Clarifying the relationship between alcohol use and dementia
Whilst heavy alcohol use has been identified as a key modifiable risk factor for dementia, previous studies have shown that low to moderate alcohol use is beneficial when compared with both abstaining and heavy alcohol use. However, previous research has limitations. With alcohol use increasing among older adults, further research is needed to clarify the relationship between low to moderate alcohol use and the risk of dementia. Using large-scale data combined across 15 international studies (48,965 people), the current project aims to investigate the relationship between different patterns of alcohol use and dementia in adults aged over 65 years. The use of large-scale data will allow an unprecedented examination of the relationship between patterns of alcohol use and dementia, and how these may differ according to key clinical and demographic characteristics. This project will contribute to evidence-based recommendations on the number of standard drinks associated with minimal dementia risk. These practical recommendations will have a clear benefit in terms of dementia risk reduction in the wider community.
Optimising daily activity patterns for brain health in older adults
Achieving enough physical activity and sleep, and limiting sedentary behaviour (e.g. prolonged sitting), improves brain function and reduces dementia risk in older adults. These three behaviours coexist to make up the 24-hour day, and to increase time spent in one of these, time must be taken away from another. We still do not know the best combination of these behaviours within a 24-hour time period for cognition or dementia risk in older adults. This project will investigate how brain health and function in older adults is affected by how much time is spent sleeping, engaging in physical activity or being sedentary across the 24-hour day. This information will be collated to understand “best day” patterns for optimal brain health and function in healthy older adults. The findings will contribute to the development of an interactive app which will predict how changing time use (e.g. reducing sitting time and increasing sleep) affects an individual’s brain health and function.
Investigating the effect of Factor Xa anticoagulant on dementia risk
Individuals with an irregular heartbeat or recurrent blood clots are often prescribed drugs that thin the blood long-term. Some of these treatments include drugs inhibiting FXa, an important protein of the blood clotting process. However, FXa is known to be capable of performing multiple tasks besides regulating clots. In platelets, a type of blood cells that are important in wound healing and clot formation, FXa is capable of controlling ADAM10, a protein responsible for managing the breakdown of Amyloid Precursor Protein (APP) into harmless fragments. Reduced function of FXa may potentially cause incorrect processing of APP into Amyloid Beta (Aβ) peptides, a sticky toxic substance that drives the development of Alzheimer's disease. As platelets are the main producer of APP in the blood, we first aim to investigate, in test-tube settings, the processing of APP in healthy platelets after exposure to FXa inhibitors. Next, we will give anti-FXa drugs to mice, and then analyse their blood for signs associated with Aβ production. Finally, we will compare the blood of patients on long-term FXa inhibitor and other anticoagulants for levels of Aβ peptides. As direct FXa inhibitors are now widely used, we must understand how these drugs may increase the risk of dementia.
In-vivo synaptic correlates of cognitive reserve
Given that the incidence of Alzheimer’s disease increases with age, it has been estimated that delaying dementia onset by 5 years would decrease the prevalence of late-onset dementia by 50%. In this project we will investigate the biological basis of Cognitive Reserve, a protective property of the brain known to delay dementia onset, but whose underlying mechanisms remain a mystery. Because the cognitive deficits in Alzheimer’s disease are strongly associated with a loss of synapses – the point of communications between neurons – we believe that Cognitive Reserve is first implemented at the synaptic level as a way to preserve neuronal communication. In this project we will take a state-of-the-art microscopy approach to directly visualise the loss of synapses inside the brain of a living Alzheimer’s disease animal model and the compensatory and regenerative events that follows that might serve as the basis of Cognitive Reserve. Given that therapeutics targeting the formation of amyloid pathology have failed in numerous clinical trials, we will focus on the protective mechanisms of the brain to cope with pathology rather than on those leading to pathology in the first place. The outcomes of this project may be instrumental in developing effective therapeutics harnessing these protective mechanisms as a way to delay the onset of dementia.
Personalising care of people with dementia through music: Development and testing of a training program for aged care workers
People living with dementia often experience mood disturbances such as depression or agitation, which can have a big impact on quality of life and carer stress levels. The use of drug-based treatments for these mood disturbances are often undesirable because of side-effects, so the development of cost-effective non-pharmaceutical treatments is highly important. There is considerable evidence that music can have a positive influence on the mood of people living with dementia. However staff buy-in and knowledge are significant barriers to the effective use of music programs in aged care facilities in Australia. This project will merge the experience of Western Sydney University and HammondCare to develop an online training program for aged care staff and home-based carers of people living with dementia. The course, to be developed in close partnership with end users and people with lived experience of dementia, will help caregivers to understand the potential for music to be used as part of individual care plans to manage mood-related symptoms in dementia.
Enhancing the TBK1-p62 axis as a therapeutic strategy for frontotemporal lobar degeneration
Frontotemporal lobar degeneration (FTLD) is the most common cause of dementia in younger people. Autophagy is a natural process where damaged proteins and mitochondria (tiny specialised structures responsible for energy production) are removed from the cell. In FTLD, autophagy is reduced, which leads to a build-up of damaged proteins (TDP-43) and damaged mitochondria in brain cells, causing them to die. Autophagy requires a protein called p62, which is activated by another protein,TBK1. In 3-4% of FTLD cases a change in the TBK1 gene leads to a mutated TBK1 protein being produced. Researchers don’t yet know how mutant TBK1 proteins cause FTLD. However, we found that two mutant TBK1 proteins did not activate p62, which reduced autophagy and caused TDP-43 to build-up in the brain. We will now test whether other mutant TBK1 proteins fail to activate p62 and cause TDP-43 and mitochondria to build-up. Our study will help researchers to understand exactly how TBK1 gene mutations cause FTLD. Increasing TBK1 levels may reduce the build-up of TDP-43 and damaged mitochondria in the brain and this could be beneficial in FTLD. Therefore, we will also test potential therapeutic compounds to find those that enhance TBK1 levels.
Harnessing habits to increase physical activity in people with Mild Cognitive Impairment and Subjective Cognitive Decline.
For older people experiencing decline to their memory and thinking skills, keeping physically active is important to maintain brain health and reduce risk of dementia. Despite this, over 80% of older Australians do not do enough physical activity in their daily lives. To date, interventions to help people increase their physical activity levels have involved setting goals, planning and self-monitoring, which are challenging for people with thinking and memory difficulties. Recent research suggests that automatic, every-day habits play an important role in maintaining physical activity levels over the long-term. The current project aims to target these habits to help people with mild cognitive impairments create healthy, automatic habits of regular physical activity, that are easy to maintain over the long-term. To achieve this, we will develop and pilot the Harnessing Automatic Behaviours Intervention Trial (HABIT), a personalised physical activity behaviour change intervention for people with mild cognitive impairment. The results of the HABIT pilot will be used to guide a larger community trial of the intervention, and produce practical advice for people experiencing thinking and memory declines about how to use habit to increase their everyday physical activity to levels that are beneficial for brain and cognitive health.
Personalising dosage regimens of medicines in Alzheimer's disease
Alzheimer’s disease is a medical condition affecting the brain. However, recent evidence suggests that our body is also affected by Alzheimer’s disease and as such, may absorb or metabolise medicines differently. Compared to those who do not have the disease, people living with Alzheimer’s disease tend to have more medical conditions and consume more medicines. Therefore, they are more likely to experience undesirable effects from medicine(s) or, as the body does not handle medicines in the same way as someone without Alzheimer’s disease, suffer the effects of under or overdosing. Prescribing practices can be improved if we understand what changes actually happen in our body when we have Alzheimer’s disease. Our project uses cutting-edge technology to thoroughly screen for the changes in a mouse model of Alzheimer’s disease as well as in human tissues. This information will be used to generate pharmacokinetic profiles of medications of interest. The profiles will promote medication safety and effectiveness in people with Alzheimer’s disease by helping doctors to decide the best treatment, with the least number of medicines, at the right dose.
Characterising and inducing a protective microglia phenotype in human Alzheimer’s disease.
Despite intensive research into Alzheimer’s disease, we still have no cure. Recent studies show a strong genetic association of late onset Alzheimer’s disease to microglia, a critical cell type in the brain essential for proper functioning of nerve cells and removing damage in the brain. We discovered two types of microglia in the brains of mice modelling Alzheimer’s disease. Our data unveiled that one type of microglia protects the brain by removing damage associated with Alzheimer’s, whereas the other show a prematurely aging identity. This project will investigate whether the same types of microglia that we discovered in the mouse also exist in the brains of human Alzheimer’s patients, and whether they play the same role in human disease. Our analyses predicted drugs that can control the switch between the two types of microglia. In this project, we will test whether turning microglia into our newly discovered beneficial type can yield new cellular manipulation technologies for therapeutic intervention to benefit people living with dementia.
Do therapeutically targetable deficits in neuroplasticity drive Frontotemporal Dementia?
Frontotemporal dementia (FTD) is a devastating neurodegenerative disease that is in desperate need of new therapeutic interventions. We have identified a novel mechanism that may be causing the nerve cell loss that causes FTD. Changes to synapses - the specialised structures that allow nerve cells to communicate with each other – may be an early disease-causing event in FTD. TDP-43, a DNA processing protein, is one of the main proteins that have been identified to play a role in FTD. We have revealed convincing evidence that the dysfunction of TDP-43 can lead to the synaptic disturbances that characterises FTD. It is now time to carefully map the earliest changes in synapses and try and prevent these changes from happening. This proposal will use live imaging in real time to pin point the earliest disease causing changes and then try and prevent these changes from happening.
Use of brain organoids and artificial intelligence for understanding dementia.
In this project, we present a novel strategy for diagnosis and treatment of Alzheimer’s disease (AD) using an innovative approach that combines technologies in stem cell research with artificial intelligence (AI). The stem cell component of this project is to develop ‘brain organoids’ or ‘mini-brains’ from stem cells taken from people living with AD as well as individuals unaffected by the disease. The stem cell derived brain organoids will essentially model brain function ‘in-the-dish’. We will then apply computational and AI-based analyses to identify key functional differences between normal and AD brain organoids and predict stimulation parameters that may promote ‘normal’ brain function. These studies are the first of their kind in combining cell biology and AI computational approaches to study and find treatments for AD.
Supporting expression of sexuality by older people with dementia in long-term care from a person-centred care approach.
Dementia causes many changes in people’s lives, including changes to intimate relationships, sex & expression of sexuality. Understanding preferences for expression of sexuality are fundamental in improving physical and sexual health, quality of life and psychosocial well-being for people living with dementia. The project develops and evaluates a tool to improve the care and support of people living with dementia in long-term care settings from a person-centred approach. Knowledge gained from the tool will allow health professionals to extend care provision into a previously neglected area via developing and/or revising guidelines for practice (e.g. care plans and procedures). It implies potential significant improvements in the understanding as well as care practices of health and care professionals towards expression of sexuality so as to enable the facilitation of a care environment that is supportive of the verbalisation and expression of sexual preference, need and desire by people living with dementia.
Investigating the impact of acute muscle injury-induced inflammation on the brain in the elderly.
A serious complication following a fall-related injury and hospitalisation is the onset of delirium, which can also lead to dementia. This occurs when the body’s defences, including the immune system, are in decline. We have previously found a major defect in key immune cells, known as macrophages, which help explains why repair following injury is slower in the elderly. This defect is likely to have profound effects at other sites, such as the brain and may lead to declining cognitive function following acute injury. Yet, few studies have examined the combined effects of declining immune function on injury repair and impact on brain function. This project will examine changes to the brain of young versus elderly hosts following injury and immune targeting therapy. This will determine whether an ageing immune system influences brain function following acute injury and has the potential to identify new avenues for treatment in the elderly.
Protein Changes that Underlie Selective Vulnerability in Alzheimer’s disease.
The aim of this research is to understand why some neurons are particularly vulnerable in Alzheimer’s disease. Determining why some neurons are vulnerable, and conversely why some neurons are protected, provides a unique opportunity to identify the protein changes that are responsible for the development of Alzheimer’s disease. This study will comprehensively profile the pathological protein changes that occur in vulnerable neurons in early stage Alzheimer’s disease. Specific protein changes that appear to be driving vulnerability in Alzheimer’s disease will be identified and additional experiments performed to determine how these specific protein changes lead to neuron death in Alzheimer’s disease. Results from this study will increase understanding about the cause of Alzheimer’s disease and will identify new drug targets for early stage Alzheimer’s disease.
Making sense of hearing-related neurocognitive impairment: The Auditory Ageing and Cognitive Impairment (AUDACIOUS) Pilot Study.
It is well established that older adults with significant hearing difficulties are more likely to experience cognitive decline and dementia. This link between hearing loss and problems with memory and thinking may be due to communication difficulties, that then lead to withdrawal from activities that are good for maintaining brain health. It is thought that managing hearing loss with hearing aids and other hearing health interventions may reduce a person’s future risk of dementia. However, quality evidence for this is lacking. The Auditory Ageing and Cognitive Impairment Study (AUDACIOUS) will examine the extent to which the relationship between poor hearing and impaired cognitive functioning is explained by lower levels of participation in mentally stimulating activities. It will also investigate if use of hearing rehabilitation services and hearing aids protect against decline. The project findings will have important implications for dementia prevention interventions and practice in hearing health.
Estimating the value of informal care provided to people with dementia in Australia.
There are approximately 200,000 Australians providing informal care to a person with dementia. While informal carers spend a significant amount of time on caregiving, the time costs of informal care are often neglected in health policy decisions, including funding decisions. This is often due to the lack of robust methods to place a monetary value on time spent on caregiving. To overcome this problem, the aim of this project is to derive a preference-based monetary value of the time costs of informal care provided to people with dementia, accounting for positive and negative impacts of informal care. This information will ultimately improve policy advice that utilises cost-effectiveness information and will facilitate the inclusion of the time costs of informal care in future economic evaluations of health care interventions. As such, this project has the potential to improve the quality of dementia care across Australia and the services that people living with dementia and their carers receive.
Getting home safely: Phase 1 - Generating agreement on national policies and procedures for reporting a missing person with dementia.
Disease causing dementia can damage areas of the brain responsible for navigation which places people with dementia at greater risk of getting lost even in familiar places. There are currently no guaranteed methods of preventing people with dementia from becoming lost other than 24/7 supervision. Internationally and in Australia there is strong evidence that delaying a search for the lost person increases the risk of finding them injured, deceased or not at all. In the US, Canada and Scotland alert systems are already being used to inform police and the broader community that a person with dementia is lost. The Getting Home Safely Project aims to revise and develop a standardised approach to reporting a missing person with dementia in Australia to improve health outcomes for this vulnerable population. In Phase one we will be working with police, carers and people with dementia to develop recommendations for this new approach.
A cognitive-mobility stress test to detect MCI and risk of conversion to dementia.
A difficulty for doctors is that not all people with cognitive problems develop dementia. This study will determine if a simple Cognitive-Mobility Stress Test can distinguish between people with subjective cognitive complaints or mild cognitive impairment. It will also provide data for a larger project aimed to predict risk of developing dementia.
The Cognitive-Mobility stress test involves performing a cognitively challenging task whilst walking. We hope that for the clinician, such a simple, inexpensive and non-invasive test will assist with risk stratification and in decision making for further assessment and management. For the individual, better knowledge of prognosis will reduce anxiety and assist in making preventative lifestyle changes and decisions for the future.
Closing the evidence-practice gap in young onset dementia care: a pilot implementation trial.
Although people with young onset dementia (under 65 years at symptom onset; YOD) have been eligible for the National Disability Insurance Scheme (NDIS) since 2016, many have reported problems with accessing support that meets their needs. Research by our team established guidelines for service delivery, but no work has been conducted to bridge the gap between this research and clinical practice. This study aims to improve the knowledge and competence in YOD service provision among NDIS Planners, who sit at the coal-face of assessing needs and developing formal support plans. We will determine whether a multi-component education and mentoring strategy can effectively improve the practices of NDIS planners, encourage innovative and meaningful collaboration with aged and community service providers, and promote best outcomes for people with YOD and their families.
Spatial convergence of dementia and cardiovascular disease risk: evidence to inform policy and practice.
Delivery of more effective preventive intervention efforts to reduce and delay onset of dementia and cardiovascular disease (CVD) events requires knowing where high levels of convergence of dementia and CVD risks occur in communities. As dementia and cardiovascular disease share many of the same risk factors, this project will develop an innovative method to identify clusters and overlap of dementia and cardiovascular disease risk across communities. These risk maps will then be overlayed and contrasted against other available data for built environment and lifestyle factors for the regions in question. These hotspot data have the potential to support targeted, area specific primary prevention activity in health service delivery. Dementia and CVD risk prediction will provide the first rigorous evaluation of future risk of dementia and CVD at the individual level, and will enable clinicians, Public Health Networks and policymakers to design tailored health promotion strategies as well as follow up individuals with higher risk profiles.