The relationship between type 2 diabetes and cognitive dysfunction: longitudinal studies and their methodological limitations Kate V. Allen a , Brian M. Frier a , Mark W.J. Strachan b, * a Department of Diabetes, Royal Infirmary of Edinburgh, Scotland, UK b Metabolic Unit, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, Scotland, UK Accepted 27 February 2004 Abstract Type 2 diabetes and dementia in the elderly are major public health problems. Cross-sectional studies have suggested that these two conditions may be inter-related, but the nature of this association is uncertain. Causation can only be established through studies with a longitudinal design, taking into account the many potential confounding factors in any study of cognition. A literature search has identified 10 studies (nine population-based and one of case-controlled design) that included a definable diabetic population and assessments of cognitive function at baseline and at follow-up. These 10 studies utilised a combination of domain-specific cognitive assessments and a clinical diagnosis of dementia in the assessment of cognitive function. Diabetes was associated with either an accelerated cognitive decline or an increased incidence of dementia in eight of nine of the population-based studies. One study demonstrated a relationship between diabetes and vascular cognitive impairment, but not with other types of dementia. No association between type 2 diabetes and cognitive decline was demonstrated in the case-controlled study. These studies provide compelling evidence to support the view that people with type 2 diabetes are at increased risk of developing cognitive impairment in comparison with the general population. D 2004 Elsevier B.V. All rights reserved. Keywords: Diabetes; Alzheimer’s disease; Cognition; Dementia 1. Introduction Type 2 diabetes and dementia are common in the elderly and both are often progressive and disabling con- ditions. Ten percent of people over the age of 65 years develop dementia, rising to more than 50% of people over the age of 85 years (Evans et al., 1989; Geldmacher and Whitehouse, 1996). Greater than 10% of the elderly population in the USA have type 2 diabetes, the prevalence of which rises with increasing age, and a global pandemic of this condition is evident (Harris, 1998; Harris et al., 1998). Cognitive function (particularly memory) declines with age, although the rate of decline is not distributed uniformly within the population. For a minority this progresses in severity to cause disability until dementia is diagnosed. A possible relationship between cognitive decline and diabetes has been posited since the discovery of insulin (Miles and Root, 1922). In type 1 diabetes, this relationship has traditionally been thought to be related to the frequency of exposure to severe hypoglycaemia (Perros and Deary, 1999), although two observational studies have related psychomotor slowing to hypertension, microvascular com- plications and duration of diabetes (Ferguson et al., 2003; Ryan et al., 2003). The relationship between type 2 diabetes and accelerated cognitive decline, however, is more com- plex and is unlikely to be associated with exposure to hypoglycaemia, which is a relatively infrequent occurrence. Cross-sectional studies have suggested an association be- tween type 2 diabetes, cognitive decline (particularly in aspects of verbal memory) and dementia (Strachan et al., 1997a; Stewart and Liolitsa, 1999) but a causal relationship can only be established through examination of the rate of change of cognitive function within an individual, which requires a longitudinal study design. In this paper the published longitudinal data relating type 2 diabetes to cognitive function are reviewed. 0014-2999/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2004.02.054 * Corresponding author. Tel.: +44-131-5372064; fax: +44-131- 5373071. E-mail address: mark.strachan@luht.scot.nhs.uk (M.W.J. Strachan). www.elsevier.com/locate/ejphar European Journal of Pharmacology 490 (2004) 169 – 175