This is the 59th instalment in a series on dementia, including the research into its causes and treatment, advice for carers and stories of hope. The so-called amyloid hypothesis has dominated thinking on Alzheimer’s disease for more than a century – since German psychiatrist and neuropathologist Alois Alzheimer found abnormal clumps of proteins called amyloids in a deceased patient’s brain in 1906. Today we know these as amyloid plaques, which, along with tau tangles – the build-up of tau proteins inside neurons – are primary features of Alzheimer’s disease. Their occurrence can set up a catastrophic chain reaction that ultimately leads to the symptoms we associate with dementia. But having amyloid deposits in the brain does not always lead to dementia. Some people exhibit amyloid plaques and tau tangles but never develop the characteristic symptoms of dementia. This is usually explained by a patient’s cognitive reserve – the brain’s resistance to damage, which we can build up by keeping the brain active and through continued social interaction as we age. A 2006 paper from the University of Minnesota in the United States, published in the journal Nature, that later became one of the most cited in the field of Alzheimer’s, seemed to prove that it was indeed amyloid that caused the memory loss and cognitive decline associated with dementia. In 2022, however, key images used in that paper were deemed to have been doctored to better fit the scientists’ conclusion. The paper has since been retracted. The incident prompted American investigative journalist and author Charles Piller to cast doubt on the amyloid hypothesis in his recent book, Doctored: Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s. There are many ideas about what might cause or influence Alzheimer’s disease beyond amyloid proteins Charles Piller, investigative journalist and author “I was stunned at first that an experiment that had been so important in supporting the amyloid hypothesis had been based on apparently doctored images and misconduct,” Piller says, noting that in every walk of life, a small minority of people will cut corners or even commit fraud for personal gain. “And although image doctoring in Alzheimer’s research represents just a small fraction of the overall body of work, it can still have serious effects in skewing ideas and slowing advances.” That is not to say amyloids have nothing at all to do with Alzheimer’s, Piller says, but there are other mechanisms at play which may not have received the attention they should have. “There are many ideas about what might cause or influence Alzheimer's disease beyond amyloid proteins,” Piller says. For a start, there is a lot of interesting work going on regarding the possible benefits of a class of drugs called GLP-1 agonists, including ongoing clinical trials that might provide important results. GLP-1 agonists include semaglutide – the basis of weight-loss drugs Ozempic and Wegovy. They mimic the action of the hormone GLP-1 that helps to regulate insulin and blood sugar levels in the body. They are also able to penetrate the blood-brain barrier and might aid in clearing toxic proteins. GLP-1 drugs also have anti-inflammatory and neuroprotective properties and the ability to balance insulin in the body – which is key: people with type 2 diabetes are at much higher risk – more than 50 per cent higher – of developing Alzheimer’s compared with people without diabetes. Alzheimer’s researchers are increasingly pointing to brain insulin resistance as a risk factor for the disease, and that explains why it is sometimes called type 3 diabetes. Daniel Drucker, a professor in the department of medicine at the University of Toronto in Ontario, Canada, has conducted significant research into GLP-1 medicine and its impact on organs including the brain. He says GLP-1 drugs “improve blood flow, decrease inflammation in the brain, improve the health of brain cells, enhance the blood-brain barrier that protects the brain, and also [increase] connectivity and communication among brain cells”. “Whether these actions will translate into a clear meaningful benefit in reducing deterioration of cognitive function is not yet known,” he says, adding studies are ongoing. There is also increasing evidence that infections which can lie dormant in the human body for years, such as herpes simplex virus (HSV) type 1, might be a significant factor in the development of Alzheimer’s later. Again, trials are ongoing, Piller says. There are eight types of herpes virus that infect people, all of which can remain latent in the body for life once a person is infected. HSV-1 is by far the most strongly implicated in Alzheimer’s disease. Ruth Itzhaki, emeritus professor of the neuroscience division at the University of Manchester in the UK, is gratified by the recognition of the possible role of the HSV virus in the development of Alzheimer’s. She and her team first published the idea in 1991, and she remembers that, “The idea of an infectious agent – HSV-1 – in a so-called sterile brain was shocking and the possibility that it had a major role in Alzheimer’s disease was even more shocking.” Yet, she says, there is evidence that HSV-1 is present in a high proportion of the brains of elderly people. But how does it predispose them to dementia? It is probably dormant in brains most of the time, she says. “But [it] can be reactivated, via brain inflammation, probably by things like stress, UV light, fever, brain injury, inflammation” – similar to stressors that would cause a flare-up of cold sores that are caused by the same virus. The virus then replicates and spreads, causing damage and inflammation and triggering a vicious circle. After repeated infections or head injuries – rugby players’ risk of developing dementia is twice as high as that of non-players – reactivation occurs repeatedly, causing cumulative damage. Eventually this may lead to the development of Alzheimer’s. Scientists continue to try to unpack the causes of dementia. In the absence of a cure we need to understand the risk factors for the disease and do our best to manage or mitigate them. Like what you read? Follow SCMP Lifestyle on Facebook, X and Instagram. You can also sign up for our eNewsletter here.