Link Between Type 2 Diabetes Mellitus and Alzheimer's Disease

Editor: David L. Joffe, BSPharm, CDE, FACA

Seventeen common biomarkers were differentially expressed in patients with Alzheimer’s Disease or type 2 diabetes when compared with healthy controls. 

According to the World Health Organization, Alzheimer’s disease is the leading cause of dementia, accounting for about 60% – 70% of cases. The etiology of Alzheimer’s disease is still unclear; however, one of the hallmarks is the aggregation and deposition of amyloid-beta peptides on the extracellular surface of neuronal cells, leading to the formation of amyloid-beta oligomers and fibrils in the brain.  

Although Alzheimer’s disease is a central nervous system disorder and type 2 diabetes mellitus is primarily a peripheral disease, both diseases share standard features, such as long prodromal phases and chronic and complex conditions. In addition, both diseases show the involvement of chronic oxidative stress and inflammation in the disease progression. Risk factors for both diseases include age, poor dietary habits, obesity, chronic stress, genetic profile, and sedentary lifestyle.  

Proteomics is one of the most important methodologies for understanding the gene’s function but is more complex when compared with genomic technology. It is the characterization of the proteome, including expression, structure, function, interaction, and modification of overall proteins present in a cell, tissue, or organism at any stage.  

Pereira and researchers systematically reviewed the studies using proteomic methodologies to identify plasma/serum proteins in Alzheimer’s disease and compare them with a database of all plasma proteomic biomarkers identified for type 2 diabetes mellitus. The identification of common biomarker proteins for both diseases could facilitate a greater understanding of the pathophysiological mechanisms linking Alzheimer’s disease to type 2 diabetes mellitus.  

The QUADOMICS methodology was used to determine the quality of the studies. It is an adaptation of QUADAS, a quality evaluation tool for use in systematic reviews of diagnostic accuracy studies, which considers the technical particularity presented by omics methodologies. Studies reaching at least 9/14 queries of the QUADOMICS were classified as high quality, and those that scored less were classified as low quality.  

A panel of 17 proteins was identified by proteomic technology, which was differently expressed in type 2 diabetes mellitus and Alzheimer’s disease than control individuals. Those promising biomarkers are alpha-2-macroglobulin, apolipoprotein A1, apolipoprotein A4, apolipoprotein B-100, apolipoprotein E, ceruloplasmin, complement C4, galectin-3-binding protein, haptoglobin, inter-alpha-trypsin inhibitor heavy chain 1, inter-alpha-trypsin inhibitor heavy chain 2, Ig alpha-1 chain C region, Ig mu chain C region, Ig kappa chain C region, pancreatic polypeptide, transthyretin, and zinc alpha 2-glycoprotein. These findings may help establish a link between these diseases.  

Alpha-2-macroglobulin has increased in both Alzheimer’s disease and type 2 diabetes mellitus groups compared to controls. Apolipoprotein A1 plays various roles in human physiology, such as cholesterol transport and regulation of inflammation. Apolipoprotein A4 is the major component of HDL and chylomicrons and occurs in a lipoprotein-free form. Apolipoprotein B-100 was observed to be decreased in Alzheimer’s disease and increased in T2DM. Apolipoprotein E is the most potent genetic risk factor related to sporadic Alzheimer’s disease.  

Complement C4 is a part of the innate immune system and plays a vital role in regulating inflammation. Galectin-3-binding proteins are secreted proteins that can interact to promote cell-to-cell adhesion and are associated with pro-inflammatory signaling cascades. Haptoglobin (an acute-phase protein that scavenges the hemoglobin-released into circulation either by hemolysis or by red blood cell turnover, preventing hemoglobin-related oxidative damage) levels are higher in patients with type 2 diabetes mellitus. 

Inter-alpha-trypsin inhibitor heavy chain one is secreted by the liver and is responsible for systemic insulin resistance in animal models. Higher levels of the Ig chain C proteins were found in urinary samples from type 2 diabetes mellitus, with or without diabetic kidney disease, compared to healthy individuals. Pancreatic polypeptide is a hormone secreted by peripheral cells on pancreatic Langerhans islets, and its expression was increased in both Alzheimer’s disease and T2DM groups. Transthyretin is associated with type 2 diabetes mellitus and triglyceride levels in diabetes patients and augmented with increasing glucose intolerance severity. Finally, zinc alpha-2 glycoprotein is secreted into many bodily fluids and increases in type 2 diabetes mellitus.  

Researchers concluded that these biomarkers could provide a helpful workflow screening for type 2 diabetes mellitus patients at risk of developing Alzheimer’s disease.  

Practice Pearls: 

  • Type 2 diabetes mellitus increases the risk for dementia, particularly Alzheimer’s disease.  
  • Seventeen common biomarkers were differentially expressed in patients with Alzheimer’s disease and type 2 diabetes mellitus than healthy controls. 
  • The identified biomarkers could provide a valuable workflow for screening type 2 diabetes mellitus patients at risk of developing Alzheimer’s disease.   


Pereira, Jessica Diniz, et al. “Alzheimer’s disease and type 2 diabetes mellitus: a systematic review of proteomic studies.” Journal of Neurochemistry. 2021;156:753-776. doi.10.1111/jnc.15166 

Azeezat Rasaki, PharmD Candidate, Florida A&M University 

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By Betty C. Giordano

Welcome to my site. My name is Betty C. Giordano and I am a blogger of everything related to mobile, news, events and reality in general. I hope you enjoy reading my content.

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