The brain is the organ in the body that scientists know the least about. What we do know is that for its size (around 1.4 kg for an adult) it uses a disproportionate amount of resources. The brain is 2% of body mass but consumes 20% of the oxygen we inhale, and this is largely spent on transmission of electrical impulses from one brain region to another or out to muscles and internal organs. In close concert to oxygen consumption in the brain is the use of glucose as the main energy source. The delivery of glucose and oxygen to the brain via the blood is tightly correlated with brain activity, and remains almost constant throughout the day and our lives. This scenario is quite distinct from organs such as muscles, the liver and fat tissue where glucose uptake is controlled by the hormone insulin. This is not to say that insulin doesn’t have a role in the brain, but we will return to that story shortly.
The latest figures for Australia have two chronic brain diseases, Alzheimer’s disease (AD) and Stroke, as second and fourth leading causes of death respectively (1). The main risk factor for both diseases is ageing, with the increase in human longevity afforded by modern medicine and good cardiovascular health, contributing to the rapid rise of AD as an unintentional side effect. Brain diseases can be broken down into those affecting the blood supply and those affecting the brain tissue itself. Stroke is a vascular disease and the risk factors for, and drugs effective against, are very similar to heart disease. AD is the result of the loss of brain tissue from areas that contribute to memory and spatial awareness although AD shares some of the same risk factors as the vascular diseases such as smoking, high blood pressure, obesity and diabetes (2).
Indeed, AD has been referred to by some researchers as type 3 diabetes (3). This is based on experiments that showed similarities in the downstream molecular features of AD brains and the liver, for example, in those with type 2 diabetes. It might seem strange to be talking about insulin resistance in the brain when we know that glucose uptake into the brain is independent of insulin. However, insulin still affects the utilisation of glucose within the brain and probably acts as a neuron protective factor. Although there is evidence for changes in the AD brain consistent with type 2 diabetes, it seems more likely that the disease is a culmination of small effects of many different factors and processes that include diabetes, being female and having fewer years of education (4).
In the AD brain there is build-up of two proteins called beta-amyloid and tau. Beta-amyloid was thought to be the main problem but experimental drugs that remove amyloid have so far failed to stop disease progression. This has led to researchers and drug companies to redirect their focus to tau, oxidative stress and inflammation but there is no other obvious target to date. A likely scenario is that a successful future drug will be a combination of medicines that address multiple targets including insulin resistance.
In the absence of a cure, is it possible to slow or prevent AD at present? Well not smoking, eating a balanced healthy diet, maintaining physical and mental activity into old age are all proven ways of reducing your risk. Yet, the answer may ultimately lie in your genes – individuals with one or both parents with AD have an incrementally higher risk of developing the disease themselves. In the not too distant future, your GP armed with your sequenced genome, will be able to advise you what food, drinks or exposures to avoid from an early age, and also what drugs you might need in middle to old age to slow AD. This is referred to as precision medicine and will be a common approach in the future management of all diseases.
- Causes of Death, Australia, 2018 Australian Bureau of Statistics; 2019.
- Livingston and colleagues. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission.
- de la Monte and colleagues. The 20-Year Voyage Aboard the Journal of Alzheimer’s Disease: Docking at ‘Type 3 Diabetes’, Environmental/Exposure Factors, Pathogenic Mechanisms, and Potential Treatments.
- Chami and colleagues. The rise and fall of insulin signaling in Alzheimer’s disease.
A/PROF GREG SUTHERLAND is a research and teaching academic in the Charles Perkins Centre (CPC) at the University of Sydney. His research interest is neurodegenerative diseases including alcohol-related brain damage and Alzheimer’s disease (AD). In the CPC he leads the ‘Brain and Body’ node that aims to understand how diseases like diabetes increase the risk of brain disorders such as AD.
Contact: via the CPC Brain and body node.