Type 2 Diabetes and Dementia

Type 2 Diabetes and Dementia details the relationship between diabetes, dementia and the future of medicine and therapeutics. Chapters range from epidemiology, clinical features, neuroimaging biomarkers, neuropathology, macrostructural and molecular mechanisms, risk assessment and prevention strategies, and the application of therapeutics. The book reflects the translational aspects of the current science in the field, with an emphasis on the display of neuroimaging and neuropathology. It contains contributions from world experts, and is ideal for clinicians and researchers in the fields of neurology, neuroscience, geriatric medicine and endocrinology.

• Presents a comprehensive overview that details the relationship between diabetes, dementia and the future of medicine and therapeutics
• Written for researchers and clinicians in neurology, neuroscience, geriatric medicine and endocrinology
• Includes topics ranging from epidemiology, clinical features, neuroimaging biomarkers, neuropathology, macrostructural and molecular mechanisms, risk assessment, prevention strategies and therapeutic applications

• Language: English
• Publisher: Academic Press
• Release date: Feb 9, 2018
• ISBN: 9780128096949

Book preview

Type 2 Diabetes and Dementia

Editors

Velandai Srikanth

Zoe Arvanitakis

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Foreword

Chapter 1. Introduction

Chapter 2. Epidemiology of Type 2 Diabetes and Dementia

Introduction

Considerations When Evaluating the Observational Epidemiologic Literature

Epidemiologic Studies Evaluating the Association of Type 2 Diabetes and Late-Onset Dementias

Conclusion

Chapter 3. Magnitude and Trajectories of Cognitive Dysfunction in Type 2 Diabetes Mellitus

Introduction

Type 2 Diabetes and Cognitive Dysfunction

Summary

Abbreviations

Chapter 4. Brain Imaging in Type 2 Diabetes

Introduction

Brain Magnetic Resonance Imaging Studies of Type 2 Diabetes

Positron Emission Tomography Studies in Type 2 Diabetes

Conclusion

Chapter 5. Cerebrospinal Fluid and Blood-Based Biomarkers in Alzheimer’s Disease and Type 2 Diabetes Spectrum Disorders

Introduction

Alzheimer’s Disease Fluid Biomarkers

Alzheimer’s Disease Biomarkers in Insulin Resistance and Type 2 Diabetes

Markers of Inflammation and Neural Injury

Markers of Blood–Brain Barrier and Endothelial/Vascular Function

Markers of Receptor-Mediated β-Amyloid Transport

Markers of MicroRNA Expression

Markers of Protein Glycation and Oxidation

Markers of Exosomal Composition

Summary and Future Directions

Chapter 6. Neuropathological Insights Into the Link Between Type 2 Diabetes and Dementia

Introduction

Vascular Neuropathology

Alzheimer’s Disease Neuropathology

Summary and Future Directions

Chapter 7. Diet, Obesity, and Physical Inactivity: Linking Diabetes and Dementia

Introduction

Deleterious Effects of Obesity on Neurocognition and the Relationship to Type 2 Diabetes

Beneficial Effects of Diet and Physical Activity on Neurocognition, and the Relationship to Neurocognitive Dysfunction in Obesity and Type 2 Diabetes

Conclusions

Future Directions

Summary

Chapter 8. The Role of Insulin Resistance and Signaling in Dementia

Introduction

Insulin and Its Diverse Cellular Actions

Insulin and the Blood–Brain Barrier

Does Insulin Synthesis Occur in the Brain?

Insulin’s Actions in the Brain

The Overarching Effects of Insulin in the Brain: Metabolism and Cognition

Brain Insulin Resistance: An Emerging Construct

Summary

Chapter 9. Advanced Glycation, Diabetes, and Dementia

Introduction

Advanced Glycation End Products and Their Precursors

Advanced Glycation End Products and Their Precursors Accumulate in Tissues of People With Type 2 Diabetes Mellitus

Nonreceptor Mediated Interaction of Advanced Glycation End Products

Advanced Glycation End Product–Receptor for Advanced Glycation End Product Interaction and Glucose Dysregulation in Type 2 Diabetes Mellitus

Advanced Glycation End Products and Their Precursors as Mechanistic Factors for Cognitive Decline in Diabetes: Clinical Studies

Pharmacotherapeutic Intervention: Decreasing Advanced Glycation End Product Accumulation and Signaling to Prevent Cognitive Decline in Type 2 Diabetes Mellitus

Future Perspective

Chapter 10. Neuroinflammation, Type 2 Diabetes, and Dementia

Introduction

Type 2 Diabetes and Systemic Inflammation

Microglial Priming, Neuroinflammation, and Alzheimer’s Disease

Type 2 Diabetes and Neuroinflammation

Conclusion and Perspectives

Chapter 11. The Blood–Brain Barrier in Diabetes Mellitus

Introduction

Structure and Function of the Blood–Brain Barrier in Health

Altered Blood–Brain Barrier Structure and Function With Diabetes

Summary and Conclusion

Chapter 12. Pharmacological and Nonpharmacological Interventions for Cognitive Impairment and Dementia Related to Type 2 Diabetes and Metabolic Disturbances in Aging

Pharmacological Interventions

Nonpharmacological Interventions

Conclusion and Future Directions

Author Index

Subject Index

Copyright

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List of Contributors

Erin L. Abner,     Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States

Steven E. Arnold,     Massachusetts General Hospital, Boston, MA, United States

Zoe Arvanitakis,     Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States

Eugene J. Barrett,     University of Virginia, Charlottesville, VA, United States

Richard Beare,     Monash University, Melbourne, VIC, Australia

Michal Schnaider Beeri

Sheba Medical Center, Ramat Gan, Israel

Icahn School of Medicine at Mount Sinai, New York, NY, United States

Tina Brinkley,     Wake Forest School of Medicine, Winston–Salem, NC, United States

David G. Bruce,     University of Western Australia, Fremantle, WA, Australia

Michele Callisaya

University of Tasmania, Hobart, TAS, Australia

Monash University, Melbourne, VIC, Australia

Suzanne Craft,     Wake Forest School of Medicine, Winston–Salem, NC, United States

Karthik Dhananjayan,     Western Sydney University, Penrith, NSW, Australia

Mark A. Espeland,     Wake Forest School of Medicine, Winston–Salem, NC, United States

Josephine Forbes

Translational Research Institute, Woolloongabba, QLD, Australia

University of Queensland, St Lucia, QLD, Australia

Ithamar Ganmore

Sheba Medical Center, Ramat Gan, Israel

Tel-Aviv University, Tel-Aviv, Israel

Sarah M. Gray,     University of Virginia, Charlottesville, VA, United States

Deborah R. Gustafson

State University of New York, Downstate Medical Center, Brooklyn, NY, United States

University of Gothenburg, Gothenburg, Sweden

University of Skövde, Skövde, Sweden

Aaron M. Koenig,     Massachusetts General Hospital, Boston, MA, United States

Samy I. McFarlane,     State University of New York, Downstate Medical Center, Brooklyn, NY, United States

Chris Moran

Monash University, Melbourne, VIC, Australia

Department of Aged Care, Alfred Health, VIC, Australia

Gerald Münch,     Western Sydney University, Penrith, NSW, Australia

Peter T. Nelson,     Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States

Thanh Phan,     Monash Medical Centre, Melbourne, VIC, Australia

Jeremy J. Pruzin,     Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States

Dana M. Small,     Yale University School of Medicine, New Haven, CT, United States

Velandai Srikanth,     Peninsula Health and Monash University, Melbourne, VIC, Australia

Luke E. Stoeckel,     National Institutes of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States

Brooke J. Wanrooy,     Monash University, Melbourne, VIC, Australia

Connie H.Y. Wong,     Monash University, Melbourne, VIC, Australia

Foreword

Diabetes and dementia rates are rising. The encouraging countertrend of the decreased incidence and prevalence of dementia in some developed countries is threatened by the growing burden of obesity and diabetes.

Diabetes and dementia can coexist but also interact. Our knowledge of their relationships has grown, but not in proportion to the problem. Part of the challenge resides in the diversity of approaches required to obtain an integrated picture. This book provides such a picture. From epidemiology to molecular biology, the chapters build on each other, culminating in one on interventional approaches in diabetes-related dementias. The pieces begin to make a pattern, highlighting the many blanks remaining to be filled by further research.

Through necessity, we all have become specialized. That implies that we need to know the larger context to understand our own area better. This volume provides such a context and may be recommended to everyone interested in diabetes and dementia, whether basic scientists, drug developers, epidemiologists, policy makers, or clinicians.

The editors have managed to recruit an impressive cadre of authors to complement their own eminent presence in the field. This book represents a milestone that shows where we are and where we need to go to counteract the twin evils of diabetes and dementia.

Vladimir Hachinski, CM, MD, DSc, FRSC, FRCPC, Dr. hon causaX4

Department of Clinical Neurological Sciences, University Hospital Western University, London, ON, Canada

Chapter 1

Introduction

Velandai Srikanth¹, and Zoe Arvanitakis²     ¹Peninsula Health and Monash University, Melbourne, VIC, Australia     ²Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States

We warmly congratulate the authors who have so graciously given their time and intellect to assist us in compiling this book. We believe that is the first book to synthesize state-of-the-art knowledge comprehensively about the complex relationship between two of the most prevalent and pressing health conditions in the world: type 2 diabetes mellitus (T2D) and dementia. This work comes from increasing recognition that the two disorders are strongly linked and at a time when we are on the cusp of a surge of research to clarify whether T2D and poor metabolic health are causal factors for dementia, and whether this understanding will advance knowledge about biological mechanisms underlying dementia and assist in devising interventions to prevent or delay the expression of dementia. The book draws from the significant expertise of internationally acclaimed researchers who have led the field in an understanding of this area. It presents a wide range of knowledge, spanning evidence from epidemiological, imaging, and neuropathological studies, through basic mechanisms linking the two disorders, and finally to potential ways to translate such findings, to modify the risk of dementia. We believe that this book will stimulate new and exciting research in dementia that will lead to discovery, translation, and ultimately, to therapeutic benefit.

Dementia is a major health condition predominantly affecting older people, a significant public health problem, and a global health priority. Dementia was highlighted as a major societal issue by the Group of Eight nations owing to the absence of effective disease-modifying medications (The Lancet, 2014). Interventions addressing risk factors and disease mechanisms in middle age or early older adult life are considered likely to be most effective in delaying the onset of dementia. Delaying symptoms by as little as 1  year could potentially lower dementia prevalence by >9  million cases worldwide over the next 30–40  years (Brookmeyer, Johnson, Ziegler-Graham, & Arrighi, 2007). Crucial to the development of interventions is an understanding of biological mechanisms underlying dementia. Study of the link between T2D and dementia provides a fertile ground for understanding new such mechanisms and a potential avenue toward developing therapeutic interventions relevant to a high-risk group.

T2D is a fast-growing chronic disease worldwide. The number of people with T2D rose from 108  million in 1980 to 422  million in 2014, resulting in an increase in adult T2D prevalence globally, particularly in the developing world (World Health Organization, 2016). It is composed of a cluster of features including adiposity, insulin resistance, insulin deficiency, hyperglycemia, high blood pressure, and hyperlipidemia that combine in various ways to cause disease in several organs including the heart, vascular tree, kidneys, eyes, and nerves. Only in the past decade or so has the potential contribution of T2D to brain health has become more obvious, leading to a surge in research efforts in the field. T2D is associated with a nearly twofold increase in the risk for incident dementia (Sutherland, Lim, Srikanth, & Bruce, 2017) irrespective of the subtype of dementia, and it is thought that 1 in 10 cases of dementia in the world are potentially attributable to T2D. Thus, study of the relationship between the two conditions provides an exciting opportunity to explore the contributions of several potential pathways and mechanisms leading to dementia. The chapters in this book take us on a journey of understanding in this field by presenting current knowledge while emphasizing gaps in knowledge and thus opportunities for future research.

The first two content-related chapters present readers with epidemiological evidence linking T2D and dementia. Gustafson et al. provide a concise introduction to this issue while bringing insights into the influence of certain important factors such as race/ethnicity and genes. Ganmore and Beeri then provide a comprehensive review of cross-sectional and longitudinal associations between T2D and cognitive function, drawing from an extensive search of the published literature to highlight particular cognitive functions that may be at risk for being affected in T2D. After this excellent introduction, the subsequent three chapters expand on evidence linking T2D to in vivo markers of dementia and to the neuropathology of dementia, to examine whether the impact of T2D on the brain may be explained by cerebrovascular disease, neurodegeneration, or both. Srikanth et al. elaborate on the impact of T2D on neuroimaging markers of dementia, drawing from studies using magnetic resonance imaging and positron emission tomography. Craft et al. provide a succinct review of the relationship of T2D with known cerebrospinal fluid biomarkers of Alzheimer’s disease and neurodegeneration. Pruzin et al. then complete this picture with a comprehensive update on the association of T2D with neuropathological markers of dementia, including evidence related to both cerebrovascular disease and neurodegeneration. The next series of chapters deal with potential causal mechanisms, modifiers or mediators that may underlie the link between T2D and dementia. Stoeckel et al. give some novel insights into the effects of diet, physical activity, and adiposity on the brain, while emphasizing the importance of disentangling their effects from those of T2D. Koening et al. then take on the complex task of reviewing the role of insulin in the brain, and whether insulin resistance and its related downstream molecular pathways may explain the pathophysiology of dementia. The subsequent two chapters deal with the potential roles of advanced glycation (Dhananjayan et al.), neuroinflammation (Bruce et al.), and blood–brain barrier integrity (Gray and Barrett) as mediators of the effect of T2D on the brain, and suggest future work to clarify their roles based on the potential for future therapies. The final chapter summarizes current clinical trial evidence regarding interventions in people with T2D designed to reduce the risk for dementia, highlighting this area as one of significant research opportunity.

In all, the book is designed not only to provide upto date knowledge but also to point to avenues for future research. We hope that it achieves its purpose and thus contribute to the betterment of health in people with T2D and those at risk for or experiencing dementia.

References

Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi H.M. Forecasting the global burden of Alzheimer’s disease. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 2007;3(3):186–191. doi: 10.1016/j.jalz.2007.04.381.

Sutherland G.T, Lim J, Srikanth V, Bruce D.G. Epidemiological approaches to understanding the link between type 2 diabetes and dementia. Journal of Alzheimers Disease. 2017;59(2):393–403. doi: 10.3233/JAD-161194.

The Lancet. G8 dementia summit: A chance for united action. Lancet Neurology. 2014;13(1):1. doi: 10.1016/S1474-4422(13)70275-8.

World Health Organization. Global report on diabetes. 2016.

Chapter 2

Epidemiology of Type 2 Diabetes and Dementia

Deborah R. Gustafson¹,²,³, and Samy I. McFarlane¹     ¹State University of New York, Downstate Medical Center, Brooklyn, NY, United States     ²University of Gothenburg, Gothenburg, Sweden     ³University of Skövde, Skövde, Sweden

Abstract

Type 2 diabetes (T2D) has been associated with dementia in countless observational epidemiology studies. The expansion of epidemiologic research on T2D and dementia is due to scientific recognition of the roles of metabolic and vascular factors as etiologic players in dementia, as well as ominous global demographic shifts in aging, obesity, and dementia. This chapter addresses epidemiologic studies evaluating the association between T2D and late-onset dementias with foci on (1) T2D and dementia as syndromes; (2) T2D and mild cognitive impairment or cognition and cognitive decline; (3) vascular and metabolic risk factors and comorbidities; (4) genetic influences on the T2D–dementia association; (5) ethnoracial considerations; (6) T2D and brain outcomes and biological markers; and (7) clinical trials of T2D medications and cognition and dementia.

Keywords

Alzheimer; Biomarkers; Cognitive impairment; Dementia; Diabetes; Genetics; Metabolic; Vascular

Introduction

Epidemiological evidence of the association of type 2 diabetes (T2D) and brain health has been evolving for over 50  years. The occurrence of cognitive changes with T2D has been noted since the early 20th century, but a PubMed search indicates the first description of mental aberrations in T2D in 1963 (Ives, 1963). Ten years later, a description of brain damage in T2D was published in the British Journal of Psychiatry (Bale, 1973). An investigation of the potential association between T2D (and other metabolic and vascular risk factors) and dementia of the Alzheimer type (DAT) was based on a clinical sample of persons with and without T2D, and suggested that T2D was not associated with DAT. In 1989 the term brittle diabetes was introduced to describe elderly individuals whose lives were disrupted by large variations in metabolic control. This was particularly observed among those termed as having prodromal or senile dementia, who mismanaged the T2D, as well as those experiencing large variations in metabolic control reflecting early mental deterioration. A first prospective study of T2D and dementia was also published in 1989 and included volunteers aged 75–85  years who were observed for 5  years (Katzman et al., 1989). Although the number of participants was not large, T2D was associated with higher risk of vascular dementia (VaD) but not Alzheimer’s disease (AD) (Katzman et al., 1989).

Since the late 1980s, case–control and prospective epidemiologic studies around the world have reported an association between T2D and dementia (Akomolafe et al., 2006; Arvanitakis, Wilson, Bienias, Evans, & Bennett, 2004; Bellou et al., 2016; Chatterjee et al., 2016; Cheng, Huang, Deng, & Wang, 2012; Cheng, Sy, Wu, Wang, & Chen, 2012; Chiu et al., 2015; Ganguli, Fu, Snitz, Hughes, & Chang, 2013; Gould, Beaudreau, & Salman, 2013; Goveas et al., 2016; Haring et al., 2013; Haroon et al., 2015; Hassing et al., 2002; Hayden et al., 2006; Huang et al., 2014; Leibson et al., 1997; Luchsinger, Tang, Stern, Shea, & Mayeux, 2001; MacKnight, Rockwood, Awalt, & McDowell, 2002; Mehlig et al., 2014; Ott et al., 1996, 1999; Peila, Rodriguez, Launer, & Honolulu-Asia Aging, 2002; Rawlings et al., 2014; Strand et al., 2013; Unverzagt et al., 2012; Wang et al., 2012; Xu, Qiu, Wahlin, Winblad, & Fratiglioni, 2004; Zhao, Xiong, Ding, Guo, & Hong, 2012). These studies generally show elevated risk for all dementias, AD, and particularly VaD with T2D. Typical multivariable-adjusted relative risk estimates range between 1.5 and 2.0. The complementary fields of molecular and genetic epidemiology are adding necessary etiologic rigor.

The increase in epidemiologic investigations on T2D and dementia results from (1) intense scientific interest in the roles of metabolic and vascular factors as etiologic players in dementia; and (2) global demographic shifts, which are captured by ecological epidemiology investigations. Global shifts are caused by aging, pandemic obesity, and increasing incidence and prevalence of diseases that accompany aging and obesity (WHO, 2015). The World Health Organization (WHO) reported that the number of people aged 60  years and older will increase from 900  million to 2  billion between 2015 and 2050 (a shift from 12% to 22% of the total global population). Overweight and obesity occurs in over 50% of adults (WHO, 2016b). Accompanying aging and obesity are expected increases in the greatest causes of disability including chronic diseases such as T2D, cerebrovascular diseases, and dementias such as AD (WHO, 2015). The number of people with T2D rose from 108  million in 1980 to 422  million in 2014, resulting in a shift in the global adult T2D prevalence of 4.7% to 8.5%. Most of this increase was observed in middle- and low-income countries (Fig. 2.1) (WHO, 2016a). WHO projected that T2D will be the seventh leading cause of death in 2030.

Figure 2.1  Trends in prevalence of diabetes, 1980–2014, by World Health Organization region.

This chapter presents epidemiologic studies evaluating the association between T2D and late-onset dementias, with foci on (1) T2D and dementia as syndromes; (2) T2D and mild cognitive impairment (MCI) or cognition and cognitive decline; (3) vascular and metabolic risk factors and comorbidities; (4) genetic influences on the T2D–dementia association; (5) ethnoracial considerations; (6) T2D and brain outcomes and biological markers; and (7) clinical trials of T2D medications and cognition and dementia. Because of the rapid evolution of the field and countless studies, this review will not be exhaustive; rather, it is selective and illustrative in scope.

Considerations When Evaluating the Observational Epidemiologic Literature

Before this review commences, it is important to realize several relevant considerations when evaluating the observational epidemiologic literature generally, and in the association of T2D and dementia. Twelve of these considerations are presented in Table 2.1. Foremost are definitions primarily of exposures and secondarily of clinical outcomes. Because both T2D and dementia are syndromes, consistently operationalized methods for making diagnoses across studies are lacking. Although this can create difficulties in comparing studies and achieving goodness of replication, it is also a strength when similar associations are observed despite slight differences in diagnostic criteria and/or operationalizing these criteria. Third, characteristics of the population at risk are important, especially with rapid increases in published observational data from around the world. It is important to take special care when reading Table 2.1 of any study. Descriptions of study samples, to include many of the items included in this chapter’s Table 2.1, are imperative for proper interpretation of the data, planning of follow-up measures and ancillary studies, identification of areas of intervention, and ultimately, prevention. Fourth, age of exposure and age of outcomes determination are critical in dementia epidemiology. Dementia is a disorder for which risk is potentially the result of exposures occurring over the life course. Studies have shown that it is important to consider early-, middle-, and late-life exposures and that associations with dementias may differ depending on when the exposure is measured. Early-life exposures relate mostly to developmental origins (in utero and neonatal development) hypotheses, in addition to educational attainment. Mid-life exposures, typically measured between age 35 and 60  years, are most evolved for vascular (e.g., hypertension, overweight and obesity, hypercholesterolemia) and metabolic (e.g., T2D, adiposity) mechanisms (Fig. 2.2). Late-life exposures, typically measured at age 65  years and older, in agreement with the age criterion for late-onset dementias, are dynamic and reflect aging-related changes in mid-life risk factors such as blood pressure and body weight decline, the presence of multiple morbidities, and maintenance of cognitive reserve and other resilience factors. Fifth, and related to the third point, the timing of association between exposure and outcome has been shown to be critical owing to the influence of underlying dementia-related neuropathological changes on systemic exposures. This is sometimes referred to as reverse causality and has been observed, for example, with body weight or body mass index, blood pressure, and blood cholesterol levels. When measured in mid-life, higher levels of these vascular risk factors have been associated with increased late-onset dementia risk; however, when measured in late life, they may not be risk factors and are sometimes protective. Sixth, duration of exposures may convey information regarding load. A leading theoretical model suggests that individual differences in susceptibility to stress are linked to behavioral responses to environmental challenges that are coupled to physiologic and pathophysiologic responses (McEwen & Stellar, 1993). Within this framework, the concept of allostasis is extended over the dimension of time, and the definition of allostatic load is extended as the cost of chronic exposure to fluctuating or heightened neural or neuroendocrine responses resulting from repeated or chronic environmental challenges and social burden to which an individual reacts as being particularly stressful (Ludwig et al., 2011; McEwen & Stellar, 1993). Seventh, survival time of the population being studied is critical in evaluation of population at risk. Eighth, birth cohort is emerging as a primary consideration regarding the role of exposures, as well as outcomes. Birth cohort reflects rapid technological societal changes, as well as the advancement of pharmacologic interventions for the chronic conditions that increase risk for dementia and neurodegeneration. Ninth, it is imperative to take note of the study design used to arrive at the conclusions of any research study. Longitudinal studies with comprehensive follow-up, adequate assessment of exposures, and definitive outcomes data including mortality are the only ones whereby risk can be calculated. Other study designs, e.g., case–control or cross-sectional studies, facilitate estimation of the odds, differences in means or proportions, and correlations. Tenth, the analysis strategy must be appropriate for the question and corresponding study design being presented. Eleventh, competing risks are continuing to increase in their importance and will do so. Competing risk generally refers to the presence of multiple morbidities, which increase with age and make it more difficult to identify the etiologic exposure or indicator. Finally, the use of genes, such as apolipoprotein E (APOE) or other biomarkers such as those provided by neuroimaging, allows for risk stratification as well as refinement of both exposures and outcomes.

Table 2.1

Figure 2.2  Mid- to late-life exposures temporally associated with cognitive impairments and dementias. HbA1c , hemoglobin A1c; T2DM , type 2 diabetes mellitus.

Epidemiologic Studies Evaluating the Association of Type 2 Diabetes and Late-Onset Dementias

Diabetes and Dementia Are Syndromes

A challenge to epidemiology in estimating exposure–disease relationships is consistent definitions of both exposure and outcomes across studies. Two major issues are: (1) clinical versus medical record diagnoses of T2D and dementia, and (2) inclusion or exclusion of T2D or dementia-associated phenotypes and markers. Because T2D and dementia are both syndromes and levels of symptoms vary within syndromes, principles of molecular epidemiology may apply (Molecular Epidemiology: Principles and Practices, 1998). These principles include consideration of biomarkers present in biological tissues, cells, and fluids, which assist in refining exposures and/or outcomes. Identification of biomarkers also provides the potential for earlier detection of preclinical forms of disease. The following studies illustrate the importance of molecular epidemiological approaches in elucidating the T2D–dementia association and represent several earlier and landmark studies in the field.

In the Swedish Kungsholmen cohort, associations were estimated between dementia (all, AD, and VaD) and T2D (diagnosis, uncontrolled T2D, and borderline T2D). Borderline T2D was associated with 90% higher AD risk and 80% higher all-dementia risk; T2D was associated with over a threefold higher VaD risk and VaD risk was even higher with high blood glucose levels (≥11.0  mmol/L or 200  mg/dL). Undiagnosed (and therefore uncontrolled) T2D exhibited an over threefold higher all-dementia and AD risk and over 17-fold higher VaD risk (Xu, von Strauss, Qiu, Winblad, & Fratiglioni, 2009). These data clearly illustrate the importance of standardized clinical outcomes criteria for both dementia and T2D and showed that biomarkers provide insights into the association of more severe phenotypes with the dementia outcome. A metaanalysis highlighted this finding, emphasizing the need to detect borderline T2D and undiagnosed T2D to prevent dementia (Li et al., 2014).

The Misayama Study in Japan investigated the association between a 75-g oral glucose tolerance test and dementia development in over 1000 community-dwelling participants without dementia for 15  years (Ohara et al., 2011). The age- and sex-adjusted incidence rates of all-cause dementia and AD were higher in T2D compared with normal glucose tolerance. Elevated 2-h postload glucose levels increased all-cause dementia, AD, and VaD risk. No associations were observed for fasting plasma glucose levels (Ohara et al., 2011). This was consistent with the notion that postprandial hyperglycemia confers more cardiovascular risk compared with elevated serum fasting levels.

Hypoglycemic episodes, a common occurrence among those who are not adherent to T2D medications, were evaluated using Kaiser Permanente of Northern California medical record data. One or more hypoglycemic episodes increased dementia risk, with the highest risk observed among individuals experiencing three hypoglycemic episodes (Whitmer, Karter, Yaffe, Quesenberry, & Selby, 2009). However, dementia also increases risk for hypoglycemic episodes (Bruce et al., 2009), and during the prodromal period, it is important to consider the role of reverse causality when interpreting observed associations in this arena.

In a cohort established to investigate mechanistic associations between T2D and dementia in Israel, changes in hemoglobin A1c (HbA1c) were associated with concurrent changes in minimental state examination (MMSE) score among community-dwelling elderly people without dementia or T2D. MMSE was inversely correlated with HbA1c levels after potentially incipient diabetes was excluded. Thus, manipulating blood glucose, even in those without T2D, may affect cognitive performance and provide avenues for intervention (Ravona-Springer et al., 2012).

The link between T2D and dementia is established, yet moderate, in the published literature. Reported findings of an elevated risk ratio are relatively consistent, albeit not always significant. A strength of these studies was the use of more than one outcome measure, e.g., dementia and MMSE score, as well as use of T2D endotypes or intermediate phenotypes as exposures, e.g., variation in blood glucose levels as a marker of severity or adherence to medications among those with T2D. A goal for the future would be standardization of clinically relevant T2D exposures and cognitive end points for clinical trials and observational studies, as well as sensitive and specific cut points for intermediate phenotypes and endophenotypes related to both exposures and outcomes.

Type 2 Diabetes and Mild Cognitive Impairment or Cognition and Cognitive Decline

MCI can be a prodromal stage of dementia within which to develop interventions targeting earlier signs and critical periods of dementia risk. MCI is classified by subtype [amnestic MCI (aMCI) and nonamnestic MCI (naMCI)] and by the number of cognitive domains affected. It is hypothesized that T2D increases aMCI risk through AD-related pathology and increases naMCI risk through vascular pathology. In the Mayo Clinic Study on Aging, the association between T2D and MCI varied by sex, subtype, and the number of cognitive domains involved. T2D was associated with 40% to 60% higher MCI and aMCI risk over a 4-year median follow-up. Men had over a twofold higher risk for multiple-domain aMCI and multiple domain naMCI; risk for single domain naMCI was elevated in women (Roberts et al., 2014). In the Beijing Ageing Brain Rejuvenation Initiative, a case–control study of MCI, T2D, hypertension, and cerebrovascular disease were associated with MCI (Li et al., 2012), without delineation of aMCI versus naMCI.

Accelerated progression from MCI to dementia among those with T2D and prediabetes was observed in the Swedish Kungsholmen Project (Xu et al., 2009). T2D and prediabetes tripled the dementia risk among MCI and accelerated progression from MCI to dementia by more than 2  years. The Whitehall II Cohort Study investigated whether duration of T2D in mid-life and/or poor glycemic control measured via blood HbA1c were associated with accelerated cognitive decline in over 5600 participants. Exposures included normoglycemia, prediabetes, newly diagnosed T2D, and known T2D. Compared with normoglycemic participants, those with known T2D had a 45% faster decline in memory, 29% faster decline in reasoning, and 24% faster decline in global cognitive score. Participants with prediabetes or newly diagnosed T2D had similar rates of decline compared with those with normoglycemia. Poorer glycemic control in participants with known T2D was associated with a faster decline in memory. This illustrates the nuances of rigorous phenotypic analyses that can better address risk of accelerated cognitive decline in T2D.

Some dementia risk scores include T2D as part of their algorithm to predict cognitive decline. In the Whitehall II Study in the United Kingdom, the Framingham stroke risk profile (FSRP) was used at mid-life. The FSRP includes T2D as well as age, sex, systolic blood pressure, smoking, prior cardiovascular disease, atrial fibrillation, left ventricular hypertrophy, and use of antihypertensive medication. When components of the FSRP were considered separately, only T2D was independently associated with faster cognitive decline (Kaffashian et al., 2013). Likewise, in a 6-year prospective study in Singapore, T2D, metabolic equivalents (MetS), central obesity, dyslipidemia, and three or more cardiovascular disease (CVD) risk factors were associated with higher MCI risk; and progression to dementia was predicted by MetS, T2D, and at least three CVD risk factors (Ng et al., 2016). Whether the underlying dementia neuropathology denoted by a clinical MCI