Bibliographic reference
Dove A, Shang Y, Xu W, Grande G, Laukka EJ, Fratiglioni L, Marseglia A. The impact of diabetes on cognitive impairment and its progression to dementia. Alzheimers Dement. 2021 Oct 12. doi: 10.1002/alz.12482.
At a glance: Type 2 diabetes is associated with an increased risk of dementia. However, there are contradictory results on the relationship between diabetes and the prodromal phase of dementia, as well as on the role played by inadequate glycemic control on the onset of cognitive disorders. In a longitudinal population study, it is reported that not diabetes per se but rather the condition of poorly controlled diabetes is associated with a two-fold higher risk of cognitive impairment and nearly three-fold higher risk of progression to dementia. In addition, the coexistence of diabetes comorbidities and cardiac impairment doubles both the risk of cognitive impairment and its progression to dementia. Taken individually, neither condition is associated with clinical outcomes. Finally, the risk of dementia is increased if diabetes is accompanied by systemic inflammation. Hence, in the absence of a treatment for dementia, careful control of diabetes is mandatory to preserve cognitive health.
The context and the starting point
Type 2 diabetes and dementia represent two major public health challenges in the context of an ageing society. Worldwide, 463 million adults suffer from overt diabetes and 374 show evidence of prediabetes. In parallel, at least 50 million people suffer from dementia, while cognitive impairment, which represents an early stage of dementia and affects about 20% of people aged above 65 years, progresses towards dementia in a third of cases in 5 years. Despite the well-known link between diabetes and dementia, disagreement exists both on whether diabetes associates with cognitive impairment and on the role played by adequate glycemic control on its progression towards dementia. In this longitudinal population study, the impact of diabetes and glycaemic control was analysed with respect to the development of cognitive impairment and its progression towards dementia.
The features of the study
This study was conducted by researchers at Karolinska Institutet on data collected by the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K) in 2522 adults aged above 60 years (age, 72.3±10.0, range 60-102 years) enrolled between March 2001 and June 2004, initially free from dementia. At baseline, participants were grouped as cognitively healthy (1840 cases, 73.0%) and cognitively impaired – no dementia (682 cases, 27.0%), and were followed over 12 years. During the follow-up, the incidence of cognitive impairment and dementia was monitored according to the revised DSM-IV criteria. At each stage of the study, participants were administered a neuropsychological battery comprising seven tasks that address five major domains, the results of which were subsequently related to socio-demographic factors, lifestyles, presence of prediabetes or diabetes, degree of glycemic control, history of cardiovascular disease (fibrillation, coronary artery disease or decompensation), and the presence of systemic inflammation estimated through C-reactive protein (CRP) assay.
The results obtained
At enrollment, 860 subjects (34%) had prediabetes and 217 (8.6%) had diabetes. During the follow-up (9.2±3.1 years), 544 participants in the cognitively healthy cohort (29.6%) developed cognitive impairment, while 151 participants in the cognitively impaired cohort (22.1%) developed dementia. The incidence of cognitive impairment and its progression to dementia was increased by two-fold and nearly three-fold, respectively, in case of poor glycemic control (i.e., glycated hemoglobin levels greater than 7.5%). In contrast, the presence of diabetes per se or prediabetes were not associated with the risk of cognitive impairment or dementia. Further, the presence of diabetic comorbidities and heart disease approximately doubled the risk of both cognitive impairment and its progression to dementia, while neither diabetes nor cardiac disease individually increased the risk of either outcomes. Finally, stratification according to the inflammatory state showed that the presence of diabetes and elevated CRP tripled the risk of progression of cognitive impairment towards dementia.
Limits of the study
Diabetes is a chronic and heterogeneous disease in terms of evolution, therapeutic response and impact of comorbidities. The use of glycated hemoglobin, which has a lower diagnostic sensitivity than the oral glucose tolerance test (OGTT), may have generated classification problems, resulting in potential underestimation of the presented associations. Another missing variable worth of mention is the duration of diabetes, a key parameter in relation to cognitive impairment, given that more years lived with diabetes leave more opportunities for the accumulation of damage related to hyperglycemia. Thirdly, less than 9% of the subjects were diabetic and the sample size for analyses stratified by heart disease and PCR level also appeared numerically limited, thus calling for caution on the evaluation of outcomes related to these events. Finally, at the time when the study was designed (early 2000s) there was a tendency to achieve strict targets of glycemic control, which later on were found to enhance the mortality risk in elderlies (ACCORD, ADVANCE and VADT studies). Thus, some of the older and longer-term disease-bearing subjects originally included in the study may have been exposed to more aggressive hypoglycemic therapies than the current ones, and this may have created selection bias leading to a younger and relatively healthier sample.
What’s new
Compared with other studies assessing the cognitive impact of diabetes per se, this study took in account the importance of adequate glycemic control, systemic inflammation status and cardiovascular disease on cognitive impairment. Currently there is no cure for dementia, so prevention is mandatory, and this study offers as a key to understanding the need for careful control of diabetes mellitus.
What are the perspectives
Future research should explore how the complexity of diabetes affects cognitive impairment in the early preclinical stage of dementia, focusing on the underlying inflammatory mechanisms. More attention should also be paid to the new therapeutic armamentarium of diabetes. In fact, new drugs have been shown to promote a systemic protection that goes beyond glycemic control, and preliminary studies have displayed their favorable effects on the risk of cognitive deterioration.
Edited by Paolo Marzullo
