New review sheds light on links between Alzheimer's and metabolic syndrome

Alzheimer's disease (AD), the most common form of dementia, continues to remain one of modern medicine's greatest challenges. This progressive neurodegenerative disorder affects millions of people worldwide, with numbers expected to reach 150 million by 2050. Characterized by declining memory and cognitive function, AD has a devastating impact on patients and families, besides imposing a heavy burden on healthcare systems, with no truly effective treatments being available.

Research in recent years has yielded a growing body of evidence linking AD to metabolic syndrome (MetS), a cluster of simultaneously-occurring conditions which includes diabetes, obesity, high blood pressure, and abnormal blood fat levels or dyslipidemia. While research has established some connections between AD and these individual conditions, the precise relationship between AD and each component of MetS remains unclear, particularly regarding the underlying biological mechanisms.

Against this backdrop, researchers led by Professor Yanping Sun and Professor Lan Tan, have now published a comprehensive literature review exploring these crucial connections. Published online in Brain Network Disorders on 13 December, 2024, their work particularly focuses on how disrupted fat metabolism might contribute to the development and progression of Alzheimer's. "The brain is largely composed of lipids, which are crucial for maintaining the structure and function of neurons," explains Professor Sun. Adding further, she says, "By knowing the connections between MetS and AD, and the specific mechanisms by which dyslipidemia contributes to AD, it will be possible to identify new treatment targets and potentially develop therapeutic strategies in the future."

The review reveals intricate connections between diabetes and AD, suggesting that issues related to insulin regulation might contribute to AD's development in unexpected ways. When the body becomes insulin resistant, it produces more of the hormone to maintain normal blood sugar levels. However, excess insulin can interfere with the brain's ability to clear away Aβ proteins, potentially leading to the formation of harmful amyloid plaques-a hallmark of AD. This connection is so significant that some researchers have begun referring to AD as "type 3 diabetes."

High blood pressure, another key component of MetS, appears to have its own distinct impact on brain health. Existing research suggest that midlife hypertension may significantly increase the risk of developing dementia later in life. Brain imaging studies have also shown that high blood pressure can reduce the thickness of the brain's cortex and potentially promote the development of AD, particularly in individuals carrying specific genetic risk factors like Apolipoprotein E4 (APOE4).

The relationship between obesity and AD presents a complex picture, with timing apparently playing a crucial role. The researchers indicated that being overweight in middle years, rather than in later life, may be more strongly linked to the development of different forms of dementia and cognitive decline. Brain scans of obese individuals have revealed changes similar to those seen in AD, including reductions in gray matter volume.

Perhaps most intriguingly, the review highlights how dyslipidemia may play a central role in connecting these various conditions to AD. Various past analyses have found links between dysregulation in the metabolism of cholesterol and fatty acids with harmful brain or neuronal conditions. These include neuronal inflammation, Aβ protein buildup, blood-brain barrier breakdown, and oxidative stress, which were all analyzed in detail from a molecular biology perspective in the article.

Importantly, this literature review points to the fact that maintaining healthy blood fat levels may be more important for brain health than previously thought. Promising preventive or therapeutic strategies that are currently under study even include cholesterol-lowering medications and dietary approaches, such as mediterranean and ketogenic diets and omega-3 fatty acid supplementation. "Approximately one-third of Alzheimer's cases worldwide may be linked to modifiable risk factors," notes Professor Sun, "With the increasing prevalence of high-fat diets and longer lifespans, understanding how MetS and dyslipidemia contribute to cognitive decline has become critical."

Overall, this comprehensive review represents a step towards cementing our current understanding of the complex relationship between lipid metabolism and brain function. Even as the occurrence of both MetS and AD continue to rise globally, these insights could play a vital role for the development of more effective prevention strategies and treatments.