Alzheimer’s disease is a complex condition that affects different parts of the brain in various ways. One key factor in the progression of the disease is the misbehavior of tau proteins, which can lead to toxic clumps forming inside neurons and impairing their function. Researchers have long sought to understand why some areas of the brain are more resilient to Alzheimer’s than others, a phenomenon known as selective vulnerability or resilience.

A recent study by researchers at the University of California, San Francisco (UCSF) has made significant strides in this area by combining advanced mathematical modeling with brain imaging and genetics. The study, published in Brain, identified multiple distinct pathways through which risk genes confer vulnerability or resilience to Alzheimer’s disease.

The researchers developed a model called the extended Network Diffusion Model (eNDM), which predicted where tau protein would spread next based on real-world brain connection data from healthy individuals. By applying this model to brain scans of 196 people at various stages of Alzheimer’s, they were able to identify areas that were resistant or vulnerable to the disease.

The study revealed four distinct types of genes: those that boost tau spread along the brain’s wiring (Network-Aligned Vulnerability), those that promote tau buildup in ways unrelated to connectivity (Network-Independent Vulnerability), those that help protect regions that are otherwise tau hotspots (Network-Aligned Resilience), and those that offer protection outside of the network’s usual path (Network-Independent Resilience).

These findings have significant implications for understanding Alzheimer’s disease and developing potential intervention targets. The study’s lead author, Ashish Raj, PhD, noted that their research offers a “hopeful map forward” in understanding and eventually stopping Alzheimer’s disease.

The researchers also highlighted the importance of considering the different biological functions of genes that respond independently of the network versus those that respond in concert with it. This nuanced approach could lead to more effective strategies for identifying potential intervention targets and developing treatments for Alzheimer’s disease.

The battle against Alzheimer’s disease and other forms of dementia has just received a surprise player: brain sugar metabolism. A new study from scientists at the Buck Institute for Research on Aging has revealed that breaking down glycogen – a stored form of glucose – in neurons may protect the brain from toxic protein buildup and degeneration.

Glycogen is typically thought of as a reserve energy source stored in the liver and muscles, but small amounts also exist in the brain. The research team, led by postdoc Sudipta Bar, PhD, discovered that in both fly and human models of tauopathy (a group of neurodegenerative diseases including Alzheimer’s), neurons accumulate excessive glycogen. This buildup appears to contribute to disease progression.

Tau, the infamous protein that clumps into tangles in Alzheimer’s patients, physically binds to glycogen, trapping it and preventing its breakdown. When glycogen can’t be broken down, the neurons lose an essential mechanism for managing oxidative stress, a key feature in aging and neurodegeneration.

By restoring the activity of an enzyme called glycogen phosphorylase (GlyP), which kicks off the process of glycogen breakdown, the researchers found they could reduce tau-related damage in fruit flies and human stem cell-derived neurons. Rather than using glycogen as a fuel for energy production, these enzyme-supported neurons rerouted the sugar molecules into the pentose phosphate pathway (PPP) – a critical route for generating NADPH (nicotinamide adenine dinucleotide phosphate) and Glutathione, molecules that protect against oxidative stress.

The team demonstrated that dietary restriction (DR) naturally enhanced GlyP activity and improved tau-related outcomes in flies. They further mimicked these effects pharmacologically using a molecule called 8-Br-cAMP, showing that the benefits of DR might be reproduced through drug-based activation of this sugar-clearing system.

Researchers also confirmed similar glycogen accumulation and protective effects of GlyP in human neurons derived from patients with frontotemporal dementia (FTD), strengthening the potential for translational therapies. The study emphasizes the power of the fly as a model system in uncovering how metabolic dysregulation impacts neurodegeneration.

The researchers acknowledge the Buck’s highly collaborative atmosphere as a major factor in the work, highlighting the expertise in fly aging and neurodegeneration, proteomics, human iPSCs, and neurodegeneration. The study not only highlights glycogen metabolism as an unexpected hero in the brain but also opens up a new direction in the search for treatments against Alzheimer’s and related diseases.

By discovering how neurons manage sugar, we may have unearthed a novel therapeutic strategy: one that targets the cell’s inner chemistry to fight age-related decline. As we continue to age as a society, findings like these offer hope that better understanding – and perhaps rebalancing – our brain’s hidden sugar code could unlock powerful tools for combating dementia.

A recent study by researchers at the Case Western Reserve School of Medicine has made an astonishing discovery that may revolutionize the way we approach dementia prevention. The research team found that semaglutide, a popular medication used to treat diabetes and aid in weight loss, could significantly lower the risk of dementia in people with type 2 diabetes (T2D).

Dementia is a devastating condition that affects millions worldwide, causing memory loss and cognitive decline. It occurs when brain cells are damaged, disrupting their connections and ultimately leading to this debilitating state. Encouragingly, studies indicate that approximately 45% of dementia cases could be prevented by addressing modifiable risk factors.

The study, published in the Journal of Alzheimer’s Disease, analyzed three years’ worth of electronic records from nearly 1.7 million T2D patients nationally. The researchers used a statistical approach that mimicked a randomized clinical trial to determine the effectiveness of semaglutide in preventing dementia.

Their findings suggest that patients prescribed semaglutide had a significantly lower risk of developing Alzheimer’s disease-related dementia compared to those taking other anti-diabetic medications, including GLP-1R-targeting medications. These results were even more pronounced in women and older adults.

Semaglutide, a glucagon-like peptide receptor (GLP-1R) molecule that decreases hunger and regulates blood sugar levels in T2D patients, has shown remarkable benefits beyond its primary use as a diabetes treatment. It also reduces the risk of cardiovascular diseases, further solidifying its potential in preventing dementia.

The study’s lead researcher, biomedical informatics professor Rong Xu, stated, “There is no cure or effective treatment for dementia, so this new study provides real-world evidence for its potential impact on preventing or slowing dementia development among at-high risk populations.”

While the findings are promising, it’s essential to note that further research through randomized clinical trials will be necessary to confirm the causal relationship between semaglutide and dementia prevention. Nevertheless, this groundbreaking study offers a glimmer of hope in the quest to combat dementia and improve the lives of millions worldwide.