Diabetes Mellitus and Cognitive Decline – Prevention Should Not Be Delayed!

The recent addition of the Diabetes and Cognitive Decline section to JPAD marks a milestone in the history of this progressive journal as it recognises the important contribution that Diabetes makes to the aetiology of both vascular and neurodegenerative dementia syndromes (1-3). It has been observed that diabetes in the presence of hypertension leads to a more pronounced cognitive decline (4) and that at an early stage of cognitive decline (mild cognitive impairment (MCI)), diabetes accelerates the progression of MCI to dementia (5). Research into diabetes and cognitive decline has not been straightforward with many earlier studies being limited in their interpretation of causal relationships between diabetes and the development of dementia because of their cross-sectional nature (6). However, a large number of prospective longitudinal studies have formed a platform to shed light on these intriguing relationships (7-9). These generally confirm that dementia risk in those with diabetes is 2-3 higher than those without diabetes and this applies to both Alzheimer’s Disease and vascular dementia. A large pooled analysis of 2.3m people from 14 studies (a large proportion of unpublished data) estimates that those with type 2 diabetes are at approximately 60% greater risk for the development dementia compared with those without diabetes, with the effect being strongest in women for vascular dementia (10). A recent study of long term study of trajectories of glucose control with cognitive performance in older people with type 2 diabetes demonstrated that instability of glucose regulation over time showed worse cognitive performance and that a trajectory of stable HbA1c levels is associated with better cognitive function (11). Furthermore, a small anatomical MRI study has demonstrated a link between glycaemic variability (measured by continuous glucose monitoring) and grey matter atrophy and cognitive decline (worse learning and memory scores) in type 2 diabetes which was independent of HbA1c level and hypoglycaemia (12). In a 9-year follow up of well-functioning older adults with type 2 diabetes, worse cognitive function and greater decline were exhibited in those with poorer glucose control (13): this should prompt clinicians to aim for stable levels of glucose within an optimal range determined by consideration of multiple factors such as physical functional status, life expectancy, comorbid profile and cognitive status. A risk score for the prediction of the 10-year risk of dementia in subjects with type 2 diabetes has recently been published (14). Out of 45 candidate predictors only 6 (after age and education) were found to be strongly predictive : microvascular, cerebrovascular and cardiovascular disease, depression, diabetic foot, and acute metabolic events. The situation in type 1 diabetes is less clear (15) and requires greater study into the similarities and differences between the underlying mechanisms seen in type 2 diabetes, what areas of cognitive performance are mainly affected, are these changes clinically relevant, and what preventative aspects are needed? Some studies in individuals with type 1 diabetes show impairments in problem solving skills or visuo-spatial ability, whilst others report changes in learning and memory or psychomotor speed but these findings are not universal (16) but in selected cases the changes seen may be sufficient to affect diabetes self -management abilities. A recent systematic review of type 1 diabetes and dementia discusses the associations in greater detail (17). Another less investigated area has been the relationship between pre-diabetes states and cognition with some studies indicating that lower MiniMental scores and reduced verbal fluency are more common in those with diabetes and is associated with an increased risk of developing a dementia syndrome (18). Whilst not always a consistent finding, a study in postmenopausal women without diabetes showed a relationship between HbA1c level and the risk of developing MCI or dementia (19) and in the secondary analysis of the Finnish Diabetes Prevention Study (involving middle-aged overweight subjects with impaired glucose tolerance) a lower mean 2-h glucose at an oral glucose test and HbA1c predicted better cognitive performance after 9 years of follow-up post-intervention (20). The pathophysiological basis remains uncertain but multiple factors are likely to play a part (21)including the hyperglycaemic state itself, hypoglycaemia,