Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications

Abstract

Cognitive dysfunction is increasingly recognized as an important comorbidity of diabetes mellitus. Different stages of diabetes-associated cognitive dysfunction exist, each with different cognitive features, affected age groups and prognoses and probably with different underlying mechanisms. Relatively subtle, slowly progressive cognitive decrements occur in all age groups. More severe stages, particularly mild cognitive impairment and dementia, with progressive deficits, occur primarily in older individuals (>65 years of age). Patients in the latter group are the most relevant for patient management and are the focus of this Review. Here, we review the evolving insights from studies on risk factors, brain imaging and neuropathology, which provide important clues on mechanisms of both the subtle cognitive decrements and the more severe stages of cognitive dysfunction. In the majority of patients, the cognitive phenotype is probably defined by multiple aetiologies. Although both the risk of clinically diagnosed Alzheimer disease and that of vascular dementia is increased in association with diabetes, the cerebral burden of the prototypical pathologies of Alzheimer disease (such as neurofibrillary tangles and neuritic plaques) is not. A major challenge for researchers is to pinpoint from the spectrum of diabetes-related disease processes those that affect the brain and contribute to development of dementia beyond the pathologies of Alzheimer disease. Observations from experimental models can help to meet that challenge, but this requires further improving the synergy between experimental and clinical scientists. The development of targeted treatment and preventive strategies will therefore depend on these translational efforts.

Figures

FIG 1

Brain imaging findings in patients with T2DM The figure summarizes findings form brain imaging studies in T2DM (for details and literature references see text). The position of each imaging marker on the X-axis reflects how intensively it has been studied in relation to T2DM. The position on the Y-axis reflects to which extent a marker is affected in individuals with T2DM relative to controls, based on the evidence from available studies. Image of white matter microstructure courtesy of Y Reijmer, UMC Utrecht.

FIG 2

risk factors and underlying pathologies for dementia in T2DM The figure provides a life course perspective on risk factors and disease processes contributing to the development of T2DM and dementia. T2DM most commonly develops in mid- or late life, in the context of environmental, behavioural and lifestyle factors – that vary over the course of life - on a background of genetic risk. People with T2DM frequently have an adverse vascular risk factor profile, including obesity, hypertension and dyslipidemia, often already in prediabetic stages. Many of the factors that predispose and co-occur with T2DM, as well as factors that are related to having T2DM (e.g. elevated glucose, glucose lowering treatment) may affect the brain. Evidently, with so many factors involved there are marked interindividual differences in risk factor profiles and exposures. Brain pathologies contributing to the development of dementia accumulate over the course of decades in the context of an individual’s risk profile. In the majority of cases multiple pathologies cooccur, with variable proportions between individuals. Vascular pathologies are more common in individuals with T2DM than in those without and may thus contribute to the elevated dementia risk in T2DM. Of note, while Alzheimer pathologies are a key contributor to dementia in people with T2DM, the burden of these pathologies is not increased compared to people with T2DM. The excess dementia risk in people with T2DM is thus likely to be also attributable to additional non-Alzheimer neurodegenerative pathologies, which are yet to be identified (for details and references see main text).

FIG 3

Pancreatic amylin forms amyloid and interacts with Aβ in the brains of patients with T2DM Sections through the brains of patients with T2DM and AD showing amylin-positive vascular wall contours in capillaries (A), small arterioles (B and C), neurons (D) and plaques (E). Vascular amylin deposits in (C) shows apple-green birefringence in the Congo red stain (F and G). Same blood vessel shows no Aβ immunoreactivity (H). Amylin interacts with Aβ forming cerebral mixed amylin-Aβ deposits (D and I). In J, vascular deposition of amylin (brown) and astroglial reaction (green stain for glial fibrillary acidic protein; GFAP) are shown. A and J are from Ref., B,C, F, G, H and I are from Ref. , D and E are from Ref. .