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Aging, Insulin Resistance, and Cognition
Ahmet Turan Isik, M.D., Gulhane School of Medicine, Department of Internal Medicine, Division of Geriatric Medicine, Ankara, Turkey
Please address correspondence to:
Ahmet Turan Isik, M.D.
Associate Professor
Gulhane School of Medicine
Department of Internal Medicine
Division of Geriatric Medicine
Ankara, Turkey
E-mail: ahmetturanisik@yahoo.com
As the world population has aged, dementia has become a common diagnosis in aging populations and the numbers will increase in the forthcoming years. Now in the
It has been suggested that normal functioning of the insulin-signaling pathway is important for the maintenance of cognitive functioning in the elderly [1]. Vascular risk factors, especially hypertension and diabetes mellitus, are thought to be involved in pathogenesis of cognitive dysfunction in elderly [2]. There is also growing evidence about the role of diabetes on cognition [3,4]. Epidemiological evidence has suggested that diabetes mellitus significantly increases the risk for Alzheimer dementia, independent from vascular risk factors [5]. However, the role of insulin and insulin resistance on cognition in non-diabetic patients is obscure, especially in elderly.
Higher fasting insulin levels and reduced CSF-to-plasma insulin ratios, suggestive of insulin resistance, have been observed in patients with AD without apolipoprotein epsilon (E) 4 alleles [6]. Alzheimer or vascular dementia (VaD) could be a part of metabolic syndrome or even type-III diabetes with some exaggerations [7,8].
It is still not completely understood how insulin resistance affects the cognitive profile. The age-associated decline in the metabolic rate and utilization of glucose by the frontal cortex imply that insulin resistance can cause executive dysfunctions in older people, not only global cognitive impairment [3,5,9]. Insulin resistance may cause decreased cortical glucose utilization especially in hippocampus and entorhinal cortex and also increased oxidative stress with advanced glycation end-products [1,4]. Insulin resistance may also cause Tau phosphorylation and neurofibrillary tangle formation and increased beta amyloid aggregation [10]. Although current literature points out that insulin resistance and hyperinsulinemia are important for cognitive decline especially in elderly women [3], we did not find any statistical significant difference among 5 different cognitive status groups such as AD, VaD, mixed dementia, mild cognitive impairment (MCI), and normal cognition group in our study [11].
In experimental mouse models of AD, there are studies showing that diet-induced insulin resistance promotes amyloidosis, suggesting that insulin resistance can influence amyloid beta production in the brain [12]. In addition, impaired insulin or IGF-1 signaling can result in the hyper-phosphorylation of tau which can cause neuronal death mediated by apoptosis, mitochondrial dysfunction, or necrosis [13,14].
It was pointed out that increased insulin levels may be associated with a cognitive decline in a prospective study but just in women patients in the
Application of The International Diabetes Federation criteria have resulted in a higher prevalence of central obesity as well as metabolic syndrome; The National Cholesterol Education Program Adult Treatment Panel III criteria were used in our study, because of its applicability for the population aged ≥ 50 years.
Although hyperinsulinemia is a critical component of the causal pathway to global cognitive impairment, studies of these associations are not consistent. Insulin resistance was not previously found to be a significant determinant of global cognitive functioning measured with mini-mental state examination as in our study [1], so the results in our study did not gather surprising evidence. We had thought that insulin resistance was not that much more important after diagnosis of dementia and did not differentiate between AD, VaD, mixed dementia, MCI and normal cognition groups. But the results can still be of research value in earlier periods before dementia [11]. Studies about potential therapeutics such as peroxisome proliferated activated receptor agonists are emerging recently [4,16]. The increased occurrence of insulin resistance in dementia suggests improving insulin effectiveness may have therapeutic benefit for patients with AD and also for prevention of dementia with thiazolidinediones and other drugs that decrease insulin resistance [6,9,12,15]. One study showed that infusion of insulin enhances the performance of cognitive functions in non-diabetic people [17]. Glycogen syntase-3 is also a potential target for central nervous system therapies [18]. The problem is which patients will benefit from the drugs and who will be the nonresponders. Also there are studies on the agents that target the cardiovascular and cerebrovascular risk factors such as hypertension, hyperlipidemia, and insulin resistance, which have sufficient epidemiological and preclinical evidence to warrant further investigation. Our results may shed light on which factors may affect the potential role of insulin resistance on cognition to prevent dementia in such cases; in other words, the negative results of our study are important for the literature by its noting of the negligible role of insulin resistance after the diagnosis especially in moderate or severe dementia cases [11]. AD is a catabolic state in advanced cases and this may also effect the role of insulin resistance in severe cases. Gauthier, clearly emphasizes that initiating treatment early in AD is important and reinforces the necessity to assess behavior and activities of daily living [19]. Improving insulin resistance may prevent dementia and is meaningful and valuable if it is possible. Our data stated that insulin resistance must be studied in pre-dementia stages, not after the diagnosis [11].
According to the present literature there are a few human studies about the possible relation of insulin resistance and cognitive function in various groups of cognitive status but unfortunately the results are not significant enough to make general comments [1,3,15]. However, aging seems more important than insulin resistance; further prospective, cohort studies following the normal cognitive group and MCI patients with and without insulin resistance are necessary to demonstrate any relation in elderly.
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