Diabetes, cognitive impairment, and dementia

Abstract

Are strongly linked, but the precise mechanisms are unclear

The Dementia UK report, published earlier this year on behalf of the Alzheimer’s Society, predicts that by 2050, 34 million people worldwide will have dementia, and 71% of these people will live in developing countries.¹ Currently, nearly 700 000 people have dementia in the United Kingdom, and worldwide this figure approaches 18 million. Dementia costs the UK economy around £17bn (€24bn; $35bn) each year, but the human cost to patients, their families, and their friends is incalculable.

Over the past 15 years, several studies have indicated that diabetes mellitus, particularly type 2 diabetes, is associated with an increased risk of cognitive impairment and dementia.²,³,⁴ If these studies are correct, then the future burden of dementia may be even greater than estimated as the prevalence of type 2 diabetes continues to rise.

Early data that linked type 2 diabetes with cognitive impairment came from cross sectional cohort studies that were generally of poor methodological quality.⁴ However, a recent systematic review of prospective observational studies identified 25 articles that assessed the link between diabetes and cognitive impairment.³ Although the studies did not usually subclassify the type of diabetes, the demographics of the people included suggest that they mainly had type 2 diabetes. Overall, people with diabetes had a 1.2-1.7 times greater decline in cognitive performance than those without diabetes. Moreover, people with diabetes were 1.6 times more likely to develop dementia.Perhaps predictably, given the association between diabetes and cardiovascular disease, diabetes conferred a 2.2-3.4 times greater risk of vascular dementia, but people with diabetes were also 1.2-2.3 times more likely to develop Alzheimer’s disease.Most of the studies excluded people with cognitive impairment at baseline assessment and did not provide information on those lost to follow-up, who may also have had poorer cognitive function, so these studies may underestimate the risk of cognitive impairment associated with diabetes.

Why might diabetes increase the risk of cognitive impairment? In people with type 1 diabetes, cross sectional studies have suggested a direct association between cognitive function and retrospectively estimated exposure to severe hypoglycaemia.⁵ However, the DCCT/EDIC (diabetes control and complications trial/epidemiology of diabetes interventions and complications) study found no association between the frequency of severe hypoglycaemia, over an average period of 18 years, and any decline in cognitive function in 1144 people with type 1 diabetes. It did, however, find an association between higher mean glycated haemoglobin concentrations and a moderate decline in motor speed and psychomotor efficiency.⁶

Microvascular disease is the hallmark of protracted poor glycaemic control in people with diabetes, so the association detected in the DCCT/EDIC study might be a consequence of cerebral microvascular disease. Direct in vivo evaluation of the cerebral microcirculation is difficult in humans and requires sophisticated neuroimaging techniques, which preclude the study of large numbers of people. The microvasculature of the retina, however, offers a window into the status of the small vessels of the brain, and studies in people with and without diabetes have shown an association between retinal microvascular abnormalities and cognitive function.⁷,⁸,⁹

Shorter term changes in blood glucose concentrations may also affect cognitive function in people with diabetes. In one experimental study, an increase of blood glucose to 16.5 mmol/l for one hour was associated with specific impairments in working memory, attention, and mood in adults with type 2 diabetes.¹⁰ Moreover, in a multicentre randomised trial, stricter glycaemic control over 26 weeks improved working memory in 141 adults with type 2 diabetes.¹¹ The relatively short timescale of these interventions (relative to the time it takes for microvascular changes to occur) imply that functional consequences of hyperglycaemia, such as altered cerebral blood flow or possibly osmotic changes in the brain, are likely to impair cognition.

Substantive longitudinal data are not available in people with type 2 diabetes to explore the relation between long term glycaemic control and cognitive function. Moreover, type 2 diabetes is a complex disorder that is not restricted to deranged glucose metabolism, so the cognitive impairments seen in people with this diabetes probably result from interactions between many other factors besides hyperglycaemia. Genetic predisposition, hypertension, dyslipidaemia, macrovascular disease, depression, and drug therapy could all contribute to cognitive impairment.

Dissecting out the relative importance of these factors is challenging. To facilitate this process, the UK Medical Research Council has funded a major prospective study of the risk factors for cognitive impairment in more than 1000 people with type 2 diabetes (theEdinburgh type 2 diabetes study; ET2DS). Ongoing multifactorial randomised controlled trials in people with type 2 diabetes have also included cognitive function as an outcome measure in a subset of participants.¹² Studies like these should help to clarify the relation between type 2 diabetes and cognitive impairment, so that appropriate preventative and therapeutic strategies can be developed.