Glycosylation – What it is and Why it May Be Harming Your Brain

One of the questions I’m most often asked is whether there is anything truly new in Alzheimer’s research. While headlines tend to focus on amyloid plaques and tau tangles, some of the most exciting discoveries are emerging, not surprisingly, from an we spend a lot of time exploring: metabolism.

For years, I’ve emphasized that Alzheimer’s disease is not simply a disease of abnormal proteins. It is, fundamentally, a  disease of impaired energy production, mitochondrial dysfunction, inflammation, and disrupted glucose metabolism. In fact, brain imaging studies have shown that reduced glucose utilization can appear decades before symptoms, like memory issues, develop. This is why  I’m making my best effort to getting this information to the cognitively intact folks who may be at risk for metabolic issues.

Now, a fascinating new study published in Nature Metabolism identifies another metabolic player in Alzheimer’s disease: hyperglycosylation, an excessive buildup of sugar-based structures called glycans on proteins. I know this is a new term for many of you, so let’s unpack.

Glycans are essential to life. They help proteins fold correctly, regulate communication between cells, influence immune function, including our microglial cells in the brain, and support healthy brain activity. The problem, according to this study, may arise when glycan production becomes excessive.

The researchers examined human Alzheimer’s brain tissue and found dramatically elevated levels of glycans compared to healthy brains. Even more striking, glycan accumulation increased as the disease progressed, suggesting a close relationship between hyperglycosylation and disease severity.

To determine whether this was simply a consequence of Alzheimer’s disease or an active contributor, the investigators turned to animal models. When they reduced glycan production in mice with Alzheimer’s disease, memory performance improved. When they increased glycan production, memory worsened. These findings suggest that hyperglycosylation may be doing more than merely accompanying the disease, it may be helping drive it.

One of the most interesting aspects of the study involved glucosamine, a supplement commonly used to support joint health. Glucosamine feeds directly into the biochemical pathway responsible for producing glycans. When the researchers gave glucosamine to mice with Alzheimer’s disease, glycan production increased and memory performance declined further.

The team then analyzed electronic health records from tens of thousands of individuals with mild cognitive impairment and dementia. Among patients with established dementia, glucosamine use was associated with faster disease progression and poorer outcomes. While these observational findings do not prove cause and effect, they certainly raise important questions and warrant further investigation.

What makes this study especially compelling is how well it fits into a broader understanding of Alzheimer’s disease as a metabolic disorder. For decades, researchers have recognized that the Alzheimer’s brain struggles to utilize glucose efficiently. Mitochondrial performance declines, inflammation increases, and energy production becomes compromised. This new research suggests that abnormal glycan production may be another downstream consequence of that metabolic dysfunction.

Importantly, this does not mean glycans are harmful. Nor does it mean everyone should immediately stop taking glucosamine. Glycans are essential for normal physiology, and much more research is needed before broad clinical recommendations can be made. The key message is one of balance. Just as inflammation is necessary but harmful when chronically excessive, glycosylation may become problematic when it exceeds normal physiological limits.

For me, perhaps the most important takeaway is that this study validates many of the recommendations I have been making for years. When I encourage people to control blood sugar, remain physically active, prioritize restorative sleep, and consume a whole-food diet, the goal is to support the metabolic machinery that keeps the brain resilient.

What can you do today? Minimize ultra-processed foods and excess added sugars. Exercise regularly to improve insulin sensitivity and mitochondrial function. Prioritize restorative sleep. Build meals around vegetables, healthy fats, quality protein, nuts, seeds, legumes, and low-glycemic fruits. These are the same lifestyle choices that support healthy metabolism throughout the body and, increasingly, they are proving to be fundamental for brain health as well.

This study introduces a fascinating new mechanism related to Alzheimer’s disease and highlights glycation as a potential therapeutic target for the future. But for now, let’s hold on to the idea that our lifestyle choices can directly impact this process for better or worse.