Emerging links between type 2 diabetes and Alzheimer's disease
Open accessAbstract
Type 2 diabetes mellitus and Alzheimer's disease are both associated with increasing age, and each increases the risk of development of the other. Epidemiological, clinical, biochemical and imaging studies have shown that elevated glucose levels and diabetes are associated with cognitive dysfunction, the most prevalent cause of which is Alzheimer's disease. Cross sectional studies have clearly shown such an association, whereas longitudinal studies are equivocal, reflecting the many complex ways in which the two interact. Despite the dichotomy, common risk and etiological factors (obesity, dyslipidemia, insulin resistance, and sedentary habits) are recognized; correction of these by lifestyle changes and pharmacological agents can be expected to prevent or retard the progression of both diseases. Common pathogenic factors in both conditions span a broad sweep including chronic hyperglycemia per se, hyperinsulinemia, insulin resistance, acute hypoglycemic episodes, especially in the elderly, microvascular disease, fibrillar deposits (in brain in Alzheimer's disease and in pancreas in type 2 diabetes), altered insulin processing, inflammation, obesity, dyslipidemia, altered levels of insulin like growth factor and occurrence of variant forms of the protein butyrylcholinesterase. Of interest not only do lifestyle measures have a protective effect against the development of cognitive impairment due to Alzheimer's disease, but so do some of the pharmacological agents used in the treatment of diabetes such as insulin (especially when delivered intranasally), metformin, peroxisome proliferator-activated receptors γ agonists, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes must be recognized as a risk for development of Alzheimer's disease; clinicians must ensure preventive care be given to control and postpone both conditions, and to identify cognitive impairment early to manage it appropriately.
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Alzheimer's disease patients are predisposed to complications including increased oxidative stress, morbidity, mortality, microvascular disease, dyslipidemia, and insulin resistance.
“AD patients are predisposed to some complications including increased oxidative stress (Sultana et al., 2011), morbidity, mortality (Schelke et al., 2016), microvascular disease, dyslipidemia, and insulin resistance (Sridhar et al., 2015).”
From Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer's Disease: A Randomized, Double-Blind and Controlled Trial (2016) · cites this paper as Sridhar et al., 2015
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Franco, R., Martínez‐Pinilla, E., Navarro, G., & Zamarbide, M. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.01.004 · Cited by 59 · see citing works
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“Therefore, apart from the specific AD-associated outcomes, the molecular, biochemical, and cytopathological consequences of insulin deficiency/resistance in the brain closely resemble those that occur in diabetes mellitus and other insulin resistance diseases [15, 40].”
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“Dyslipidemia can be a result of genetic and diet factors, and several lipid subgroups, including fatty acids (saturated or unsaturated), triglycerides, cholesterol, and phospholipids, are altered in AD.(58,73,74) Hypertriglyceridemia is the main dyslipidemia linked to metabolic syndrome, a syndrome that also includes…”
BackgroundNew Insight into Diabetes Management: From Glycemic Index to Dietary Insulin Index
Yari, Z., Behrouz, V., Zand, H., & Pourvali, K. (2019) · Current Diabetes Reviews · doi:10.2174/1573399815666190614122626 · Cited by 50 · see citing works
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Emerging significance of butyrylcholinesterase
Sridhar, G. R., & Gumpeny, L. (2024) · World Journal of Experimental Medicine · doi:10.5493/wjem.v14.i1.87202 · Cited by 43 · see citing works
“Alzheimer’s disease (AD) that often accompanies aging is the most common cause of cognitive decline[36].”
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“Additionally, evidence from animal models suggests that metformin can decrease inflammatory responses in relation to cognition.(11,40) To address this, future studies could consider whether proinflammatory markers may confound, mediate, or modify the association between diabetes treatment type and cognitive outcomes.”
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Focus on the Correlations between Alzheimer’s Disease and Type 2 Diabetes
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“Evidence in the literature shows that hyperphosphorylation of tau protein leads to the formation of NFTs.”
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“Emerging therapies for the treatment of T2D and AD targeting Glucagon-like peptide-1 receptor (GLP1R) agonists have been proposed 31 .”
BackgroundAmylin in Alzheimer's disease: Pathological peptide or potential treatment?
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“Patients with AD are prone to a variety of complications, such as increased inflammatory markers and oxidative damage, mortality (35), microvascular disease, dyslipidemia, and insulin resistance (36).”
BackgroundEnzyme inhibitors from the aril of Myristica fragrans
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Alzheimer’s Disease: A Report From the 7th Kuopio Alzheimer Symposium
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“Intrana-sal insulin has shown significant improvement in various cognitive tests in patients with AD, mild cognitive impairment and in patients who are cognitively intact (Craft et al., 2012; Reger et al. 2006a, b; Reger et al., 2008; Benedict et al. 2004; Sridhar et al. 2015; Benedict et al. 2004).”
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“Met exhibits neuroprotective effects in Alzheimer’s disease and other neurodegenerative diseases (Ma et al. 2007; Sridhar et al. 2015).”
RetractedRobbins, J., Busquets, O., Tong, M., & de la Monte, S. M. (2020) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-200238 · Cited by 19 · see citing works
“Therefore, apart from the specific ADassociated outcomes, the molecular, biochemical, and cytopathological consequences of insulin deficiency/resistance in the brain closely resemble those that occur in diabetes mellitus and other insulin resistance diseases [8, 30].”
BackgroundHyperpolarized [1-13C]lactate flux increased in the hippocampal region in diabetic mice
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“Several studies have solidified the connection between diabetes and Alzheimer’s disease (Moreira, 2013; Crane et al., 2013; Sridhar et al., 2015; Barbagallo and Dominguez, 2014; Oskarsson et al., 2015; Akter et al., 2011; Kroner, 2009; Janson et al., 2004; Zhao and Townsend, 2009; Verdile et al., 2015).”
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“The Alzheimer’s disease connection appearing in this CABG vs CABG+T2DM comparison is interesting as Alzheimer links to both T2DM and atherosclerosis have been previously reported [34, 35].”
BackgroundDiabetic ketoacidosis further increases risk of Alzheimer’s disease in patients with type 2 diabetes
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“Strong evidence has underscored that type 2 diabetes and midlife obesity associated with insulin resistance are risk factors for development of dementia, PD, AD and HD (155-158).”
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“resistance and cognitive decline that can lead to associated psychiatric symptoms.[108] In addition, it is possible to”
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“Indeed, brain microvascular maladaptation and dysfunction may serve as key pathological links between these two diseases [8].”
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The ER chaperone, BIP protects Microglia from ER stress-mediated Apoptosis in Hyperglycemia
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Dietary Impact on Neuronal Autophagy Control and Brain Health
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“Patients with type 2 diabetes have an increased risk of developing AD [90], as insulin has been shown to prevent Aβ oligomer formation in a dose-dependent matter [90].”
Pre-structured hydrophobic peptide β-strands: A universal amyloid trap?
Sivanesam, K., & Andersen, N. H. (2019) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2019.01.032 · Cited by 8 · see citing works
“Clinical studies show that patients suffering from Type II Diabetes are at a higher risk of developing Alzheimer's disease and vice versa [145] [146] [147] .”
BackgroundZinc Transporters in Diseases, Including Diabetes and Related Conditions
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Diabetes Mellitus and Cognitive Decline – Prevention Should Not Be Delayed!
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“The pathophysiological basis remains uncertain but multiple factors are likely to play a part (21)including the hyperglycaemic state itself, hypoglycaemia, impaired neuroregulatory aspects of insulin action (leading to dysregulation of Aβ amyloid peptide, inflammation, modulating neurotransmitter…”
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“Furthermore, patients with T2DM generally show worse cognitive performance [10] and a higher risk of dementia [11,12].”
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The neurogenic effects of rosmarinic acid in a mouse model of type 2 diabetes mellitus
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“For example, it was reported that type II diabetes is a risk factor for developing AD (50,51) .”
BackgroundCognitive Impairment and the Diabetic Brain
Jellinger, K. A. (2015) · International Journal of Neurology and Neurotherapy · doi:10.23937/2378-3001/2/2/1033 · Cited by 4 · see citing works
“Intranasal administration of insulin successfully improved memory deficits without the risk of peripheral hypoglycaemia in AD patients [20,73,101,102].”
InfluentialEffects of long-term exposure to aluminum in the hippocampus in the type 2 diabetes model rats
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Wybrane zagadnienia z zakresu przemysłu spożywczego oraz zarządzania i inżynierii produkcji
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C-peptide: an essential ally in microvascular complications of type 2 diabetes mellitus and obesity
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“Cerebral microvascular impairments induced by metabolic dysfunction lead to perfusion abnormalities that represent an increased likelihood for the development of cognitive dysfunction and neurodegenerative disorders [4–8].”
BackgroundAdipobiology of the brain: From brain diabetes to adipose Alzheimer‘s disease
Aloe, L., Tonchev, A. B., Maucher, A., Fiore, M., Zhelezov, M., & Chaldakov, G. N. (2015) · Adipobiology · doi:10.14748/adipo.v7.1559 · Cited by 3 · see citing works
“brain-metabolism link (36-55) the concept of cognitive diabetes and brain diabetes was recently introduced (56, 57; for the antidiabetic drug metformin and APP processing, see 58, 59).”
BackgroundSridhar, G. R. (2017) · SpringerBriefs in applied sciences and technology · doi:10.1007/978-981-10-6653-5_4 · Cited by 3 · see citing works
Self-citationPrediction of Alzheimer Disease Using Pearson Recursive Graph Convolutional Neural NetworkPreprint
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“Recent research proves that there is a relation between the type 2 diabetes and AD [8].”
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“9,10 AD can be considered a central metabolic disorder characterized by impaired glucose metabolism, which is associated with compromised insulin and IGF (insulin-like growth factor) signaling pathways in the brain.”
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“38,39 Therefore, the Zn − Sl − MPM complex was incubated in cells for real-time tracking of lysosomes to effectively monitor the change in microviscosity of lysosomes within a hyperglycemic environment.”
Serum levels of acetylcholinesterase in metabolic syndrome
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“(14, 15) and since NGF and BDNF are also implicated in the pathogenesis of cardiometabolic and neurodegenerative diseases (16, 17), further studies are required on the possible role of NGF/BDNF and acetylcholinesterase/CRP in the development of these diseases.”
BackgroundDiabetes and data in many forms
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“A series of other studies have suggested that it could be one of the mediators between type 2 diabetes mellitus and Alzheimer’s disease [39].”
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НЕЙРОПРОТЕКТОРНІ ВЛАСТИВОСТІ α-ЛІПОЄВОЇ КИСЛОТИ У ХВОРИХ НА ДІАБЕТ
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“An epidemiological study reported the frequency of dementia in patients among diabetic patients.(1) Since type 2 diabetes mellitus Hyperpolarized [1-(13)C]pyruvate Magnetic Resonance Spectroscopy Shows That Agmatine Increased Lactate Production in the Brain of Type 2 Diabetic Mice”
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“Apart from its well-known vascular and metabolic complications, T2DM is increasingly recognized as a significant risk factor for cognitive decline and dementia, including Alzheimer’s disease (AD) and vascular cognitive impairment (VCI) [1].”
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FONKSİYONEL GIDA BİLEŞENLERİNİN BİLİŞSEL FONKSİYONLAR ÜZERİNE MOLEKÜLER ETKİ MEKANİZMALARI
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Amylin and amylin receptors in Alzheimer's disease
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- Authors
- Sridhar, G. R.
- Corresponding author
- Sridhar, Gumpeny R
- ORCID
- Sridhar, Gumpeny R
- Venue
- World Journal of Diabetes
- Publisher
- Baishideng Publishing Group Inc.
- Published
- 2015
- Volume
- 6
- Issue
- 5
- Pages
- 744
- ISSN
- 1948-9358 (ISSN-L)
- PMC
- PMC4458503
- OpenAlex
- W563315964
- Cited by
- 123
- References
- 65
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 5 · 2023: 8 · 2022: 19 · 2021: 7 · 2020: 14 · 2019: 14 · 2018: 11 · 2017: 12 · 2016: 13 · 2015: 8
- FWCI
- 2.02
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by-nc
- Locations
- World Journal of Diabetes (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- type 2 diabetes, Alzheimer's disease, cognitive impairment, hyperglycemia, insulin resistance, hyperinsulinemia, obesity, dyslipidemia, sedentary lifestyle, insulin-like growth factor, butyrylcholinesterase, insulin therapy, metformin, PPARγ agonists, GLP-1 receptor agonists, DPP-4 inhibitors, dementia prevention
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