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Promising ‘first’ in Alzheimer’s drug development

An international team of researchers has made a promising breakthrough in the development of drugs to treat Alzheimer’s Disease.
For the first time, scientists have developed a drug that works on both major aggregation-promoting ‘hotspots’ of the Tau protein – addressing a critical gap in current treatments.
The drug, a peptide inhibitor called RI-AG03, was effective at preventing the build-up of Tau proteins – a key driver of neurodegeneration – in both lab and fruit fly studies.
The research was undertaken by the University of Southampton in collaboration with Lancaster University, Nottingham Trent University, Tokyo Metropolitan Institute of Medical Science and UT Southwestern Medical Centre.
Dr Anthony Aggidis is lead author of the paper, Visiting Researcher at the University of Southampton and former Postdoctoral Research Associate at Lancaster University.
He said: “Our research represents an important step toward creating treatments that can prevent the progression of diseases like Alzheimer’s disease.
“By targeting both of the key areas on the Tau protein, this unique approach could help address the growing impact of dementia on society, providing a much-needed new option for treating these devastating diseases.”
Tau proteins play a crucial role in maintaining the structure and function of neurons (brain cells).
But in Alzheimer’s disease, these proteins malfunction, clumping together to form long, twisting fibrils.
As the fibrils accumulate, they create what are called neurofibrillary tangles – masses of twisted Tau proteins that clog the neurons, preventing them from getting the nutrients and signals they need to survive.
As more neurons die, memory, thinking, and behaviour become increasingly impaired, leading to the cognitive decline seen in Alzheimer’s.
There are two specific ‘hotspots’ of the Tau protein where this clumping tends to happen.
While current treatments target one or the other of these hotspots, RI-AG03 uniquely targets and blocks both.
The peptide-based approach is also more targeted than current treatments, potentially making it safer, with fewer side effects.
The paper describes how RI-AG03 was first developed by Dr Aggidis, in the laboratory of the late Prof David Allsop, using computational biology at Lancaster University, where it was tested in lab dishes.
To test its effectiveness in cells within a living organism, researchers at the University of Southampton then gave the drug to fruit flies that had pathogenic Tau.
These fruit fly models of Alzheimer’s Disease were generated by Dr Shreyasi Chatterjee who is a Senior Lecturer at Nottingham Trent University.
The researchers found the drug suppressed neurodegeneration and extended the lives of the flies by around two weeks – a significant extension considering the life span of the insects.
To understand what was happening, Southampton’s scientists looked deep into the brains of the fruit flies.
Prof Mudher said: “When we didn’t feed the flies with the peptide inhibitor, they had lots of the pathogenic fibrils, which group together to make up a tangle. But when we fed them with the drug, the pathogenic fibrils decreased significantly in quantity.”
“The higher the dosage given, the greater the improvement we saw in the fruit fly’s lifespan.”
To make sure this wasn’t unique to fruit flies, researchers at UT Southwestern Medical Centre tested the drug in a biosensor cell – a type of living human cell line that is engineered to detect pathogenic tau fibril formation.
Here too, they found the drug successfully penetrated the cells and reduced the aggregation of Tau proteins.
The team believe their work will have a significant impact on drug discovery efforts in the field of neurodegenerative diseases and now plans to test RI-AG03 in rodents, before proceeding to clinical trials.
The research was funded by the Alzheimer’s Society.
Dr Richard Oakley, Associate Director of Research and Innovation, said: “Dementia is the UK’s biggest killer, and it applies enormous cost and pressure to our healthcare system which is why we’re committed to funding world leading studies like this one.
“This research is taking promising steps towards a new one-of-a-kind therapy which targets Tau, a damaging protein in the brains of people living with Alzheimer’s, preventing it from clumping together.
“This drug has the potential to be more targeted than others currently being studied, and we hope it will result in fewer toxic side effects.
“It’s important to note that the study is in its early stages, so we don’t yet know if it will work or be safe for humans, but it’s an exciting development and we look forward to seeing where it leads.
“Research will beat dementia, but we need to make it a reality sooner through more funding, more partnerships, and more people taking part in dementia research.
Image: University of Southampton
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AI can predict Alzheimer’s with almost 93% accuracy, researchers say

Alzheimer’s AI can predict the disease with nearly 93 per cent accuracy using more than 800 brain scans, researchers say.
The system identified anatomical changes in the brain linked to the onset of the most common form of dementia, a condition that gradually damages memory and thinking.
The findings build on years of research suggesting AI could help spot early Alzheimer’s risk, predict disease and identify patients whose condition has not yet been diagnosed.
Benjamin Nephew, an assistant research professor at the Worcester Polytechnic Institute in Massachusetts, said: “Early diagnosis of Alzheimer’s disease can be difficult because symptoms can be mistaken for normal ageing.
“We found that machine-learning technologies, however, can analyse large amounts of data from scans to identify subtle changes and accurately predict Alzheimer’s disease and related cognitive states.”
The study used MRI scans, a type of detailed brain imaging, from 344 people aged 69 to 84.
The dataset included 281 scans showing normal mental function, 332 with mild cognitive impairment, an early stage of memory and thinking decline, and 202 with Alzheimer’s.
The scans covered 95 of the brain’s nearly 200 distinct regions and used an AI algorithm to predict patients’ health.
Being able to use AI to help diagnose Alzheimer’s earlier could give patients and doctors crucial time to prepare and potentially slow the progression of the disease.
The analysis showed that one of the top predictive factors was brain volume loss, or shrinkage, in the hippocampus, which helps form memories, the amygdala, which processes fear, and the entorhinal cortex, which helps provide a sense of time.
This pattern held across age and sex, with both men and women aged 69 to 76 showing volume loss in the right part of the hippocampus, suggesting it may be an important area for early diagnosis, the researchers noted.
However, the research also found that the way brain regions shrink differs by sex.
In females, volume loss occurred in the brain’s left middle temporal cortex, which is involved in language and visual perception. In males, it was mainly seen in the right entorhinal cortex
The researchers believe this could be linked to changes in sex hormones, including the loss of oestrogen in women and testosterone in men.
These conclusions could help improve methods of diagnosis and treatment going forward, Nephew said.
More than 7.2m Americans are living with Alzheimer’s, according to the Alzheimer’s Association.
More research is being done to reveal other impacting factors.
Nephew said: “The critical challenge in this research is to build a generalisable machine-learning model that captures the difference between healthy brains and brains from people with mild cognitive impairment or Alzheimer’s disease.”
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