Alzheimer's Disease as Type 3 Diabetes: Understanding the Link and Implications

Abstract

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two prevalent conditions that present considerable public health issue in aging populations worldwide. Recent research has proposed a novel conceptualization of AD as "type 3 diabetes", highlighting the critical roles of insulin resistance and impaired glucose metabolism in the pathogenesis of the disease. This article examines the implications of this association, exploring potential new avenues for treatment and preventive strategies for AD. Key evidence linking diabetes to AD emphasizes critical metabolic processes that contribute to neurodegeneration, including inflammation, oxidative stress, and alterations in insulin signaling pathways. By framing AD within this metabolic context, we can enhance our understanding of its etiology, which in turn may influence early diagnosis, treatment plans, and preventive measures. Understanding AD as a manifestation of diabetes opens up the possibility of employing novel therapeutic strategies that incorporate lifestyle modifications and the use of antidiabetic medications to mitigate cognitive decline. This integrated approach has the potential to improve patient outcomes and deepen our comprehension of the intricate relationship between neurodegenerative diseases and metabolic disorders.

Keywords: Alzheimer’s disease; glucose metabolism; neurodegeneration; public health; type 2 diabetes.

Figure 1

Common molecular pathologies between type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD). In T2DM, cells become less responsive to insulin, leading to hyperglycemia. Hyperglycemia results in oxidative stress and inflammation, both of which contribute to mitochondrial dysfunction, reducing glucose metabolism and accelerating AD pathology. The BBB breakdown limits insulin transport into the brain, causing brain insulin resistance, which prolongs hyperinsulinemia. This downregulation of insulin receptors correlates with increased glycogen synthase kinase 3 beta (GSK-3β) activity and elevated amyloid precursor protein (APP) mRNA expression, resulting in the accumulation of Aβ and neurofibrillary tangles (NFT). High levels of pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), activate the nuclear factor kappa-light-chain-enhancer of the activated B cells (NF-κB) pathway and the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, perpetuating chronic inflammation, which exacerbates amyloid beta (Aβ) and tau pathologies in neurons. These inflammatory processes are further sustained by the oxidative stress and mitochondrial dysfunction present in both T2DM and AD. High levels of glycosylated hemoglobin (Hb), another consequence of hyperglycemia, are linked to cognitive dysfunction. Created with BioRender.com, accessed on 25 October 2024.

Figure 2

The risk factors and symptoms associated with Alzheimer’s Disease. Abbreviations: APOE ε4—apolipoprotein E4; APP—amyloid precursor protein; PDPKs—phosphoinositide-dependent protein kinases; PSEN1—presenilin 1; PSEN2—presenilin 2. Created with BioRender.com, accessed on 25 October 2024.

Figure 3

Current treatment options for Alzheimer’s disease (AD). FDA-approved drugs include both symptom-mitigating agents (brexpiprazole, galantamine, and rivastigmine) and disease-modifying treatments (aducanumab, lecanemab). Insulin resistance targeting focuses on pioglitazone, which improves insulin sensitivity via peroxisome proliferator-activated receptor gamma (PPAR-γ) activation, with the potential to reduce inflammation and cognitive decline. Growing interest has been directed toward the potential use of glucagon-like peptide-1 (GLP-1) receptor agonists in AD, based on their success in treating T2DM and their effects on neural health. GLP-1 receptor agonists, such as liraglutide, semaglutide, and exenatide exert neuroprotective actions by promoting insulin sensitivity, reducing neuroinflammation, and enhancing neuronal survival. Similarly, sodium–glucose cotransporter-2 (SGLT-2) inhibitors, another class of antidiabetic agents, are being explored for their neuroprotective potential in AD. SGLT-2 inhibitors, such as empagliflozin and dapagliflozin, work by reducing glucose reabsorption in the kidneys, thus improving glycemic control in T2DM patients and showing potential in AD treatment. Psychological therapies, such as music and reminiscence therapy, have been shown to alleviate symptoms and enhance the quality of life in patients. Physical activity, particularly aerobic exercise and resistance training, can promote neurogenesis, improve blood flow, and support cognitive functions. The Mediterranean diet, rich in fruits, vegetables, whole grains, and healthy fats, is associated with a reduced risk of AD. This figure highlights the importance of combining pharmacological and lifestyle interventions to optimize AD management and improve patient outcomes. Created with BioRender.com, accessed on 25 October 2024.