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| Year & Author, Country |
Design |
Aim |
Findings |
Level of Evidence |
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| Aljanabi et al. (2020, USA) [2] |
Review Paper |
1. To investigate the association between insulin resistance and cognitive impairment, with a focus on Alzheimer's disease (AD). 2. Identify the most effective therapy regimen for reducing AD development in people with impaired glucose metabolism. |
A link between Alzheimer's disease (AD) and impaired insulin signaling, where insulin resistance leads to the hyperphosphorylation of tau proteins, contributing to neurofibrillary tangles, oxidative stress, and cognitive decline. Insulin influences cognition in a bidirectional way: peripheral insulin increases dementia risk, while controlled intranasal or intravenous insulin shows potential for improving cognitive function. Therapeutic options like Metformin and GLP-1 agonists have shown mixed results, with some studies suggesting neuroprotective benefits. Intranasal insulin holds promise, but further research is needed to confirm the effectiveness and safety of these treatments in preventing or slowing AD progression. |
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| Baglietto-Vargas et al. (2016, USA) [13] |
Review Paper |
To tackle new results in animal model and clinical research including the use of anti-diabetic drugs as promising therapies for AD, as well as highlight the participation of numerous novel pathogenic molecular processes caused by DM that contribute to AD pathogenesis. |
A strong link between diabetes and Alzheimer's disease. In people with diabetes, the brain has trouble using insulin, which may lead to memory loss and cognitive decline. High blood sugar can make this worse by increasing harmful proteins in the brain that cause damage. Diabetes also causes inflammation and stress on brain cells, making them weaker over time. Some diabetes medications, like insulin taken through the nose, have shown promise in improving memory and brain function. However, other treatments, like Metformin, may need to be used carefully, as they could increase the risk of Alzheimer’s in certain cases. |
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| Burillo et al. (2021, Spain) [1] |
Review Paper |
To examine the primary molecular pathways implicated in the link between type 2 diabetes and neurodegeneration, specifically Alzheimer's disease. |
This research highlights the connection between type 2 diabetes (T2DM) and Alzheimer's disease (AD), focusing on shared mechanisms like insulin resistance, inflammation, and oxidative stress. Impaired insulin signaling disrupts glucose metabolism and increases the risk of brain damage, including amyloid-beta (Aβ) plaque buildup and tau protein dysfunction, both key contributors to AD. Endoplasmic reticulum (ER) stress and autophagy dysfunction also play a role, leading to cell death and further cognitive decline. Chronic inflammation and the buildup of advanced glycation end-products (AGEs) worsen insulin resistance and contribute to neurodegeneration. Treatments targeting these pathways, such as autophagy enhancers and insulin therapies, show potential, but more research is needed to fully understand their therapeutic effects on AD progression in T2DM patients. |
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| Čater & Hölter (2022, Germany) [3] |
Review Paper |
To provide an overview of the existing animal models that are used to study the overlap between diabetes and Alzheimer’s disease, and to discuss the potential mechanisms linking the two conditions. |
Recent research has shed light on the complex connection between diabetes and Alzheimer's disease, revealing that both conditions share key physiological pathways, including impaired insulin signaling, disrupted glucose transport, and cholesterol dysfunction, which primarily impact brain regions like the hypothalamus and hippocampus. These shared mechanisms lead to overlapping symptoms such as metabolic dysregulation, neurodegeneration, and cognitive decline. Core pathological processes include inflammation, oxidative stress, mitochondrial dysfunction, and amyloid plaque formation. While animal models, especially rodents, have been essential in advancing research, their physiological differences from humans pose challenges for translating findings into human treatments. Transgenic models, which more accurately reflect human disease, are helping researchers better understand these diseases and test potential therapies. Further research is needed to refine these models and pinpoint precise therapeutic targets for both diabetes and Alzheimer's. |
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| Chatterjee & Mudher (2018, United Kingdom) [4] |
Review Paper |
To explore how insulin resistance in T2DM worsens Aβ and tau diseases and identify similar pathological features. |
Insulin resistance (IR) in Type 2 diabetes mellitus (T2DM) worsens Alzheimer's disease (AD) pathology by impairing glucose uptake in the brain and disrupting key signaling pathways, such as PI3K/AKT and MAPK. This leads to increased GSK-3β activity, which results in the hyperphosphorylation of tau proteins, forming neurofibrillary tangles (NFTs) that contribute to synaptic dysfunction and neuronal death. Additionally, insulin resistance affects the brain's ability to manage amyloid-beta (Aβ) proteins, which accumulate as plaques in AD. Studies using animal models have shown that both insulin resistance and hyperglycemia accelerate these neurodegenerative processes, linking T2DM with increased tau phosphorylation and impaired amyloid-beta clearance. Impaired lipid metabolism further exacerbates these effects, highlighting the critical role of metabolic dysfunction in the progression of AD. |
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| Fiore et al. (2019, Italy) [9] |
Review Paper |
To demonstrate the strong correlation between AD and DM. |
Alzheimer's disease (AD) risk is heightened by hyperinsulinemia and insulin resistance, which promote the buildup of amyloid plaques and increased tau protein synthesis, leading to neurodegeneration. Impaired insulin signaling contributes to decreased brain glucose metabolism, resembling an AD-like pattern. Hyperinsulinemia also accelerates the formation of neurofibrillary tangles and senile plaques, further exacerbating insulin resistance. Additionally, both T2DM and AD are associated with vascular damage, although the precise mechanism connecting vasculopathy in T2DM to AD remains unclear. Effective diabetes management—through exercise, a low-fat diet, and medication for glycemic control—can help prevent hyperglycemia and hypoglycemia, potentially reducing the risk of cognitive decline and AD. |
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| Huang et al. (2017, China) [7] |
Review Paper |
To draw awareness to the connection between diabetes mellitus and Alzheimer's disease, as well as the function that TLR4 activation plays in insulin resistance. |
Toll-like receptor 4 (TLR4) plays a crucial role in both diabetes mellitus (DM) and Alzheimer's disease (AD). TLR4 is strongly linked to insulin resistance, influenced by gut microbiota changes and free fatty acids from adipose tissue, contributing to persistent insulin resistance. Chronic TLR4 activation leads to inflammation, impacting both the body's internal environment and the brain, causing complications such as diabetic retinopathy, neuropathy, and nephropathy. In Alzheimer's disease, TLR4-mediated neuroinflammation is present at all stages, contributing to amyloid-beta (Aβ) buildup and brain damage. The activation of TLR4 is a key factor connecting DM and AD, as it contributes to both insulin resistance and neuroinflammation, potentially linking the progression of these two diseases. |
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| Kimura (2016, Japan) [12] |
Review Paper |
To summarize histological evidence indicating diabetes mellitus (DM) causes Alzheimer's disease (AD) pathology in animal models and examine the notion that abnormal insulin signaling is a critical factor in AD pathology. |
Type II diabetes significantly increases the risk of developing Alzheimer's disease (AD), primarily due to abnormal insulin signaling. Both type I and type II diabetes worsen AD pathology, as shown in animal models, where disrupted insulin signaling accelerates the formation of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFTs). Diabetes exacerbates Aβ pathology by increasing its production and decreasing its clearance, due to the heightened activity of enzymes responsible for Aβ accumulation. It also aggravates tau pathology by overactivating GSK3β, an enzyme that promotes tau phosphorylation. Normally, insulin signaling inhibits GSK3β, but insulin resistance in diabetes leads to its abnormal activation, resulting in more tau tangles and neuronal damage. Studies have shown that insulin treatment improves AD pathology in animal models, highlighting the link between diabetes and AD progression. |
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| Kubis-Kubiak et al. (2020, Poland) [5] |
Review Paper |
The main goal is to investigate and identify potential biomarkers for Alzheimer’s disease that could aid in early diagnosis and track disease progression, especially in the context of diabetes mellitus. |
Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) share several pathophysiological characteristics, such as insulin resistance, disrupted glucose metabolism, and the buildup of toxic proteins like amyloid-beta (Aβ) and tau. Impaired insulin signaling in the brain is central to both conditions, affecting memory, cognitive function, and neuronal survival. Abnormal glucose metabolism not only contributes to T2DM but also exacerbates AD by increasing the production and accumulation of amyloid plaques and promoting tau hyperphosphorylation. Metabolic disturbances are key contributors to the progression of AD, emphasizing the importance of biomarkers related to glucose and insulin metabolism for early diagnosis. Biomarkers like Aβ42, total tau, and phosphorylated tau, though promising, still have limitations in preclinical detection, underscoring the need for more reliable diagnostic tools. The use of diabetic medications, such as insulin therapy, shows potential in improving cognitive function in AD patients, with some studies indicating that intranasal insulin may slow cognitive decline. However, the effectiveness of such treatments remains a topic of debate, highlighting the need for further research. |
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| Madhusudhanan et al. (2020, India) [10] |
Review Paper |
- to examine the pathophysiology of AD from the standpoints of the more recent T2DM-dependent pathways that are backed by data from T2DM patients, as well as the traditional protein accumulation theory.
- to examine the various mechanisms by which hyperglycemia exacerbates neurodegeneration, using AD as a case study.
- to discuss some of the most recent improvements in the understanding of how metabolic problems cause neurodegeneration and how this has led to advancements in the treatment of AD. |
The understanding of Alzheimer's disease (AD) is expanding beyond its traditional view as a neurodegenerative disorder, with growing research linking it to Type 2 Diabetes Mellitus (T2DM). Studies suggest that insulin resistance, common in T2DM, may contribute to cognitive decline and memory issues, supporting the theory that diabetic individuals are at higher risk of developing AD. Animal models have shown that diet-induced insulin resistance worsens AD pathology. Amylin, a neuropeptide from the pancreas, is also implicated in AD progression, with its accumulation exacerbating symptoms in T2DM patients. Elevated tau hyperphosphorylation, a hallmark of AD, is linked to insulin signaling disruptions in the brain. Inflammation, particularly through toll-like receptor 4 (TLR4) activation, plays a role in both diseases, contributing to insulin resistance and neuroinflammation. Therapeutic options like Metformin, Thiazolidinediones (TZDs), and amylin analogues show potential in improving cognitive function for both conditions, while fibroblast growth factor 21 (FGF21) has demonstrated similar benefits in preclinical studies. |
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| Michailidis et al. (2022, Greece) [8] |
Review Paper |
To discuss the shared pathophysiological connections between AD and T2DM |
Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share several common pathological processes. Insulin resistance, a hallmark of T2DM, impairs glucose regulation and is linked to hyperglycemia, while also contributing to neuroinflammation and disease progression in AD. Neuroinflammation, driven by insulin and IGF-1 resistance, worsens both conditions. Oxidative stress, caused by an imbalance in reactive oxygen species (ROS), leads to neuronal damage, amyloid plaques, tau tangles in AD, and impaired insulin signaling in T2DM. Advanced Glycosylation End Products (AGEs) further contribute to amyloid aggregation and neurotoxicity in AD. Mitochondrial dysfunction exacerbates oxidative stress and insulin resistance, leading to neurodegeneration. Metabolic syndrome, characterized by high blood pressure, high blood sugar, and abnormal cholesterol, increases the risk of both AD and T2DM by promoting these shared pathological mechanisms. |
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| Nguyen et al. (2020a, Vietnam) [11] |
Review Paper |
To demonstrate the basic mechanisms of insulin resistance mediates dysregulation of bioenergetics and its progress to Alzheimer's Disease (AD). |
The findings highlight a strong connection between insulin resistance and cognitive decline, indicating that insulin-sensitizing drugs could potentially alleviate Alzheimer’s disease (AD) symptoms. Insulin signaling in the brain is crucial for maintaining glucose metabolism, and insulin resistance is a common feature in both diabetes and AD. Therapeutic approaches aimed at improving insulin sensitivity, such as the use of anti-diabetic drugs, lifestyle changes, and nutraceuticals, show promise in slowing AD progression by enhancing glucose metabolism, reducing amyloid-beta buildup, and mitigating neuroinflammation. Research on rodents also suggests that vegetables and fruits rich in bioactive components like carotenoids, antioxidants, polyphenols, and flavonoids may protect against cognitive decline and brain damage caused by oxidative stress. Curcumin and other nutraceuticals offer further potential as therapeutic options for enhancing cognitive function in AD. |
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| Nguyen et al. (2020b, Vietnam) [27] |
Review Paper |
- to illustrates how the basic processes of insulin resistance promote dysregulation of bioenergetics and advance to AD.
- to establish a viable and promising zone for improved hypometabolism and changed insulin signalling, which could lead to the development of therapeutics for AD. |
To fully understand insulin’s role in both healthy and diseased brains, more data on the relationship between Alzheimer’s disease (AD) severity and age-matched controls is needed. Lower central nervous system (CNS) insulin levels are linked to increased amyloid-beta (Aβ) accumulation and reduced clearance, worsening AD pathology. Several mouse models of AD exhibit impaired insulin signaling, but more research is required to understand how AD affects the diabetes phenotype. Insulin receptors are most abundant in the olfactory bulb, cerebral cortex, and hippocampus, and insulin plays a vital role in cell survival by influencing apoptotic pathways. Insulin resistance is a shared feature of diabetes, obesity, and AD, with excess insulin leading to disrupted neuronal processes and cognitive decline. Hypometabolism in AD is driven by reduced glucose availability, affecting synapse function and contributing to neurodegeneration. Therapeutic approaches that target insulin resistance and aim to improve energy metabolism are crucial, as no specific treatments have yet proven effective in preventing cognitive decline or AD progression. |
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| Nisar et al. (2020, Pakistan) [19] |
Literature
review |
Explore the genetic link between the two illnesses ( DM and AD). |
The pathophysiology of both diabetes mellitus (T2DM) and Alzheimer's disease (AD) involves a combination of genetic and environmental factors. Insulin resistance is a key mechanism that impairs brain function, linking T2DM directly to cognitive decline and AD progression. Uncontrolled inflammatory stress in neurons promotes the buildup of amyloid and tau proteins, which worsen AD. Genetic mutations in the amyloid precursor protein (APP) contribute to amyloid-beta aggregation, with APP present in both brain and pancreatic tissues, suggesting shared pathways between AD and T2DM. Research has identified around 759 genes linked to both conditions, with pathways like CREBBP, MAPK, and PI3K-AKT playing crucial roles in insulin signaling and memory processes. Both genetic predispositions and environmental factors, such as diet and lifestyle, accelerate brain atrophy, making these shared mechanisms critical to understanding and treating both diseases. |
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| Rorbach-Dolata & Piwowar (2019, Poland) [20] |
Review Paper |
To present the most recent and significant data related to the phenomena of Type 3 Diabetes. From a pharmacological standpoint, it also addresses the possible gaps in diabetes prevention and diagnosis that could lead to neurometabolic problems. |
The relationship between Alzheimer’s disease (AD) and diabetes, particularly Type 2 diabetes mellitus (T2DM), is increasingly understood through mechanisms such as poor insulin signaling, brain insulin resistance, and hyperglycemia-induced excitotoxicity. Glutamate, an excitatory neurotransmitter, plays a significant role in neurodegeneration through overstimulation, leading to neuronal death. Studies in diabetic mouse models have shown that hyperglycemia and insulin abnormalities increase tau protein phosphorylation and cleavage, contributing to AD pathology. Amyloid-beta (Aβ) deposits, common in both AD and T2DM, along with advanced glycation end products (AGEs), further aggravate these conditions. Impaired brain glucose metabolism, particularly in individuals carrying the APOE4 gene mutation, is considered a valuable marker for AD, often presenting years before cognitive impairment. Insulin resistance in the brain disrupts synaptic plasticity and contributes to neurodegeneration. Amylin, an amyloid polypeptide, is also implicated, with higher levels observed in insulin-dependent T2DM patients. Experimental treatments for Type 3 diabetes (T3D), such as the drug T3D-959, are showing promise. This PPAR agonist improves insulin signaling, reduces neuroinflammation, and normalizes neuropathology in clinical trials, highlighting the potential of treating AD as a neurometabolic disorder linked to hyperglycemia and insulin signaling dysfunction. |
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| Salas & De Strooper (2019, Belgium) [17] |
Review Paper |
Critically examine and understand the connection between Alzheimer's disease (AD) and metabolic disorders such as type 2 diabetes mellitus (T2DM), and review significant clinical and preclinical findings to determine how these metabolic conditions may elevate the risk of developing AD, particularly in the aging population. |
Epidemiological studies indicate a link between diabetes, particularly Type 2 diabetes mellitus (T2DM), and an increased risk of developing dementia, though the exact metabolic alterations responsible remain unclear. Cognitive impairments are more common in individuals with diabetes, with deficits noted in areas such as attention and cognitive flexibility. Population-based studies, like the Rotterdam study, suggest a nearly two-fold increase in dementia risk for T2DM patients, particularly for Alzheimer's and vascular dementia. T2DM is associated with decreased brain glucose metabolism, observed through reduced [18F]-fluorodeoxyglucose (FDG) uptake, which correlates with a higher risk of Alzheimer's disease. Structural brain abnormalities, including hippocampal volume loss and white matter dysfunction, are linked to cognitive decline in T2DM patients. Impaired insulin signaling, a hallmark of T2DM, contributes to amyloid buildup and tau hyperphosphorylation, both key processes in Alzheimer's pathology. Moreover, T2DM-related oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation further exacerbate Alzheimer's disease progression. Obesity, a common comorbidity with T2DM, adds to this risk by promoting systemic inflammation, which may lead to brain inflammation and increased dementia susceptibility. |
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| Shieh et al. (2020, Taiwan) [6] |
Review Paper |
To be able to obtain existing research studies on key proteins involved or link between neurodegenerative conditions and Diabetes Mellitus. |
Evidence showed that lifestyle choices are becoming significant contributors for accelerating onset of AD and Diabetes Mellitus (DM) is a major risk for neurodegeneration. Statistics: 1. 29% of Type II DM patients will eventually suffer severe decline in cognition and degeneration. 2. Vascular degeneration secondary to DM disrupts blood flow to the brain resulting in neuronal inflammation and further degeneration. Mitochondrial dysfunction has a significant impact in accelerating dementia onset especially AD. |
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| Schilling (2016, USA) [16] |
Review Paper |
Research has shown a significant correlation between diabetes and Alzheimer's disease, but the exact nature of this relationship is still unknown. To address this, this study will evaluate the data for each pathway and determine any important therapeutic implications. |
The findings suggest that maintaining healthy insulin-degrading enzyme (IDE) levels and avoiding excessive insulin may help prevent or reduce the effects of Alzheimer’s disease (AD). Insufficient IDE activity, linked to severe insulin insufficiency, can contribute to amyloid-beta buildup, a hallmark of AD. Reduced IDE synthesis is also associated with the Apolipoprotein E4 (ApoE4) allele, a significant genetic risk factor for AD. Excess insulin or amylin can inhibit the breakdown of amyloid-beta, as IDE’s ability to degrade amyloid-beta diminishes at higher insulin levels, a common issue in early-stage type 2 diabetes. The use of pramlintide, an amylin analogue, has shown promise in alleviating memory problems in AD mouse models. Further research is needed to confirm these findings and their implications for AD treatment strategies. |
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