Update on the T2D-Dementia Link: Interview With Experts

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Diabetes has been linked with Alzheimer disease, forms of cognitive dysfunction that are not as severe as dementia, such as MCI, and even more subtle cognitive changes.
Diabetes has been linked with Alzheimer disease, forms of cognitive dysfunction that are not as severe as dementia, such as MCI, and even more subtle cognitive changes.

With increasing prevalence of both dementia and diabetes, in part because of greater longevity and certain lifestyle factors, there has also been an increase in the co-occurrence of these diseases.1 Research has shown that this comorbidity is not simply the result of chance. An increased risk for dementia has been observed among individuals with diabetes, with the vast majority of data pertaining to type 2 diabetes (T2D) specifically. In addition, diabetes has been “linked to forms of cognitive dysfunction that are not as severe as dementia, such as mild cognitive impairment (MCI), but also to even more subtle cognitive changes, which are referred to as diabetes-associated cognitive decrements,” according to a 2018 review.1

Whereas dementia primarily affects individuals >65 years of age, causing recognizable symptoms with clear progression year to year, diabetes-associated cognitive decrements can affect patients of all ages, are likely develop over a period of many years, and can be difficult to detect through imaging or neuropsychological examination. “Hence, considering these different features, diabetes-associated cognitive decrements and dementia should be regarded as different entities that probably have different underlying mechanisms,” added the investigators. 1

Regarding associations with MCI and dementia, the researchers noted the following findings:

  • One prospective study published in 2014 found a hazard ratio of 1.6 (95% CI, 1.2-2.2) for amnesic MCI and 1.4 (95% CI, 0.8-2.2) for non-amnesic MCI in individuals with diabetes.1 
  • Prognosis of MCI is worse in those with vs without diabetes, with a 1.7 relative risk for conversion to dementia reported in meta-analyses.1
  • In combined results from various studies totaling >2 million participants, the reported relative risk was 1.73 (95% CI, 1.65-1.82) for all types of dementia, 1.53 (95% CI, 1.42-1.63) for Alzheimer disease, and 2.27 (95% CI, 1.94-2.66) for vascular dementia.1
  • In other research, the relative risk for all types of dementia was 1.62 (95% CI, 1.45-1.80) in women and 1.58 (95% CI, 1.38-1.81) in men.2
  • For vascular dementia, women showed a 19% higher risk than men.1
  • Increased dementia risk has been observed even in patients with newly diagnosed diabetes (hazard ratio 1.16; 95% CI, 1.15-1.18).3

Endocrinology Advisor interviewed the following experts to explore the mechanisms, clinical implications, and research needs pertaining to the diabetes-dementia link: Marwan Sabbagh, MD, director of the Cleveland Clinic Lou Ruvo Center for Brain Health; Rebecca Gottesman, MD, PhD, professor of neurology and epidemiology in the division of cerebrovascular neurology at Johns Hopkins University, and director of research at Johns Hopkins Bayview Neurology; and David John Irwin, MD, assistant professor of neurology at the Perelman School of Medicine at the University of Pennsylvania.

Endocrinology Advisor: What is known thus far regarding the link between diabetes and dementia and other forms of cognitive dysfunction, and what are the proposed underlying mechanisms?

Dr Sabbagh: There is clearly a risk link between T2D and Alzheimer's dementia. There is no literature around other types of dementia — frontotemporal, Lewy body, or Parkinson's dementia, for example — but there is clearly a link with Alzheimer's. This is particularly true for people with T2D, who are much more likely to [have Alzheimer's dementia] compared [with those without diabetes]. In addition, insulin resistance has been found in the brain of people with Alzheimer's pathology, even if they don't have insulin resistance elsewhere in the body. Suzanne de la Monte of Brown University has published papers stating that Alzheimer's is basically type 3 diabetes.4

Dr Gottesman: There are several probable mechanisms. One possibility is that patients with diabetes experience more clinical or even subclinical strokes, which themselves can [have a direct] impact on cognition, ultimately increasing risk for cognitive impairment or dementia. Another leading hypothesis is that insulin resistance [has an] impact on the brain directly, impairing the brain's ability to respond appropriately to insulin and levels of glycemia. There are a lot of other hypothesized mechanisms, including increased inflammation, which can lead to downstream cognitive problems; alterations in ability to clear toxins in the brain such as amyloid because of adverse effects on blood vessels, might also increase the risk for Alzheimer's dementia specifically.

Dr Irwin: [The links] are not fully understood but likely involve several mechanisms, including cerebrovascular disease induced reductions in brain health. Peripheral insulin resistance in diabetes has a significant impact on vascular health, which includes cerebral vasculature. This chronic damage to cerebral vasculature can cause clinically silent microscopic infarctions in deep white matter of the brain which can impair multiple cognitive functions or lead to increased risk for larger clinically manifested cerebrovascular accidents.

There is also emerging evidence of an important role of insulin in regulating brain function. Patients with T2D and patients with Alzheimer disease without T2D have both been found to have evidence of insulin resistance of brain cells, which may contribute to the pathophysiologic process of cognitive impairment and dementia.

Endocrinology Advisor: How should this risk be monitored and assessed in clinical practice? What are common signs and screening tools, for example?

Dr Sabbagh: We would not routinely test [hemoglobin (Hb)] A1C levels or fasting sugars as part of management or screening of a patient with dementia. That is not a common practice. Not that it couldn't be, but what we would typically do is try to optimize the medical care of their diabetes with drugs to normalize their HbA1C. In turn, we could expect to see some risk reduction, but you might not necessarily see a correlative improvement in cognition.

Dr Gottesman: Standard screening for cognitive impairment isn't necessarily indicated, but if patients or their family members are reporting problems with memory or other aspects of cognition, or certain problems functioning in their daily routine because of cognitive problems, a more detailed initial screening can be considered with a test such as the Montreal Cognitive Assessment or even more detailed neuropsychological testing. Screening for diabetes has value for many disease end points, with more clear benefits from glycemic control.

Dr Irwin: Promotion of healthy aging strategies is helpful to reduce risk for age-associated memory changes in patients with diabetes and in all individuals. These include a heart-healthy diet with tight glucose control and preventive care for other vascular risk factors such as smoking, obstructive sleep apnea, hypertension, and high cholesterol. Regular exercise and cognitive and social engagement are also very helpful to promote healthy aging.

It is important to have regular follow up with a primary care physician to manage these risk factors and to help detect early signs of cognitive impairment. Basic cognitive screening tools are helpful to quantify subjective memory complaints, and referral to a neurologist may be helpful for more detailed evaluation. Reports of functional decline such as needing assistance with complex activities of daily living, including finances or appointments, should prompt further clinical investigation.

Endocrinology Advisor: What are the relevant treatment recommendations and other important implications for clinicians?

Dr Sabbagh: There is a currently a convergence of data going on around that very question. There have been many studies [investigating] treatment of Alzheimer's using diabetic drugs. The glitazones Actos (pioglitazone) and Avandia (rosiglitazone) were tried in Alzheimer's dementia.5 The Avandia data was equivocal. There was a large prevention trial (the TOMORROW trial) that was just closed to enrollment. The investigators used a low-dose of pioglitazone as a prevention strategy to reduce the probability of progression to Alzheimer's dementia. The trial stopped because of futility.6 There have also been studies suggesting that metformin could be used as a treatment for Alzheimer's,7 so there is now an ongoing clinical trial on metformin as a treatment for Alzheimer's dementia.

Finally, and probably most intriguing, my colleague Suzanne Craft at Wake Forest has demonstrated that administration of insulin itself could have robust effects.8 The problem, of course, is if you give insulin to a normal person, you're going to crash their sugars, so she has come up with a brilliant pathway — intranasal administration. This allows delivery of insulin to the brain, which has been shown to have multiple mechanisms of action. For one, it affects insulin-degrading enzyme and can facilitate more rapid amyloid turnover. She is preparing to announce the results of a phase II program of intranasal insulin treatment for Alzheimer's dementia.

Dr Gottesman: Although there's growing evidence that diabetes, and even HbA1c level, is associated with risk for cognitive impairment and dementia, there is no clear evidence that treating diabetes with intensive control is beneficial for cognitive outcomes. For example, the ACCORD MIND trial failed to show a benefit in cognitive outcomes in the intensive group, although brain volumes were slightly better in the intensive group.9 However, this is probably because relationships between diabetes and dementia take many years or even decades to occur, and clinical trials lasting just a few years are unlikely to note a benefit of treatment.

Thus, it seems that maintaining glucose within a normal range is likely to be helpful for cognitive end points, although this is not supported by data. Avoiding hypoglycemia is also likely to be important, however, since there's evidence that episodes of severe hypoglycemia are associated with poor cognitive outcomes.

Dr Irwin: If there is evidence for a decline in cognitive function over time, either by history or objectively on serial evaluations, it is important to have the patient referred for a comprehensive evaluation for a possible early stage of Alzheimer disease or related dementia. This includes a careful history, examination, and often ancillary tests to help exclude reversible causes of cognitive impairment with aging. Treatment of dementia is largely supportive with a benefit of early intervention to help reduce risk for safety issues, such as driving or leaving the stove on, while providing support to encourage socialization and cognitive stimulation.

Endocrinology Advisor: What should be the focus of future research on the dementia-diabetes connection?

Dr Sabbagh: Research should continue in the current directions. There are a lot of unanswered questions, including whether we can we use diabetic medications effectively as a treatment for Alzheimer's dementia. The reason we think about this is that if you look at positron emission tomography scans, you can see that [fludeoxyglucose] metabolism is compromised or altered in Alzheimer's brains, particularly in the frontotemporal regions. That's potentially a marker of neurodegeneration. The question, then, is can we enhance metabolic activity and sugar metabolism in the brain? And the logical target would be the use of diabetic medications. [The findings thus far indicate] that there is clearly a strong intersection between diabetes and diabetic therapeutics and Alzheimer's.

Dr Gottesman: More research needs to continue to evaluate mechanisms of diabetes' effects on the brain but also on treatment and prevention. In addition, individuals with diabetes frequently have other vascular risk factors, and it's apparent that having several uncontrolled risk factors is especially associated with bad cognitive outcomes. Thus, focusing research on multimodal interventions is likely to be important in [future] studies, with several ongoing trials currently evaluating these multimodal approaches.

Dr Irwin: Further understanding of mechanisms of peripheral and central insulin resistance in relationship to brain health, as well as Alzheimer disease and vascular pathology, will be very useful to identify preventative and mechanistic treatment strategies for age-associated memory loss. 

Edited and revised for clarity by Endocrinology Advisor.

References

1. Biessels GJ, Despa F. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol. 2018;14:591-604.

2. Chatterjee S, Peters SAE, Woodward M, et al. Type 2 diabetes as a risk factor for dementia in women compared with men: a pooled analysis of 2.3 million people comprising more than 100,000 cases of dementia. Diabetes Care. 2016;39(2):300-307.

3. Haroon NN, Austin PC, Shah BR, Wu J, Gill SS, Booth GL. Risk of dementia in seniors with newly diagnosed diabetes: a population-based study. Diabetes Care. 2015;38(10):1868-1875.

4. de la Monte SM, Wands JR. Alzheimer's disease is type 3 diabetes—evidence reviewed. J Diabetes Sci Technol. 2008;2(6):1101-1113.

5. Miller BW, Willett KC, Desilets AR. Rosiglitazone and pioglitazone for the treatment of Alzheimer's disease. Ann Pharmacother. 2011;45(11):1416-1424.

6. Takeda. Takeda and Zinfandel Pharmaceuticals Discontinue TOMMORROW Trial Following Planned Futility Analysis [news release]. https://www.takeda.com/newsroom/newsreleases/2018/takeda-tommorrow-trial/. January 25, 2018. Accessed September 19, 2018.

7. Luchsinger JA, Perez T, Chang H, et al. Metformin in amnestic mild cognitive impairment: results of a pilot randomized placebo controlled clinical trial. J Alzheimers Dis. 2016;51(2):501-514.

8. Craft S. Therapeutic effect of intranasal insulin on cognition, function, and AD biomarker. Grantome - National Institutes of Health. http://grantome.com/grant/NIH/RF1-AG041845-01. Accessed September 10, 2018.

9. Launer LJ, Miller ME, Williamson JD, et al. Effects of randomization to intensive glucose lowering on brain structure and function in type 2 diabetes ACCORD Memory in Diabetes Study. Lancet Neurol. 2011;10(11):969-977.

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