The Diabetic Brain and Dementia

Abstract

Alzheimer's Disease (AD) and Diabetes Mellitus (DM) are the two most common and devastating health problems in the elderly. They share a number of common features among which are important impact on quality of life and substantial health care costs. Epidemiological and biological evidence support a pathophysiological link between Type 2 Diabetes Mellitus (DMT2) and cognitive impairment (1-3). A causative association between DM and Alzheimer's disease has been suggested on the basis of clinical, epidemiological, genetic and experimental studies (2,4-9). Persons with DM have a higher incidence of cognitive decline and an increased risk of developing AD and other types of dementia, and comorbidity increases the risk (10,11). Insulin resistance predicts medial temporal hypermetabolism in Mild Cognitive Impairment (MCI) conversion to AD (12) and glucose uptake changes in AD in medial temporal regions predicting worse memory performance (13). DM has been shown to influence the rate of functional decline among patients with mild AD dementia than in those without comorbid DM (14). However, the precise mechanisms involved in the development of AD in diabetics are not yet fully understood, and several pathogenic pathways have been discussed (3,4,15-20). Autopsy studies stated that diabetic patients show significantly less AD pathology (senile plaques, neurofibrillary tangles, cerebral amyloid angiopathy, etc.) but more cerebrovascular lesions including microvascular lesions and white matter changes than subjects without DM (5,21-27). Vasculo-neural dysfunction has been suggested to represent a potential etiological linkage between DMT2 and AD (6,28), while others suggested that the association between DM and dementia is only partially mediated through cerebrovascular disease and that DM is associated independently with overal dementia among elderly, but not with AD or vascular dementia (29). Positive DMT2 status appears to exacerbate AD pathology in the presence of ApoE e4 (30). Although insulin mitigates Aβ deposition and hyperphosphorylation of tau (17,31), DM in combination with ApoE e4 may lead to excessive phosphorylation of tau (32), but only in subjects with late stage AD (21). DM modifies metabolism of Aβ and tau causing Aβ/tau-dependent pathological changes, although there is evidence that suggests an interaction of Aβ/tau-dependent and -independent mechanisms (31). Evidence supports insulin's role in cognition, synaptic remodelling and facilitation of memory (33). On the other hand, insulin has been shown to modulate the level of Aβ, to protect neurons against detrimental effects of Aβ on synapses (33). It further facilitates reduction of amyloid plaques, downregulation of Aβ-derived diffusible ligand-binding sites and also to promote tau hypophosphorylation, which stabilizes microtubules. These data and the observation that the combination of insulin and other antidiabetic medication is associated with lower neuritic plaque density (23,34) are providing a rationale for using insulin to treat AD high-risk patients (35-37).