroy them
More than 57.4 million people worldwide are living with dementia and, without new therapeutics to slow or halt disease progression, this number is expected to grow to 152.8 million by 2050.
Learn more about Oxford’s research on dementia.
Early detection
Early detection and diagnosis of Alzheimer’s disease is a challenge for researchers working to develop treatments to slow cognitive decline.
Experts are increasingly looking to biomarkers to identify and monitor disease progression.
Biomarker:
A naturally occurring molecule, gene, or characteristic by which a particular pathological or physiological process, disease, etc., can be identified
Oxford’s MRC Brain Network Dynamics Unit (MRC BNDU) is a strategic partnership between the Medical Research Council and the University, operating over three sites affiliated to the Nuffield Department of Clinical Neurosciences and the Department of Engineering Science.
In March 2023, experts from the MRC BNDU received funding for a multi-year research partnership designed to advance the understanding of early changes to the operations of brain circuits in Alzheimer's disease.
The UK DRI Grand Challenge Award will support a collaboration between the Dupret Group, led by Professor David Dupret, and researchers based at University College London, to develop a biomarker for Alzheimer's that can be used to identify and monitor early signs of the disease.
The MRC Unit will leverage its leading expertise in the electrophysiological interrogation of brain functions underlying memory, focusing on state-of-the-art mouse models of Alzheimer's.
‘The work funded by this award will tackle a genuinely grand challenge in dementia research, that is, the development and validation of a functional circuit-based biomarker for Alzheimer's.’
Researchers from the Big Data Institute and Oxford Population Health collaborated with Alzheimer’s Society to develop a brain game app for smartphones, aimed at improving speed and accuracy of dementia diagnosis.
The GameChanger study, led by Dr Chris Hines, involved the development of a series of games designed to test specific aspects of memory and thinking that are affected in the early stages of Alzheimer’s disease.
With a third of dementia cases in the UK going undiagnosed, Alzheimer’s Society is calling on the public to download the app and play the games for five minutes a day, every day for a month, so that researchers can see how people usually perform – which will later help them see the warning signs of Alzheimer’s.
It is hoped the app can eventually be used to find people in the very early stages of the disease and develop new treatments to stop it in its tracks.
‘People using the app are just playing games but their phones are doing much more – collecting data we can use to learn about the brain, to help us understand what is a natural part of ageing and what’s a warning sign.’
What causes Alzheimer’s?
Molecular mechanisms of disease
Establishing preclinical models of Alzheimer’s that reflect in-life clinical symptoms of each individual is a critically important goal, yet so far it has not been fully realised.
The Wade-Martins Group, led by Professor Richard Wade-Martins, is part of the Department of Physiology, Anatomy and Genetics and is based in the Kavli Institute for Nanoscience Discovery.
The highly collaborative and multidisciplinary group is focused on better understanding the molecular and genetic mechanisms of age-related neurodegenerative diseases such as Alzheimer’s, with a view towards developing new treatments.
A collaborative study involving researchers from the Wade-Martins Group revealed that clinical symptoms for Alzheimer’s can be predicted in preclinical models.
‘We are excited to have found that brain cells generated in the laboratory from individual Alzheimer’s patients reflect their clinical vulnerability to amyloid-beta. This will help us better understand mechanisms of resilience and will help in the search for new therapeutic strategies.’
The team utilised blood samples donated by patients with early Alzheimer’s to convert blood cells into stem cells, before generating brain cells specific to each donor.
They then were able to mimic the synapse loss caused by the disease to examine process of cognitive decline, crucially linking the build-up of amyloid-beta in the brain with clinical symptoms.
A look inside the Wade-Martins lab for World Alzheimer’s Day, 2022.
The Wade-Martins group heads the Alzheimer's Research UK Thames Valley Network (ARUK) which brings together researchers from the Thames Valley region with expertise in dementia and cognition using a range of techniques including imaging, neuropathology, genetics and model systems.
In September 2022 Dr Becky Carlyle, Academic Coordinator of ARUK and researcher in the Wade-Martins group, was awarded £420K in funding from Alzheimer’s Research UK. The funding was awarded for Dr Carlyle to establish her own research group to investigate boosting resilience to Alzheimer’s.
The researchers hope to reveal potential targets for new drugs that could help slow the progression of the disease by identifying the proteins that are most important for protecting nerve cells from amyloid damage and the second critical protein tau.
‘Thanks to this new funding, we will be closer to understanding a key feature of Alzheimer’s, designing treatments to increase resilience in those at risk, and helping limit the impact of this devastating disease.’
A review led by Professor Simon Lovestone, from the Department of Psychiatry, discovered signs of Alzheimer’s disease in dolphins, testing the idea that living long after the end of fertility might be linked to Alzheimer’s disease.
Like humans, dolphins are almost unique in living long after they are capable of having children while most animals tend to die shortly after the end of their fertile years.
The collaborative team from Oxford and the Universities of St. Andrews, Edinburgh and Florida, found signs of Alzheimer’s in the brains of dolphins which had died after washing up ashore on the Spanish coast, making it the first study to find unambiguous signs of the disease in a wild animal.
‘We think that in humans, insulin signalling has evolved, with the effect of prolonging lifespan beyond the fertile years, but it also leaves us open to diabetes and Alzheimer’s Disease.’
Without studying the behaviour of dolphins in the wild, it is difficult to know if older dolphins have similar memory problems and confusion as seen in people with Alzheimer’s disease.
However, the research team do not advocate carrying out tests on captive dolphins, and now hope to use this understanding in the lab to improve the way new drugs for Alzheimer’s disease are tested.
The role of viruses
While the causes of most cases of Alzheimer’s are currently unknown, experts at Oxford have discovered that common viruses appear to play a role in some cases of Alzheimer’s disease – in particular, herpes simplex virus type 1 (HSV-1), the so-called cold sore virus.
Professor Ruth Itzhaki from the Oxford Institute of Population Ageing has been researching the potential role of HSV-1 in Alzheimer’s disease for more than 30 years.
In a recent collaborative study with Tufts University and the University of Manchester, the researchers discovered major links between the effects of the VZV virus (which causes chickenpox) and the characteristic features of Alzheimer’s.
‘This striking result appears to confirm that, in humans, infections…can cause an increase in inflammation in the brain, which can reactivate dormant HSV-1. The damage in the brain by repeated infections over a lifetime would lead eventually to the development of Alzheimer’s disease and dementia.’
In a piece written for The Conversation, Professor Itzhaki discusses the exciting developments being made investigating the neurological impacts of infectious diseases and a possible role for vaccinations in reducing Alzheimer’s risk.
Genetic risk factors
Uncovering the genetic link
Currently, there is no cure for Alzheimer’s disease; however, the disease is known to have a strong genetic component.
An estimated 60-80% of the risk of Alzheimer’s disease can be explained by genetic factors, and for early onset Alzheimer's (before age 65) this increases to more than 90%.
As part of an international collaboration involving researchers from Europe, the USA and Australia, Oxford Population Health contributed to the largest genetic study to date on patients with Alzheimer’s, the results of which more than doubled the number of genetic regions associated with the disease.
The researchers, including co-author of the study Professor Cornelia van Duijn, performed a genome-wide association study (GWAS), an approach which analyses the entire genome of thousands or tens of thousands of people, whether healthy or sick, to identify genetic risk factors associated with specific aspects of the disease.
‘This study has expanded our current understanding of Alzheimer’s disease, and opened up new avenues for translational genomics and personalised medicine.’
The study used samples in the European Alzheimer & Dementia Biobank, which includes 20,464 clinically diagnosed cases of Alzheimer’s disease and 22,244 controls from 15 European countries, as well as data from the UK Biobank, which were analysed by the Oxford Population Health team.
Using this method, the scientists were able to identify 75 regions of the genome associated with Alzheimer's, 42 of which had never previously been associated with the disease.
The results were also used to devise a new genetic risk score which could be applied within clinical care in the near future, also enabling clinical trials to test therapeutic treatments for people genetically at high risk of Alzheimer’s disease, but who have not yet developed the condition.
‘If we can show anti-neurodegenerative effects at a 'younger age' in those genetically at high risk, we can move the field forward towards effective, early-stage interventions.’
A collaborative study involving a large group of international researchers, including Professor Cornelia van Duijn and Dr Najaf Amin from Oxford Population Health, led to the discovery of two new 'Alzheimer genes', and evidence for a third. A genetic alteration in any one of these genes can lead to a significantly increased risk of Alzheimer's disease.
Researchers compared more than 32,000 genomes from patients with Alzheimer’s disease and healthy individuals, discovering that damaging mutations in two genes could lead to Alzheimer's disease, that had not been previously observed.
This significant find suggests that using each person’s unique genome, it may become possible to identify, before symptoms occur, those individuals with an increased risk of Alzheimer’s disease, enabling the timely application of personalised treatment strategies in the future.
‘This new study demonstrates the value of investigating rare genetic mutations to further our understanding of this devastating disease.’
Treating Alzheimer’s
Rethinking Alzheimer’s treatments
Alzheimer’s disease has a long prodromal period – a time when the disease is active in the brain but not yet causing substantial, if any, symptoms.
Researchers believe identifying people in this pre-clinical phase may reveal a window of opportunity where drugs would be more likely to be effective.
The Translational Neuroscience & Dementia Research group, led by Professor Noel Buckley and part of the Department of Psychiatry, undertakes translational research with the aim of developing prevention strategies for Alzheimer’s disease and related dementia disorders.
The Deep and Frequent Phenotyping (DFP) study is a is a multi-site study involving researchers from the Translational Neuroscience & Dementia Research group and the Department of Psychiatry, and is funded by the MRC and NIHR as part of Dementias Platform UK.
The study will observe individuals showing signs of pre-clinical Alzheimer’s as they undergo a regular range of tests to assess changes to their condition.
Dr Vanessa Raymont, chief investigator of the Deep and Frequent Phenotyping (DFP) study and senior clinical researcher in the Department of Psychiatry, discusses why DFP is unique in the quest to know more about the earliest stages of Alzheimer's disease.
The DFP study aims to address the difficulties of developing early-stage treatments by creating a database of different measures taken from people at risk of Alzheimer's disease. Researchers are recruiting 250 participants from across the UK who are over 60 and in good health, but with a family history of dementia.
For its size, DFP is the world's most detailed study to date into preclinical Alzheimer's disease.
Professors Simon Lovestone and Clare Mackay from the Department of Psychiatry spoke to BBC World at One about the DFP study. The researchers hope that the broad range of tests on people in middle-age will open up paths to early diagnosis and offer clues to effective treatments for Alzheimer’s disease before major damage to the brain has been done.
Professor Lovestone appeared on BBC File on 4, exploring balancing the need for more research with the need for better care for people living with dementia.
In a piece written for The Conversation, Dr Ivan Koychev from the Department of Psychiatry discusses the importance of identifying Alzheimer’s in its pre-clinical stages, and the digital technologies that could provide these solutions in the not-too-distant future.
Discovering life-changing treatments
Your beautiful, complex brain is a network of microscopic cells that connect together to form your thoughts and personality, and control your body. The network is fragile and requires constant upkeep, like a garden. The brain has its own gardeners, specialised cells called microglia.
In this animation, Oxford Sparks looks at how researchers at the University of Oxford are developing drug treatments for Alzheimer’s disease, by harnessing the power of the brain’s microglia.
From genes to medication
The Alzheimer’s Research UK Oxford Drug Discovery Institute (ODDI) couples the deep disease knowledge and biology expertise of Oxford’s academic community with high quality, innovative drug discovery technologies, to accelerate the discovery of effective therapies for Alzheimer's disease and other neurodegenerative diseases.
Housed within the Target Discovery Unit, part of the Nuffield Department of Medicine, the institute is part of a newly formed, world-class, network of three drug discovery institutes, sponsored by Alzheimer’s Research UK.
The ODDI is led by Dr John Davis and acts as a hub for Alzheimer’s drug discovery research, by collaborating with laboratories from several departments across Oxford, other universities and industrial partners.
A collaborative agreement between the ODDI, the Oxford Parkinson’s Disease Centre (OPDC) and FORMA Therapeutics, was formed to develop enzyme inhibitors for the treatment of neurodegenerative diseases.
The group of enzymes targeted in the research offers an exciting opportunity for the generation of new disease-modifying therapies.
‘We hope to make rapid progress towards identifying new treatment approaches and raising hope of some relief for the families coping with these dreadful conditions.’
In another industry collaboration, ODDI has joined forces with Exscientia, a leading AI Drug Discovery company, to develop medicines targeting neuroinflammation for the treatment of Alzheimer’s disease.
This exciting partnership unites Exscientia's AI-driven molecular design capabilities with the deep therapy area knowledge and technical expertise of the Alzheimer’s Research UK Oxford Drug Discovery Institute.
‘Human genetic variation points towards a critical role for the body’s immune system in an individual’s risk of developing Alzheimer’s disease. It is vital that we develop treatments that target neuroinflammatory mechanisms underlying dementia.’
The burden caused by Alzheimer’s disease and other dementias represents one of the biggest problems for our healthcare systems.
The ODDI brings together chemists, biologist, psychiatrists and neuroscientists, many of them with pharmaceutical background, aiming to accelerate the discovery of new and effective treatments.
Dr John Davis discusses why improving treatments for Alzheimer’s is so vital.
Patient-focused trials
Researchers across Oxford are conducting clinical trials investigating how existing pharmaceutical drugs could be used to tackle the symptoms and progression of Alzheimer’s disease.
The Impact of Semaglutide in Amyloid Positivity (ISAP) trial is a collaboration between the Diabetes Trials Unit, the Department of Psychiatry and the global healthcare company Novo Nordisk.
The ISAP trial, led by Dr Ivan Koychev, will test the effects of Semaglutide, a drug used to treat diabetes, on the build-up of a protein (tau) in the brain that characterises Alzheimer's disease, as well as brain inflammation, and people's memory and thinking abilities.
The trial is at the forefront of further testing the concept that the long 'preclinical' stage of dementia, that is, the 10-20 years period during which the condition develops without symptoms, is a window of opportunity delay or even prevent dementia.
‘The ISAP study will be critical in establishing if brain glucose metabolism and neuroinflammation treatments (such as semaglutide) hold potential for delaying, or even preventing Alzheimer's disease.’
Innovation at Oxford
Oxford Brain Diagnostics (OBD), a spinout from researchers at the Nuffield Department of Clinical Neurosciences, has developed a breakthrough diagnostics platform offering clinicians a new path to evaluating the potential advancement of Alzheimer's disease.
OBD’s Cortical Disarray Measurement (CDM®) Software Device uses non-invasive MRI brain scan data linked to changes in the brain at a cellular level, offering sensitive and accurate assessment of the neurodegeneration associated with Alzheimer’s disease and other dementias.
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