Review
Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions

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Summary

Type 2 diabetes is associated with dementia, and also with more slight cognitive decrements. In this Review we discuss trajectories from normal cognition to dementia in people with type 2 diabetes, and explore opportunities for treatment. Slight diabetes-associated cognitive decrements and dementia affect different age groups and show a different evolution. These cognitive entities should therefore not be regarded as a continuum, although their effects might be additive. Vascular damage is a key underlying process in both entities. Glucose-mediated processes and other metabolic disturbances might also have a role. No treatment has been established, but management of vascular risk factors and optimisation of glycaemic control could have therapeutic benefit. We identify possible opportunities for intervention to improve cognitive outcomes in people with type 2 diabetes, and suggest how treatment can be tailored to individual risk profiles and comorbidities.

Introduction

It has been estimated that there will be more than 80 million dementia cases worldwide by 2040.1 People with diabetes have a 50% greater risk of dementia than do those without diabetes.2, 3 Type 2 diabetes in midlife is also associated with an increased long-term risk of dementia.2 With a prevalence of type 2 diabetes of 12–25% in people older than 65 years,4, 5 one in ten to 15 dementia cases worldwide are attributable to type 2 diabetes (population attributable risk). If prediabetes is also taken into account, these estimates increase to one in seven to ten dementia cases.4

In this Review, we address whether type 2 diabetes and prediabetic stages could be targets for the prevention of cognitive impairment. A particular focus will be on the trajectories from normal cognition to dementia, and from normal metabolism to diabetes. By drawing attention to different stages in these trajectories, risk factors, and underlying mechanisms, we aim to build a framework that can be used to identify treatment opportunities.

In the first section of the Review we define the scope of the problem. What is the association between diabetes and prediabetic stages and dementia? What are the trajectories of cognitive dysfunction in people with diabetes without dementia? We also review data from brain imaging studies in type 2 diabetes and describe structural correlates of impaired cognition. Next, we address risk factors for accelerated cognitive decline, and the possible mechanisms involved. Finally, we review results from treatment studies and suggest approaches to the development of targeted interventions against accelerated cognitive decline in people with diabetes, in which the ultimate goal is to establish the optimum treatment for the right individual at the right stage of their disease.

Section snippets

Diabetes, prediabetes, and dementia risk

Findings from many prospective population-based studies, including several meta-analyses using pooled data, have shown an increased risk of dementia in people with diabetes.2, 3 In the largest and most recent meta-analysis of type 2 diabetes and dementia risk, data was pooled from 19 published studies in 6184 individuals with diabetes and 38 350 without diabetes.3 The combined overall relative risk (RR) for dementia was 1·51 (95% CI 1·31–1·74). Results of analyses that separated dementia

Diabetes, mild cognitive impairment, and early dementia

Dementia is generally preceded by a stage in which patients have cognitive complaints and objective disturbances on cognitive testing, but in which their daily functioning is largely preserved. This stage is termed mild cognitive impairment (MCI).10 MCI thus represents an intermediate stage between normal cognitive functioning and dementia, although not all people with MCI will develop dementia.10 Prospective population-based studies link type 2 diabetes to an increased risk of MCI,11, 12 but

Cognitive trajectories in people with diabetes without dementia

Type 2 diabetes is also associated with slight cognitive decrements in people without dementia.17, 18 These decrements affect several domains, including verbal memory, information processing speed, attention, and executive functioning. Results of cross-sectional studies generally show slight effect sizes of about 0·3–0·5 SD units,18 which implies that the cognitive performance of people with type 2 diabetes is around the 35th to the 40th percentile of that of control groups. This shift in

Slight cognitive decrements and dementia risk: continuum or additive effects?

What is the association between slight diabetes-associated cognitive decrements and the increased dementia risk in people with type 2 diabetes? In our opinion, slight cognitive decrements, at least up to the age of 65 years, are unlikely to indicate the earliest stage of a dementia process. Dementia typically occurs after the age of 65–70 years.25 No evidence exists that diabetes increases the risk of early-onset dementia. In fact, the 50% increased dementia risk in people with type 2 diabetes

Brain imaging studies

Over the past decade, findings from brain imaging studies, mostly using MRI and including people without dementia, have provided important insights into structural correlates of cognitive dysfunction in people with type 2 diabetes.17, 28 Slight brain atrophy—both cortical and subcortical—is a very consistent finding from MRI studies in people with type 2 diabetes.28 Results of cross-sectional studies show reductions in average total brain volume of 0·5–2·0% in patients with type 2 diabetes

Vascular risk factors

In the general population, hypertension, hyperlipidaemia, and obesity in midlife are associated with increased risk of late-life dementia and cognitive decrements.9, 40, 41 In line with these findings, elderly and middle-aged individuals with type 2 diabetes who are also hypertensive are at greater risk of dementia and cognitive impairment than are those without hypertension (figure 3);42, 43 treatment for hypertension could therefore lower this risk.44, 45 The link between hypertension and

Accelerated cognitive decline: degenerative or vascular abnormalities?

Theories about the general causes of cognitive decline and dementia focus on the processes underlying the two major subtypes of clinical dementia—vascular dementia and Alzheimer's disease. Vascular dementia is caused by the accumulation of various forms of vascular damage in the brain. Alzheimer's disease is thought to be due to aberrant amyloid-β processing, involving generation of small, toxic amyloid-β oligomers, and aggregation of the microtubule-associated protein tau.71 This aberrant

Treatment and cognitive outcomes in type 2 diabetes

In an observational study in a large cohort of people with type 2 diabetes not using insulin, use of metformin and sulphonylureas decreased dementia risk compared with patients with type 2 diabetes who did not take glucose-lowering drugs.94 By contrast, other researchers reported increased dementia risk with metformin use (which was not recorded for other glucose-lowering drugs),95 increased risk of dementia with insulin treatment,96 or accelerated cognitive decline with thiazolidinedione use.97

Search strategy and selection criteria

We searched PubMed for papers published in English from January, 1990, to August, 2013, with the terms (and synonyms thereof) “dementia”, “Alzheimer's disease”, “cognitive impairment”, “diabetes”, “metabolic syndrome”, and “obesity”, in combination with the key terms “epidemiology”, “risk factors”, “brain MRI”, “prevention”, and “treatment”. We searched reference lists of papers identified and extracted relevant papers from our records. We also searched ClinicalTrials.gov. From the large amount

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