Dr Shibley Rahman, friend and supporter of Dementia Alliance International writes for our April 2016 Research wrap:
I have just returned from the 31st Alzheimer’s Disease International conference in Budapest, Hungary (#ADI2016). I feel that this conference was unique and remarkable in firmly putting rights-based advocacy on the map.
This was in no small part thanks to the demands made by Dementia Alliance International. The atmosphere was great.
In keeping with the universal ‘right to health’ under current WHO and United Nations instruments, I believe all people including individuals living with dementia have a right to the best health possible. There’s been a recent drive to promote the message that ‘what’s best for the body is best for the mind’; generally “brain health”. And I feel that’s entirely fair. One of the research plenary sessions at #ADI2016 was on the relationship between diabetes and Alzheimer’s disease, and this relationship has meaning for both prevention and management of Alzheimer’s disease.
For my ‘research wrap’ this month, I’d like therefore to give an overview of where this arm of work is heading to, and why it actually might provide a legitimate source of hope for the future for all. I think of it as “the diabetes story”.
[Abbreviations: In this blogpost, I will refer to a number of abbreviations. These include: AD – Alzheimer’s disease, IDE – insulin degrading enzyme, ILWD – individuals living with dementia, MCI – mild cognitive impairment, MRI – magnetic resonance imaging, T2DM – Type 2 diabetes mellitus, TIA – transient ischaemic attack].
Introduction
Alzheimer’s disease, of course, needs no introduction to readers of the Dementia Alliance International. It is a progressive chronic disease of the brain, which tends to affect learning, memory, attention, and navigation in space as initial symptoms. It is also the most common cause of dementia worldwide. It is perfectly possible to live beyond the diagnosis of Alzheimer’s disease (AD) with optimism given the right help.
Diabetes is a condition affecting metabolism, specifically in how the chemical hormone insulin works in the body. But now it is being increasingly recognised that insulin has important functions in the brain - and that the relationship between type 2 diabetes (T2DM) (due to insensitivity of insulin tending to be adult onset) and Alzheimer’s disease is an interesting one. Up to date research is now providing clues that this critical relationship may have repercussions for the prevention and management of Alzheimer’s disease.
The scale of the relationship between AD and T2DM
Both T2DM and AD affect large populations in the world.
Just because they co-exist therefore does not necessarily mean that they’re related to one another. Today, over 46 million people live with dementia worldwide, more than the current population of Spain. This number is estimated to increase to 131.5 million by 2050 (“World Dementia Report 2015” from Alzheimer’s Disease International, 2015). It is currently anticipated that, though ageing, a sedentary lifestyle and obesity of people explain gradual rise in numbers with T2DM in Europe, effects of rapid transition in nutritional status of population - and of maternal hyperglycaemia on the risk of offspring developing glucose intolerance -further add to rapid and accelerated rises in the global number of people with T2DM (Bhattarai, 2009).
People with T2DM may have twice the risk of developing dementia compared with people without diabetes. In combination, dementia can make the management of diabetes difficult, but poorly controlled diabetes can also impact on the safety and well-being of people with dementia (for an excellent review, see Biessels et al, 2006). This blogpost for the DAI blog is on the relationship between T2DM and AD, and is not on the practical management of diabetes in dementia, diabetes or dementia.
The customary rules of the DAI blog hold as always. For an interesting pamphlet, however, on key issues of managing dementia in individuals living with dementia (ILWD), please see the Institute of Diabetes for Older People IDOP’s excellent document (2013) on this subject entitled “Diabetes and Dementia: Guidance on Practical Management”.
Prevention of AD
“Vascular” essentially means ‘relating to blood vessels’. The organisation of the blood supply to the brain is highly relevant to what happens to the brain in dementia, and research funding is essential for identifying the main issues involved. Given the evidence that there may be a vascular component to many dementias, the “Blackfriars Consensus” talks about interventions to address vascular risk factors. These risk factors might include, for example, tobacco, poor diet, physical inactivity and alcohol; and also raised blood pressure, raised blood cholesterol, obesity and diabetes should also help reduce the risk, progression, and severity of dementia. Protective factors also play a part and these include education and intellectual and social engagement, according to the hugely influential Blackfriars Consensus statement (Public Health England, 2015).
Insulin is a hormone made by the pancreas that allows your body to use glucose from carbohydrates in the food that you eat for energy or to store glucose for future use. Insulin helps keeps your blood sugar level from getting too high (hyperglycemia) or too low (hypoglycemia). Diabetes mellitus is controversially associated with a proportion of patients who convert from mild cognitive impairment (MCI) to dementia. In addition to MCI and dementia, the stages of diabetes-associated cognitive dysfunction might include subtle cognitive changes that are unlikely to affect activities of daily life or diabetes self-management. These “diabetes-associated cognitive decrements” have structural brain correlates detectable on brain scanning with brain MRI, but usually show little progression over time (Koekkoek et al., 2015).
Epidemiological studies show that patients with T2DM and individuals with a diabetes-independent elevation in blood glucose have an increased risk for developing dementia, specifically dementia due to AD. These observations suggest that abnormal glucose metabolism likely plays a role in some aspects of AD pathogenesis, leading us to investigate the link between aberrant glucose metabolism, T2DM, and AD in mouse models (Macauley et al., 2015). Factors involved in the pathogenesis of AD (how AD comes about) include metabolic alterations such as insulin resistance and hyperglycemia, both of which are also hallmarks of T2DM.
There has, further, been historically huge interest in the possible rôle of substances called “β-amyloid peptides” and “tau” in the brain. The accumulation of β-amyloid peptides in the brain of Alzheimer´s patients is responsible in part for the neurotoxicity underlying the loss of synaptic plasticity that triggers a cascade of events leading to cell death. With cell death, ultimately, there’s shrinkage of the brain, and progressive loss of functions in AD. A large number of studies have now revealed the key role of the hippocampus, a part of the brain in the temporal lobe (so called “temporal” as it’s geographically near the ear) in the memory and learning deficits of Alzheimer´s disease (Arrieta-Cruz and Gutiérrez-Juárez, 2016).
Possible plausible mechanisms of action
Several plausible mechanisms could help to explain this proposed link; so it’s essential to be appreciative that this is very much research work ‘in progress’. Thus far, studies have shown that insulin resistance and deficiency can interact with amyloid-β protein and tau protein phosphorylation, each leading to the onset and development of AD (Li et al., 2015). Specifically, the Alzheimer’s Association believes there is sufficiently strong evidence, from a population-based perspective, to conclude that regular physical activity and management of cardiovascular risk factors (diabetes, obesity, smoking, and hypertension) reduce the risk of cognitive decline and may reduce the risk of dementia (Baumgart et al., 2015).
Insulin, as well as being crucially important in the body, performs unique functions within the central nervous system. Produced nearly exclusively by an organ called the pancreas, insulin crosses the blood-brain barrier affecting feeding and cognition through central nervous system mechanisms largely independent of glucose utilisation. Whereas peripheral insulin acts primarily as a metabolic regulatory hormone, central nervous system insulin has an array of effects on brain that may more closely resemble the actions of the ancestral insulin molecule. Brain endothelial cells, the cells that form the vascular blood brain barrier and contain the transporter that translocates insulin from blood to brain, are themselves regulated by insulin. The insulin transporter is altered by physiological and pathological factors including hyperglycemia and the diabetic state. The latter can lead to blood brain barrier disruption. Certain cells of the body, namely pericytes and pluripotent cells, protect the integrity of the blood brain barrier and its ability to transport insulin (Banks, Owen and Erickson, 2012).
Existing dementia risk scores require much careful collection of additional data from patients, limiting their use in practice. On the other hand, routinely collected healthcare data have the potential to assess dementia risk without the need to collect further information. An objective of a recent study was to develop and validate a 5-year dementia risk score derived from primary healthcare data, using data from general practices in The Health Improvement Network database from across the UK, randomly selecting 377 practices (Walters et al., 2016). Predictors of dementia incidence in those aged 60-79 included age, sex, social deprivation, smoking, BMI, heavy alcohol use, anti-hypertensive drugs, diabetes, stroke/TIA, atrial fibrillation, aspirin, depression. Recent research has provided evidence that insulin resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders (Verdile et al., 2015).
Although epidemiological and biological evidence has highlighted this increased incidence of cognitive decline and AD in patients with T2DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β (Aβ) protein accumulation, and mitochondrial dysfunction link T2DM and AD. At the present time, it is becoming evident that subtle, but continuous “neuroinflammation” can provide the ground for disorders such as cerebral small vessel disease. Moreover, advanced aging and a number of highly prevalent risk factors such as obesity, hypertension, diabetes and atherosclerosis could act as "silent contributors" promoting a chronic pro-inflammatory state. This could aggravate the outcome of various pathological entities and can contribute to a number of subsequent post-stroke complications such as dementia, depression and neurodegeneration creating a pathological “vicious cycle” (Sandu et al., 2015).
Amongst ILWD, there is a high prevalence of comorbid medical conditions, but little is actually known about the effects of comorbidity on processes and quality of care and patient needs or how services are adapting to address the particular needs of this population. Bunn and colleagues undertook a scoping review, cross-sectional analysis of a population cohort database, interviews with ILWD and comorbidity and their family carers and focus groups or interviews with health-care professionals, and found that ILWD had poorer access to services than those without dementia (Bunn et al., 2016).
Analysis of a population cohort database found that 17% of ILWD had diabetes. The nature of the relationship, however, has frustratingly remained a puzzle, in part because of seemingly incongruent findings (Schilling, 2016). For example, some studies have concluded that insulin deficiency is primarily at fault, suggesting that intranasal insulin or inhibiting the insulin-degrading enzyme (IDE) could be beneficial. Conversely, other research clues appear to have concluded concluded that hyperinsulinemia is to blame, which implies that intranasal insulin or the inhibition of IDE would exacerbate the disease. Such somewhat contradictory conclusions could potentially pose a serious obstacle to making progress on treatments.
What to do next?
With such a rapid explosion in shared knowledge about diabetes and dementia, the question for scientists and the funding authorities is “where now?”.
A useful starting point could be that a progressive microvascular dysfunction in T2DM may impair the ability of cerebral vessels to supply blood to brain regions during local metabolic demand, thereby increasing risks of dementia. This essentially means small changes in the structural organisation of the blood supply to the brain. Having previously demonstrated that a drug called resveratrol can enhance vasodilator function in the systemic circulation, Wong and colleagues (2016) then hypothesised that resveratrol could similarly benefit the cerebral circulation. Their results, published most recently, arguably provide the first clinical evidence of an acute enhancement of vasodilator responsiveness in cerebral vessels following consumption of resveratrol in a certain population who are known to have endothelial dysfunction and sub-clinical cognitive impairment. This is important stuff.
Of interest not only do lifestyle measures have a protective effect against the development of cognitive impairment due to AD, but might do some of the pharmacological agents used in the management of T2DM. These include: insulin (especially when delivered intranasally), metformin, peroxisome proliferator-activated receptors γ agonists, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.
In particular, peroxisome proliferator activated receptor γ-activating drugs such as pioglitazone show various effects in preclinical models of neurodegenerative disease. The decade-long clinical usage of these drugs used to treat diabetics now allows for evaluation of patient-oriented data sources. Using observational data from 2004-2010, the association of pioglitazone and incidence of dementia has been looked at by following across time145,928 subjects aged ≥60 years who, at baseline, were free of dementia and insulin-dependent diabetes mellitus (Heneka et al., 2015). Using data from 2004-2010, they analysed the association of pioglitazone and incidence of dementia in a prospective cohort study of 145,928 subjects aged ≥60 years who, at baseline, were free of dementia and insulin-dependent diabetes mellitus. Long-term use of pioglitazone was associated with a lower dementia incidence. Prospective clinical trials are needed to evaluate a possible neuroprotective effect in these patients in an ageing population.
It is now felt quite strongly that clinicians must ensure preventive care be given to control and postpone both conditions, and to identify cognitive impairment early to manage it appropriately (Sridhar, Lakshmi and Nagamani, 2015). A team of scientists led by Prof Christian Holscher at Lancaster University have been investigating the link between disrupted insulin signalling and Alzheimer’s disease. If this all works well, then these drugs could be quite easily brought to market, compared to other novel therapies for dementia.
More recently, they have investigated the effect of liraglutide – a drug licensed for treatment of T2DM – in mice with some of the hallmark features of AD, as well as in healthy mice. T2DM is a risk factor in the development of AD. It has been shown that insulin signalling is desensitised in the brains of AD patients. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and long-lasting analogues such as liraglutide are on the market as T2DM treatments (McClean and Hölscher C., 2014).
Previously, this excellent research group had shown that the diabetes drug liraglutide is protective in certain middle aged and old mice. Recent results from studies with mice demonstrate that liraglutide may indeed protect from progressive neurodegeneration that develops in AD. Promisingly, the drug is currently in clinical trials in patients with AD. The main hallmarks of AD were much reduced; memory formation was normalised and synapse loss and the loss of synaptic plasticity was prevented (McClean, Jalewa and Hölscher, 2015).
Numerous in vitro and in vivo studies have shown that GLP-1 analogues have a range of neuroprotective properties. GLP-1Rs are expressed in the hippocampal area of the brain an important site of adult neurogenesis and maintenance of cognition and memory formation `(Hunter and Hölscher C, 2012), GLP-1 analogues can cross the blood brain barrier, diffuse through the brain to reach the receptors and most importantly activate them, their neuroprotective effects may be realised.
Conclusion
It can be far too easy to be hyperbolic about the research achievements from the scientific community about dementia. Sometimes, it feels that there is no in-between in the spectrum ranging from extreme optimism to extreme despair.
Just look at an English newspaper headline, virtually daily, on ‘the next big thing’ as “a cure for dementia”. There is no doubt that in general social care funding in England is unacceptably low, many feel. Notwithstanding this, it would be a real shame to throw “the baby out with the bathwater”, the baby in this particular case an approach based on diabetes basic research which might actually be of some benefit. It is noteworthy that this arm of research is highly relevant also to the millions of people living with Alzheimer’s disease worldwide. A big unanswered question is how the ‘diabetes story’ might also be relevant to the causes of dementia other than Alzheimer’s disease.
Author: Dr Shibley Rahman
Dr Shibley Rahman and Dementia Alliance International © 2016
References
Alzheimer’s Disease International (2015) World Alzheimer Report 2015. The global impact of dementia: an analysis of prevalence, incidence, cost and trends. https://www.alz.co.uk/research/WorldAlzheimerReport2015.pdf, (accessed 28 April 2016).
Arrieta-Cruz I, Gutiérrez-Juárez R. The Role of Insulin Resistance and Glucose Metabolism Dysregulation in the Development of Alzheimer´s Disease. Rev Invest Clin. 2016 Mar-Apr;68(2):53-8.
Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther. 2012 Oct;136(1):82-93. doi: 10.1016/j.pharmthera.2012.07.006. Epub 2012 Jul 17.
Baumgart M, Snyder HM, Carrillo MC, Fazio S, Kim H, Johns H. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective. Alzheimers Dement. 2015 Jun;11(6):718-26. doi: 10.1016/j.jalz.2015.05.016. Epub 2015 Jun 1.
Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 2006 Jan;5(1):64-74.
Bunn F, Burn AM, Goodman C, Robinson L, Rait G, Norton S, Bennett H, Poole M, Schoeman J, Brayne C. (editors) (2016) Comorbidity and dementia: a mixed method study on improving health care for people with dementia (CoDem). NIHR Journals Library; 2016 Feb., available at http://www.ncbi.nlm.nih.gov/books/NBK344389/, (accessed 28 April 2016).
Hunter K, Hölscher C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. Neurosci. 2012 Mar 23;13:33. doi: 10.1186/1471-2202-13-33.
Institute of Diabetes for Older People “IDOP” (2013) “Diabetes and Dementia Guidance on Practical Management”, https://www.diabetes.org.uk/Documents/Professionals/Professional%20resources/Diabetes_And_Dementia_Guidance_2013.pdf, (accessed 28 April 2016).
Koekkoek PS, Kappelle LJ, van den Berg E, Rutten GE, Biessels GJ. Cognitive function in patients with diabetes mellitus: guidance for daily care. Lancet Neurol. 2015 Mar;14(3):329-40. doi: 10.1016/S1474-4422(14)70249-2. Epub 2015 Feb 16.
Li X, Song D, Leng SX. Link between type 2 diabetes and Alzheimer's disease: from epidemiology to mechanism and treatment. Clin Interv Aging. 2015 Mar 10;10:549-60. doi: 10.2147/CIA.S74042. eCollection 2015.
Macauley SL, Stanley M, Caesar EE, Yamada SA, Raichle ME, Perez R, Mahan TE, Sutphen CL, Holtzman DM. Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo. J Clin Invest. 2015 Jun;125(6):2463-7. doi: 10.1172/JCI79742. Epub 2015 May 4.
McClean PL, Hölscher C. Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease. Neuropharmacology. 2014 Jan;76 Pt A:57-67. doi: 10.1016/j.neuropharm.2013.08.005. Epub 2013 Aug 21.
McClean PL, Jalewa J, Hölscher C. Prophylactic liraglutide treatment prevents amyloid plaque deposition, chronic inflammation and memory impairment in APP/PS1 mice. Behav Brain Res. 2015 Oct 15;293:96-106. doi: 10.1016/j.bbr.2015.07.024. Epub 2015 Jul 20.
Public Health England/UK health forum (2015) Blackfriars Consensus on promoting brain health: Reducing risks for dementia in the population, http://nhfshare.heartforum.org.uk/RMAssets/Reports/Blackfriars%20consensus%20%20_V18.pdf, (accessed 28 April 2016).
Sandu RE, Buga AM, Uzoni A, Petcu EB, Popa-Wagner A. Neuroinflammation and comorbidities are frequently ignored factors in CNS pathology. Neural Regen Res. 2015 Sep;10(9):1349-55. doi: 10.4103/1673-5374.165208.
Schilling MA. Unraveling Alzheimer's: Making Sense of the Relationship between Diabetes and Alzheimer's Disease. J Alzheimers Dis. 2016 Feb 27;51(4):961-77. doi: 10.3233/JAD-150980.
Sridhar GR, Lakshmi G, Nagamani G. Emerging links between type 2 diabetes and Alzheimer's disease. World J Diabetes. 2015 Jun 10;6(5):744-51. doi: 10.4239/wjd.v6.i5.744.
Verdile G, Keane KN, Cruzat VF, Medic S, Sabale M, Rowles J, Wijesekara N, Martins RN, Fraser PE, Newsholme P. Inflammation and Oxidative Stress: The Molecular Connectivity between Insulin Resistance, Obesity, and Alzheimer's Disease. Mediators Inflamm. 2015;2015:105828. doi: 10.1155/2015/105828. Epub 2015 Nov 26.
Walters K, Hardoon S, Petersen I, Iliffe S, Omar RZ, Nazareth I, Rait G. Predicting dementia risk in primary care: development and validation of the Dementia Risk Score using routinely collected data. BMC Med. 2016 Jan 21;14(1):6. doi: 10.1186/s12916-016-0549-y.
Wong RH, Nealon RS, Scholey A, Howe PR. Low dose resveratrol improves cerebrovascular function in type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis. 2016 Mar 14. pii: S0939-4753(16)00045-4. doi: 10.1016/j.numecd.2016.03.003. [Epub ahead of print].