For decades, type 2 diabetes (T2D) has been a crucial disease medically and socially worldwide [1]. Its prevalence and incidence are increasing across the world [2]. From clinical point of view, T2D affects macroangiopathy and microangiopathy, associated with central nervous system (CNS), neurotransmitter impairment, memory damage, cognitive dysfunction and deficits in insulin signaling [3]. Consequently, T2D would be also evaluated for neurodegenerative disease, such as Alzheimer’s disease (AD) [4]. AD has been known for most common dementia type, which shows mild cognitive impairment (MCI), decreased behavioral abilities/personality and characteristic changes [5].

From the statistics of World Health Organization (WHO), >55 million patients have been affected by dementia, where AD probably shows 60% of them. Furthermore, the number of AD cases seems to increase with 10 million per year, which suggests the necessity of prevention, care and cure for neurodegenerative disease [6]. Recently, health and medical problems of T2D and AD reached alarming levels [7]. From the evidence that AD is a significant comorbidity of T2D, the risk of AD would be 1.4--2.0-fold increase among T2D cases. Common triggers for pathogenesis of both diseases would include various factors, in which lipotoxicity may be the missing ring for pathogenetic perspective linking T2D to AD [8].

Previous investigation has shown the bidirectional connection situation between T2D and AD. A large investigation was conducted involving 14 studies (2.3 million cases). Among them, 102 thousand dementia patients were analyzed associated with T2D cases. They showed close relationship with the fact that AD is often found in diabetes cases [9]. Similar results were found for retrospective case-control and prospective cohort studies. In addition, 11 year-follow up study showed that T2D cases usually have higher risk of MCI and AD compared with healthy population [10]. For another study, 80% of AD cases had various degrees of impaired glucose metabolism. Thus, underlying pathophysiological mechanisms may exist so far and their detail function are still unknown [11].

The incidence and prevalence of T2D and AD are involved in the age with elevation for aging, and are related with some etiologic factors and genetic components. In the light of function mechanism, biochemical and molecular factors may contribute energy metabolism, impaired brain glucose utilization, insulin signaling and so on [12]. Then, AD has been considered as type 3 diabetes or brain diabetes [3,13]. In particular, impaired diabetic condition may bring chronic cascade, which includes mitochondrial dysfunction, oxidative stress leading to AD symptoms [14]. Consequently, existing common mechanism would contribute preventing such development, establishing adequate therapeutic measures.

AD has been characteristic for senile plaques and their neurofibrillary tangles have been involved in pathophysiological processes. Various experimental investigation has suggested that AD may be comorbid metabolic diseases such as T2D, and then AD has been considered as brain diabetes [15]. Thus, T2D and AD can share multiple biochemical and molecular function. For latest topics, novel potential therapeutic agents may be proposed, that would be dietary polyphenols’ antioxidative and antidiabetic properties for beneficial influence of AD symptoms [16].

From the background point of view of various diseases, oxidative stress has been evaluated for involving in the pathophysiological characteristics for T2D and AD. Free radicals have included the dual nature, which have both of beneficial and deleterious roles in the cellular activity and signaling pathway [17]. For the usual body function metabolism, reactive oxygen species (ROS) have acted as signaling molecules and also promoted physiological activity and signal transduction. They can include synaptic-related mechanism, memory function, and insulin signaling.

An increasing number of epidemiological and medical investigations can support the hypothesis for the significant correlation between T2D and elevated risk of AD. The proposal can be found that the definition of AD as type 3 diabetes seems to be the key perspective, since insulin signaling to accumulated aggregation of amyloid beta peptides may exist for the senile plaques in the brain [3]. This mechanism promotes the production and deposition of Aβ. At the same time, the impairment of the microtubule-associated protein Tau leads to neurodegeneration and cognitive decline [17]. In addition, T2D patients often show their reduced antioxidant capacity. This condition leads to impaired glucose metabolism and also reduced mitochondrial activity in the brain. These situations exacerbate the pathological various changes of oxidative damage, mitochondrial dysfunction, and cognitive impairment. The series of such mechanisms suggest the existence of mutual relationship among them. As mentioned above, there is a strong possibility of a common pathophysiological relationship between T2D and AZ.

Common features of T2D and AD can be explained, in which most important risk factor would be the aging process. For common pathological mechanisms of two diseases, several crucial factors are observed, such as neuroinflammation, oxidative stress, amyloidosis, insulin resistance, increasing cell death, impaired mitochondrial dysfunctions and so on [18]. Currently, available agents for therapy of T2D and AZ show limited therapeutic efficacy. As an impressive fact, medical agents for AD such as acetylcholinesterase inhibitors (AChEI), can present beneficial potential for therapeutic measure for T2D. Similarly, some agents for T2D can prevent certain pathologies that are characteristic for AD. A promising direction in the search for a strategy for the treatment of T2D and AZ may be the creation of complex multi-target drugs. They would have neuroprotective potential and affect specific common targets for T2D and AD. Regarding the therapeutic strategies for T2D and AZ, exploring neuroprotection research seems to be a promising direction. By setting common disease targets for T2D and AZ, special multi-target agents are expected to be developed in the future.

In addition to AD, Parkinson’s disease (PD) has been also involved in some therapeutic relationship with antidiabetic agents from several overview of recent literature [19]. Underlying mechanisms of neurodegenerative disease may be commonly present in the light of inflammation protein misfolding mitochondrial dysfunction and oxidative stress [20]. Further, possible potential mechanisms by which antidiabetic agents might present some neuroprotective efficacy, such as anti-inflammatory effects, insulin signaling, regulation of glucose metabolism, bioenergetics and mitochondrial function.

In summary, numerous studies have supported the hypotheses which oxidative stress and mitochondrial dysfunction of T2D may bring neurodegenerative changes in AD. AD seems to be type 3 diabetes. Future research in this region will develop including T2D, AD, PD and other diseases.

Conflict of interest: The authors declare no conflict of interest.

Funding: There was no funding received for this paper.

1. Patil RS, Tupe RS. Communal interaction of glycation and gut microbes in diabetes mellitus, Alzheimer's disease, and Parkinson's disease pathogenesis. Med Res Rev. 2024; 44: 365-405.
2. Ding X, Yin L, Zhang L, Zhang Y, Zha T, Zhang W, et al. Diabetes accelerates Alzheimer's disease progression in the first year post mild cognitive impairment diagnosis. Alzheimer's Disease Neuroimaging Initiative. Alzheimers Dement. 2024; 20: 4583-4593.
3. Peng Y, Yao SY, Chen Q, Jin H, Du MQ, Xue YH, et al. True or false? Alzheimer's disease is type 3 diabetes: Evidences from bench to bedside. Ageing Res Rev. 2024; 99: 102383.
4. Athanasaki A, Melanis K, Tsantzali I, Stefanou MI, Ntymenou S, Paraskevas SG, et al. Type 2 Diabetes mellitus as a risk factor for alzheimer's disease: Review and Meta-Analysis. Biomedicines. 2022; 10: 778.
5. Wang L, Dong S, Zhao C, Gao Z, Jiang L, Zhang R, et al. Association of stressful life events with cognitive impairment in patients with type 2 diabetes mellitus. J Diabetes Investig. 2023; 14: 792-800.
6. Messina A, Amati R, Annoni AM, Bano B, Albanese E, Fiordelli M. Culturally adapting the world health organization digital intervention for family caregivers of People with dementia (iSupport): community-Based Participatory approach. JMIR Form Res 2024; 8: e46941.
7. Marrano N, Biondi G, Borrelli A, Rella M, Zambetta T, Di Gioia L, et al. Type 2 Diabetes and Alzheimer's Disease: The Emerging Role of Cellular Lipotoxicity. Biomolecules. 2023; 13: 183.
8. Pan Y, Li J, Lin P, Wan L, Qu Y, Cao L, et al. A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer's disease, and their co-morbidities. Front Pharmacol. 2024; 15: 1348410.
9. Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. Lancet. 2017; 389: 2239-2251. ISSN 0140-6736.
10. Canal MP, Nini KA, Baez MV. Impaired fasting glucose, oxidative distress, and cognitive impairment. Is this the starting point on DBT cognitive decline? Front Aging Neurosci. 2022; 14: 911331.
11. Veteleanu A, Stevenson-Hoare J, Keat S, Daskoulidou N, Zetterberg H, Heslegrave A, et al. Alzheimer's disease-associated complement gene variants influence plasma complement protein levels. J Neuroinflammation. 2023; 20: 169.
12. Bai X, Zhao X, Liu K, Yang X, He Q, Gao Y, et al. Mulberry Leaf Compounds and Gut Microbiota in Alzheimer's Disease and Diabetes: A Study Using Network Pharmacology, Molecular Dynamics Simulation, and Cellular Assays. Int J Mol Sci. 2024; 25: 4062.
13. Burillo J, Marques P, Jimenez B, Gonzalez-Blanco C, Benito M, Guillen C. Insulin Resistance and Diabetes Mellitus in Alzheimer's Disease. Cells. 2021; 10: 1236.
14. Sultana MA, Hia RA, Akinsiku O, Hegde V. Peripheral mitochondrial dysfunction: A Potential Contributor to the development of metabolic disorders and alzheimer's disease. Biology (Basel). 2023; 12: 1019.
15. Veteleanu A, Stevenson-Hoare J, Keat S, Daskoulidou N, Zetterberg H, Heslegrave A, et al. Alzheimer's disease-associated complement gene variants influence plasma complement protein levels. J Neuroinflammation. 2023; 20: 169.
16. Wang J, Zhang J, Yu ZL, Chung SK, Xu B. The roles of dietary polyphenols at crosstalk between type 2 diabetes and alzheimer's disease in ameliorating oxidative stress and mitochondrial dysfunction via PI3K/Akt signaling pathways. Ageing Res Rev. 2024; 99: 102416.
17. Potenza MA, Sgarra L, Desantis V, Nacci C, Montagnani M. Diabetes and alzheimer's disease: Might mitochondrial dysfunction help deciphering the common Path? Antioxidants (Basel). 2021; 10: 1257.
18. Veselov IM, Vinogradova DV, Maltsev AV, Shevtsov PN, Spirkova EA, Bachurin SO, et al. Mitochondria and oxidative stress as a link between alzheimer's disease and diabetes mellitus. Int J Mol Sci. 2023; 24: 14450.
19. Kalinderi K, Papaliagkas V, Fidani L. GLP-1 Receptor Agonists: A new treatment in parkinson's disease. Int J Mol Sci. 2024; 25: 3812.
20. Koshatwar M, Acharya S, Prasad R, Lohakare T, Wanjari M, Taksande AB. Exploring the Potential of antidiabetic agents as therapeutic approaches for alzheimer's and parkinson's diseases: A Comprehensive Review. Cureus. 2023; 15: e44763.