Diabetes and Dementia: a potential ticking bomb to be explored?

Neurosciences has, for some part of it, entered its own winter, by abandoning old hypotheses discarded by failures and evidences, and launching now a hunt for new theories and approaches. Generating new ideas is often described as looking at an old topic from a new angle; one of these new angles can be found in the link between two issues usually seen as dissociated: here, Diabetes and Dementia. Taking into account the prevalence of diabetes at global level and the human and financial burden of dementia, proven right, this link could be considered a ticking bomb for the mid-term future but also a new avenue for R&D efforts. At Alcimed, we explored the existing hypotheses on this question.

Dementia and Diabetes, two connected pressing problems

Dementia is now recognized by the World Health Organization as a major public health priority and its costs are projected to rise from US$818 billion in 2015 to US$2 trillion in 2030. This triggered the launch of the Global action plan on the public health response to dementia 2017-2025 in May 2017.

As a first time in such a document, the 2015 WHO report suggested the existence of a plausible association between diabetes and dementia [1]. Indeed, several studies have shown the existence of a link between diabetes and cognitive impairments:

– Type 2 Diabetes (T2D) patients have a 50% greater risk of dementia than non-diabetic people [2].

– It has also been suggested that T2D patients affected earlier by the disease or with poorer glucose control have higher risks to develop dementia [3].

– More recently, it has been proven that anti-diabetic drugs and insulin are likely to ameliorate cognitive dysfunction in Alzheimer patients [4].

Causal links yet to be found to crack the puzzle and consider new treatments

Clinical observations supporting the hypothesis of a link between Diabetes and Dementia are piling up and, especially in the case of Vascular dementia, the mechanisms underlying such link start to be widely recognized. Nevertheless, given that Dementia groups a large spectrum of conditions, more research is needed to decipher the nature and variants of the relationship between these two pathologies eventually allowing to initiate new treatment possibilities.

In particular, multiple mechanisms have been envisioned/studied so far to explain the impact of badly controlled insulin on the pathological mechanisms leading to different types of dementia:

– In the case of vascular dementia, hyperglycemia or high levels of insulin among diabetic patients could harm brain cells and blood vessels generating micro-vascular complications in the brain leading to insufficient oxygen and nutrient supply.

– In the case of Alzheimer Disease instead, the increased level of insulin could prevent the clearance of Amyloid β by limiting the action of the enzyme degrading it. [2][3][5][6]; other hypotheses have also been proposed related to T2D impact on Tau.

These pathologies and the biological mechanisms involved are complex. At the point that some studies  even propose an opposite cause – consequence link: the Canadian Alzheimer Society in fact recently suggested that Alzheimer may likely impact insulin production and cause brain cells to become insensitive [7].

The opportunity of a new R&D avenue for both researchers and pharmaceutical companies

All of this raises fundamental questions for researchers and industrial players all around the world. Given the difficulty to find new breakthroughs in diabetes and the subsequent increasing field of research dedicated to diabetes complications & comorbidities, could the impact of T2D in the development of dementia be a new orientation to tackle? Would this path lead to new candidates both treating diabetes but also selected for their protection of brain cells? At Alcimed, we believe so.

To move further towards a solution, 3 questions will have to be answered:

– What is the size of the problem? Total number of diabetic patients will rise from 425 million in 2017 to 629 million in 2045 [8].Dementia represents currently the 7th leading cause of death and the number of people affected by dementia worldwide will triple from 50 million in 2015 to 152 million in 2050 [9]. If a causal relationship is demonstrated, it would mean that the abovementioned projections on dementia epidemiology, impact and burden are underestimating the problem. Having a first assessment of what could be the size of the problem will be critical to generate awareness and the required both public and private funding to explore further this stake.

– What kind of consensus can we generate as of today and out of all these researches? It is strongly necessary to clearly define what data is available in the field and what is lacking; from that it will be easier to design new and appropriate hypotheses on the pathological mechanisms and potential treatment approaches.

– What about then new methods or approaches to be used to test these hypotheses and find new drug candidates? Indeed, we may have now to envision to test the influence of existing drugs on brain cells -both neurons and glial cells- protection in order to see their influence in delaying the arrival of dementia symptoms. Being able to both deal with diabetes while managing to avoid its consequence on the brain may be a breakthrough in the future.

About the authors

Angela, Senior Consultant, Alcimed Healthcare Paris
Luc, Partner and Business Unit Director, Alcimed Healthcare Paris

[1] WHO, « Epidemiology and impact of dementia, » 2015.
[2] Biessels, M. Strachan, F. Visseren, L. J. Kappelle and R. A. Whitmer, « Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions, » 2014.
[3] R. Mayeda and e. al, « Diabetes and Cognition, » 2014.
[4] Tai, W. Liu, Y. Li, L. Li and C. Hölscher, « Neuroprotective effects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse model of Alzheimer’s disease, » 2018.
[5] Alzheimer’s Australia, « Dementia and diabetes, a toolkit for a community care workers, » 2014.
[6] Craft, B. Cholerton and L. Baker, « Insulin and Alzheimer’s disease: untangling the web, » 2013.
[7] Alzheimer Society Canada, « Diabetes and dementia – is there a connection ?, » 2017.
[8] International Diabetes Federation, « IDF Diabetes Atlas – 8th Edition, » 2017.
[9] WHO, « Dementia – a public health priority, » 2017.