Current Alzheimer Research (www.bentham.org/car),
2004, 1, 47-54
Bentham Science Publishers Ltd.(www.bentham.org)
The Clinical and Biological Relationship between Type II Diabetes Mellitus and Alzheimer’s Disease
Mark R. Nicolls*
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 E. 9th Ave, Box C272 Denver, CO 80262, USA
*Address correspondence to this author at the Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 E. 9th Ave, Box C272, Denver, CO 80262, USA; Tel: 303-315-0624; Fax: 303-315-5632; E-mail: mark.nicolls@uchsc.edu Research sponsored by NIDDK P30 DK57516 and K08 DK02704
Abstract: The clinical
relationship between Type II diabetes mellitus and Alzheimer’s disease has been
debated for over a decade. While several studies have not shown a clear
clinical correlation, others have demonstrated that Type II diabetes is an
independent risk factor for Alzheimer’s disease. Why diabetes would increase
the likelihood of Alzheimer’s disease is not immediately clear, although recent
studies have demonstrated an impact of insulin abnormalities, insulin
resistance and advanced glycation end products on both the development of
neural amyloid plaques and neurofibrillary tangles. Although endodermal in
embryologic development, the pancreas is a highly innervated organ that shares
a number of molecular similarities with brain at the level of the transcriptome
and proteome. Type II diabetes and Alzheimer’s disease are characterized by
localized amyloid deposits that progress during the course of the disease.
Comparing amyloid deposition in the brain and pancreas reveals some striking
pathophysiologic similarities. Neurodegeneration in pancreatic islets, as
manifested by neurofibrillary tangles, is less well studied than in Alzheimer’s
disease but may also occur. This review summarizes what is currently known about
the clinical and biological relationships and similarities between Type II
diabetes and Alzheimer’s disease.
Keywords: Type II Diabetes Mellitus, Alzheimer’s disease, islet, pancreas, islet transplantation
1. Introduction
As an individual ages, their endocrine pancreas and brain may be linked in ways not previously considered. Clinical and basic studies that examine the two most prominent diseases of these organs, diabetes and dementia, are revealing interesting connections between these conditions that show how diseases are not only epidemiologically linked but also how they may share similar pathophysiological pathways. Both Type II diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are generally associated with senescence and advanced localized amyloid deposition that likely interferes with proper cellular functioning. AD is also associated with neural degeneration as manifested in part by the formation of neurofibrillary tangles (NFTs). Neurodegeneration is also a prominent feature of T2DM as manifested by peripheral and autonomic neuropathy, but the extent to which this actually occurs in the endocrine pancreas is less well studied. Whether T2DM is indeed “Alzheimer’s of the pancreas” is currently only a provocative question. Given these epidemiological and biological considerations, this review will discuss how T2DM and AD are related and how they are, in fact, comparable processes. T2DM and AD are very common diseases associated with the aging population. According to the American Diabetes Association, approximately 90-95% of Americans with diabetes have T2DM with an estimated 16 million people being affected and 798,000 new cases diagnosed per year. According to the Alzheimer’s Association, an estimated 4.5 million Americans have AD with one in 10 people over age 65 and nearly half of those over 85 being affected. Diseases normally associated with advancing age may reflect common underlying pathological processes such as cellular responses to chronic stress that will be discussed in this review.
2. Clinical Relationship between T2DM and AD
There have been variable reports on whether or not T2DM is a clinical risk factor for AD. Part of the ambiguity of this relationship may stem between the already known association between diabetes and vascular dementia. Vascular-related dementia may depend on the presence of subclinical cerebrovascular disease or overt stroke pathology [1] and is associated with classical cardiovascular risk factors such as hypertension and hyperlipidemia [2, 3]. Therefore, studies examining a putative relationship between the metabolic disturbances of T2DM and the presumably non-ischemic development of AD have needed to tease out dementia caused by non-vascular insults as opposed to disease attributable to vascular pathology. It is not surprising that some early epidemiologic studies were inconsistent. For example, the results of a historical, prospective survey of a cohort of Japanese-Americans did not support an association between diabetes and AD [4]. Other smaller case-control studies have also suggested no definitive relationship [5-9]. Despite these reports, the preponderance of recent evidence from population-based studies does indicate a link between T2DM and AD with an incidence of AD as high as 2-5 fold higher in T2DM patients [10-17]. The reasons for the discrepancies between studies are not immediately clear. As Gasparini and colleagues note [18], seemingly contradictory results may be due to the design limitations of individual studies. Small sample sizes and selection biases can account for the differing results between case-control studies. In some studies, institutionalized patients are evaluated preferentially [7, 8, 19] and other studies exclude patients with cardiovascular diseases. Two successive reports from the Rotterdam Study which surveyed over 6300 patients showed a relation between diabetes and AD with relative risks of 1.3 (95% CI:1.0-1.9) in the initial study [11] and 1.9 (95% CI: 1.2-3.1) in the follow-up study [15]. Diabetes itself doubled the risk of all causes of dementia. Of particular note given the recent interest in insulin dysfunction and AD [18, 20-22], patients in the Rotterdam study receiving exogenous insulin therapy were at the highest risk of dementia (RR4.3; 95% CI: 1.7-10.5). The recently published Honolulu-Asia Aging Study examined a cohort of 2,574 patients [17]. In this study, T2DM patients’ risk of all types of dementia was 1.5 (95% CI: 1.01-2-2), of AD was 1.8 (95% CI: 1.1-2.9) and vascular dementia was 2.3 (95% CI: 1.1-5.0). The apolipoprotein E (APOE) e4 allele, which is a known risk factor for AD