The bridge between type 2 diabetes and Alzheimer’s disease





Stefania MAGGI,MD,
MPH, PhD
Research Director
CNR Neuroscience Institute
Aging Branch, Padova
ITALY
Gaetano CREPALDI,
MD, PhD
Emeritus Professor
Internal Medicine
University of Padova
ITALY

The bridge between
type 2 diabetes
and Alzheimer’s disease

 

by S. Maggi and G. Crepaldi, Italy

Approximately 382 million people worldwide are affected by type 2 diabetes mellitus (T2DM) making it the most common form of diabetes. Its prevalence in elderly subjects is greater than that in the younger population, and it has been attracting increasing attention because of its disabling complications and the co-occurrence of other chronic conditions. High glucose levels can damage nerves and blood vessels leading to multiple diabetic complications, such as retinopathy, nephropathy, peripheral neuropathy, and vascular diseases. An increasing number of studies have shown that diabetes is also a risk factor for both vascular dementia and Alzheimer’s disease and that it may accelerate the progression from mild cognitive impairment (MCI) to dementia. It has, in fact, been found that T2DM is associated with poor performance in cognitive tasks involving attention, executive functions, episodic memory, psychomotor speed, and visual-constructive skills in persons without dementia. Preclinical studies in animals have demonstrated that some antidiabetic drugs can have an effect on brain metabolism, neuroinflammation, and neuroregeneration, which indicates that these drugs could be also used to treat major neurodegenerative diseases, such as Alzheimer’s disease. Several clinical trials are now underway to assess their efficacy in MCI and in the early stages of Alzheimer’s disease.

Medicographia. 2016;38:92-97(see French abstract on page 97)

Type 2 diabetes mellitus (T2DM) is one of the most common chronic conditions in the world. Its prevalence rate increases sharply with age, rising from about 3% in individuals between 20-39 years to rates between 12% and 25% in those 65 years and over; in recent years, the largest increase has been noted in the oldest age groups. the general trend being seen in both developed and developing countries is that of an increasing prevalence of prediabetes and diabetes linked to increments in obesity, mostly due to a modern sedentary lifestyle. It is predicted that by 2035, the number of patients with diabetes will increase by over 50%, from 382 million individuals today to 592 million. Many cases of T2DM could be prevented through appropriate lifestyle strategies, such as participating in a physical exercise program, losing weight, or following a healthy diet. Once diagnosed with T2DM, patients can be treated with diet, oral hypoglycemic agents, or insulin.1

Alzheimer’s disease is the most common form of dementia and constitutes one of the most pressing problems challenging health-care systems. the number of persons affected with dementia worldwide today is estimated to be approximately 35.6 million; that number is predicted to almost double by 2030 and to more than triple by 2050.2 Alzheimer’s disease is characterized by the cortical accumulation of β-amyloid plaques and neurofibrillary tangles, which are aggregates of hyperphosphorylated τprotein, responsible for the neuroinflammation and the oxidative stress that lead to brain atrophy and widespread synaptic and neuronal loss.

Given the magnitude of the phenomenon, its social and clinical implications, and the fact that there is at yet no effective cure, it is of the upmost importance to reduce the risk of dementia or to delay its onset.

T2DM causes accelerated aging in most organ systems and severe complications, such as nephropathy, coronary artery disease, peripheral artery disease, blindness, and peripheral neuropathy.3 T2DM’s effect on the central nervous system (CNS) has been clearly delineated, and it has been identified as an independent risk factor for cognitive decline and for vascular and neurodegenerative dementia.4,5 T2DM is also associated with poor performance in cognitive tasks involving attention, executive functions, episodic memory, psychomotor speed, and visual-constructive skills in individuals without dementia. Minor diabetes-associated cognitive decrements seem to affect all age groups, tend to progress slowly over time, and could reduce the threshold at which the process of dementia becomes symptomatic in older individuals.6,7 While T2DM’s association with vascular dementia seems straightforward in view of the fact that the vascular system, including the cerebrovascular sector, is damaged by hyperglycemia, its association with neurodegenerative conditions continues to be unclear. The epidemiological evidence and the biological plausibility of the association between t2DM and Alzheimer’s disease, as well as the potential benefits of the treatment of t2DM in preventing neurodegeneration, are outlined below.

Table I
Table I. Results from
meta-analyses on the relative
risk versus controls
for vascular dementia,
Alzheimer’s disease, and
for the progression from
mild cognitive impairment
to Alzheimer’s disease
in patients with type 2
diabetes mellitus.

Is there any epidemiological evidence of an association between T2DM and Alzheimer’s disease?

Given the many risks and confounding factors involved in the association between T2DM and dementia, a causal association between the two is difficult to establish. Moreover, dementia is more likely to be present when vascular and Alzheimer’s disease lesions coexist, a situation that is especially common with increasing age, when mixed dementia cases are the ones most commonly found in the population. Potential risk factors include diabetes-specific characteristics (hyperglycemia, hypoglycemia, endothelial dysfunction, inflammation, and micro- or macrovascular complications). Longitudinal studies focusing on changes in cognitive functions over time are the best way to establish a causal relation. Some longitudinal studies have attempted to identify specific cognitive deficits using batteries of neuropsychological tests and the Mini Mental State Examination. Several population-based longitudinal studies have demonstrated that diabetics have an increased risk of stroke and vascular dementia, although some studies have also reported an increased risk of neurodegenerative forms of dementia, in particular Alzheimer’s disease.

A recent meta-analysis on T2DM and dementia risk8 examining data from 19 published studies including 6184 patients with T2DM and 38 350 controls found a relative risk for vascular dementia at 2.48 (95% confidence interval [CI], 2.08- 2.96) and a relative risk for Alzheimer’s disease at 1.46 (95% CI, 1.20-1.77).

The relationship between T2DM and mild cognitive impairment (MCI), considered an intermediate stage characterized by selective impairments on cognitive testing, but normal performance in activities of daily living, is particularly interesting. It has been seen that 10% to 15% of MCI cases progress to overt Alzheimer’s disease in the subsequent year. A recent meta-analysis9 analyzing 60 cohort studies including 14 821 participants from 16 countries sought to identify the risk factors for predicting the progression from MCI to dementia. T2DM patients with MCI were found to have a relative risk of progression to Alzheimer’s disease of 1.52 (95% CI 1.2-1.91) and— out of all cardiovascular risk factors assessed—T2DM was the only independent predictor of progression from MCI to dementia (Table I).

As the high prevalence of diabetes makes it potentially one of the most important modifiable risk factors for Alzheimer’s disease, clinicians and researchers are exerting every effort to decrease the prevalence of T2DM and to control its progression, with a view to preventing Alzheimer’s disease and learning more about the potential CNS benefits of selected antidiabetic drugs.

Is there a plausible biological mechanism for Alzheimer’s disease development in T2DM?

The pathophysiological mechanism linking T2DM and Alzheimer’s disease is still obscure. A common genetic predisposition to both T2DM and Alzheimer’s disease could explain, at least in part, the link. However, it is quite probable that vascular factors, hyperinsulinemia, dyslipidemia, and hypertension also play a role.10 the fact that the elderly are more susceptible than younger subjects to the effects of T2DM on cognitive function indicates that the disease interacts with or accelerates the process of cerebral aging.11 Changes in the CNS observed in t2DM patients are very similar to those characterizing aging, and neuropsychological testing has confirmed this hypothesis: patients with T2DM, in fact, show a decline in verbal memory and information processing velocity, alterations which are typical of changes associated with aging.12 Pathogenetic factors involved in cognitive deficits in T2DM include hyperglycemia and increased production of advanced glycation end products (AGEs), which damage the vascular system and endothelial functions and lead to inflammatory reactions and amyloid deposition. In rat experimental models, treatment with AGEs induces τ hyperphosphorylation and impairs synapse and memory through upregulation of the AGE receptor.13 Hyperglycemia may also affect blood flow to the brain, neurotransmitter functions, and the supply of nutrients to the brain, thus causing cerebral neurodegeneration. Hyperinsulinemia also seems to contribute to the development of Alzheimer’s disease in type 2 diabetes mellitus. Insulin crosses the blood-brain barrier, and insulin receptors are present in the hippocampus and several other areas of the brain. Insulin-degrading enzyme breaks down amyloid βand, in cases of insulin resistance, the increased concentration of insulin that occurs means that competition from insulin for binding sites of this enzyme may reduce the clearance of amyloid β.14 As many of the abnormalities attributable to insulin resistance seen in T2DM at the cellular level, including inflammation, metabolic stress, mitochondrial dysfunction, and endoplasmic reticulum stress, are also observed in Alzheimer’s disease, Alzheimer’s disease is often referred as type 3 diabetes.15

Brain imaging reveals that T2DM is associated with brain atrophy that only slightly exceeds the expected age-related brain volume reduction: lacunar infarcts occur approximately twice as often in T2DM, and alterations in structural and functional connectivity have been identified as possible brain imaging markers of T2DM.7

Is there any evidence that we can decrease the risk of Alzheimer’s disease by treating T2DM?

As diabetes might increase the risk of dementia by affecting the amyloid cascade and by means of vascular complications, investigators have begun to wonder if tight glycemic control could prevent dementia. It has been hypothesized that patients with T2DM and MCI or mild Alzheimer’s disease might benefit from pharmacological treatment for diabetes because at these stages, T2DM is still a risk factor for progression of cognitive decline. When dementia is at more advanced stages, diabetes-specific treatment would no longer, hypothetically, affect its progression. As diabetes complications, such as retinopathy,16 diabetic foot, microvascular complications, and cerebrovascular and cardiovascular diseases, are all associated with an increased risk of dementia,17 tighter glycemic control should, in principle, reduce the risk of dementia. Findings from large clinical trials have not, however, provided fully convincing results. the ACCORD-MIND (Action to Control CardiOvascular Risk in Diabetes–Memory IN Diabetes) trial showed that patients with diabetes and high cardiovascular risk who were randomized to tighter than normal glycemic control had a cognitive performance that was similar to that in controls receiving standard care after 40 months and their magnetic resonance imaging (MRI) scans showed a nonsignificantly lower level of brain atrophy.18 the Health ABC (Health, Aging, and BodyComposition) study found a twofold increased risk for developing dementia in the participants who experienced hypoglycemic events and a three fold increased risk of having a subsequent hypoglycemic event in those who developed dementia. this finding underlines the bidirectional association between hypoglycemia and dementia.19 the riskbenefit ratio of tight glycemic control is, in any case, less favorable in T2DM patients with cognitive impairment, in view of their risk of hypoglycemia, which in turn increases the risk of cognitive decline. All of these variables need to be considered by a physician entrusted with the care and management of elderly diabetics, who also need to be monitored for MCI and the initial phases of dementia.20

Treating cardiovascular complications and hypertension in T2DM patients using statins,21 angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers22 might decrease the risk of dementia and thus be an effective preventive strategy. The use of different hypoglycemic agents and insulin remains controversial. The choice of different drugs to treat T2DM is often determined by the severity of the disease and this factor, more than the drug itself, may account for differences noted in Alzheimer’s disease risk. However, in view of common mechanisms shared by T2DM and Alzheimer’s disease, antidiabetic drugs might indeed positively affect braincell metabolism. Table II presents the potential impact of particular antidiabetic treatments on the CNS.

Table II
Table II. Potential beneficial central nervous system (CNS) effects
of antidiabetic drugs (insulin, metformin, sulfonylureas, thiazolidinediones,
glucagonlike peptide 1 [GLP-1] agonists, dipeptidyl-4
[DPP-4] inhibitors).

Insulin
Growing evidence has shown that insulin has multiple functions in the brain, and that its dysregulation may contribute to the pathogenesis of Alzheimer’s disease. However, the risk of hypoglycemia associated with peripherally-administered insulin as a treatment for Alzheimer’s disease makes this approach unsuitable, but it has been demonstrated that administering insulin directly to the brain of animals can recover streptozotocin-induced cognitive decline.23 A novel therapeutic approach consisting of intranasal insulin has been demonstrated to be efficacious in short-term clinical trials.24 An ongoing clinical trial in the US, SNIFF (Study of Nasal Insulin in the Fight against Forgetfulness), is examining the effects of intranasal insulin on cognition, entorhinal cortex and hippocampal atrophy, and cerebrospinal fluid biomarkers in amnestic MCI or mild Alzheimer’s disease. The study also aims to examine whether baseline Alzheimer’s disease biomarker profile, gender, or apolipoprotein E ε4 allele carriage predict treatment response. In this study, 240 individuals with amnestic MCI or Alzheimer’s disease will be given either intranasal insulin or placebo for 12 months, following an open-label period of 6 months during which all participants will be given active drug.

Metformin
Metformin is the most commonly prescribed drug for T2DM and exerts its prevailing, glucose-lowering effect by inhibiting hepatic gluconeogenesis and opposing the action of glucagon. It crosses the blood-brain barrier, decreases the hyperphosphorylation of τ protein, and improves cognitive performance in obese, leptin-resistant mice.25 Nevertheless, in human studies metformin has been associated with worsening cognitive performance in diabetic patients26 and increased β amyloid production.27

Sulfonylureas
Sulfonylureas may protect against neurodegeneration by preventing neurofibrillary tangle formation, increasing the brain’s antioxidant capacity, and preventing inflammation. Indeed, glibenclamide has been shown to reduce hyperphosphorylated τ protein levels and lipid peroxidation in rats’ brains, while gliclazide seems to reduce the total oxidant index and increase total antioxidant defence in the brain.28

As results in humans are contradictory,27,29 long-term longitudinal studies on these agents, perhaps in combination with other drugs, are required to verify their therapeutic efficacy.

Thiazolidinediones
Rosiglitazone and pioglitazone are both potent insulin sensitizers that work by activating peroxisome proliferator-activated receptor ϒ (PPAR-ϒ), but the former has been withdrawn from the market because it was shown to have negative cardiovascular disease effects. Pioglitazone is now widely used, although at high doses it also might cause negative effects, such as bone fractures and bladder cancers.30 While preliminary studies have not shown significant benefits in patients with mild Alzheimer’s disease, it is possible that the neurodegeneration was too advanced to allow any potential benefit from the drug.

A multicenter trial is currently ongoing in 50 centers worldwide, with two goals: (i) to verify if a new genetic risk algorithm comprising apolipoprotein E (APOE) and TOMM40 genotypes can determine if participants are at risk of developing MCI due to Alzheimer’s disease within the next five years; and (ii) to evaluate if pioglitazone is able to delay the onset of MCI due to Alzheimer’s disease in cognitively normal individuals who are at high risk of developing MCI due to Alzheimer’s disease, as identified by the biomarker risk algorithm. The results will be available in 2019.

Glucagon-like peptide receptor 1 agonists and dipeptidyl peptidase 4 inhibitors
Two drug classes have been developed more recently: glucagon- like peptide 1 (GlP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors. Clinical data have revealed that these agents improve glycemic control while reducing body weight (GlP-1 receptor agonists, specifically) and systolic blood pressure in patients with type 2 diabetes. Furthermore, the incidence of hypoglycemia is lower with these treatments because of their glucose-dependent mechanism of action.

Due to the rapid degradation of GlP-1, several more stable analogues have been generated, the most recent being liraglutide, which reduces peripheral insulin resistance, has an excellent safety profile, and is accompanied by a low incidence of hypoglycemia during chronic administration.31,32 These drugs have also been shown to have a neuroprotective effect,33 as they promote the formation of new synapses and neurogenesis and protect against oxidative injury.34 In mice, they have been shown to lower β-amyloid and τ-protein levels, leading to reduced inflammation and improved cognition.35,36 Two important clinical trials are currently ongoing: one to determine the safety and tolerability of exendin-4, as well as to acquire preliminary evidence for its effectiveness administered twice daily, as a treatment for early-stage of Alzheimer’s disease and MCI; the other is a 12-month, multicenter, randomized, double-blind, placebo-controlled phase 2b study in patients with mild Alzheimer’s dementia, which is being carried out to test the effect of liraglutide on cerebral glucose utilization, cognition, structural and functional MRI, and cerebrospinal fluid biomarkers.

DPP-4 is the enzyme that degrades GlP-1, so by inhibiting this enzyme the DPP-4 inhibitors stabilize the level of GlP-1. Saxagliptin, sitagliptin, and vildagliptin have all been proven to be effective in controlling diabetes, and two studies have demonstrated their efficacy in reducing amyloid burden, τ phosphorylation, and inflammation and in improving cognition in rats.37,38 Further studies comparing these drugs with the GlP-1 agonists, perhaps in combination with other antidiabetic drugs, are required to determine their impact in human cognition.

Other drugs
Other antidiabetic drugs may be of interest for their potential neuroprotective actions. In particular, amylin, a hormone secreted from pancreatic β cells, like insulin, plays a role in glycemic regulation by delaying gastric emptying and promoting satiety, thereby preventing postprandial spikes in glycemia. It passes through the blood-brain barrier easily and mediates brain functions, including inhibiting appetite to improve glucose metabolism, and probably enhances neural regeneration. However, amylin tends to aggregate in oligomers and fibrils in the pancreas, leading to β-cell dysfunction and reduced insulin secretion. A recent study found an accumulation of amylin amyloid in the cerebrovascular system in an Alzheimer’s disease brain; abundant amyloid β in an Alzheimer’s disease brain may block the ability of amylin to bind to its receptor and hinder normal amylin functions that are essential for the brain.39 A soluble, nonaggregating analogue, pramlintide, has been developed to be used with insulin in the treatment of diabetes and, recently, it was found to be effective in reducing β-amyloid burden and improving cognition in Alzheimer’s disease transgenic mice,40 as well as in increasing synaptogenesis and reducing oxidative stress and neuroinflammation.41 Studies in humans are expected in the near future.

Conclusions

The risk of Alzheimer’s disease is significantly increased in T2DM, although the risk for vascular dementia is even higher. Vascular risk factors might explain, in part, the association with Alzheimer’s disease, but other mechanisms directly affecting the neurodegeneration typical of Alzheimer’s disease also exist. Insulin resistance, which is the hallmark of T2DM, seems to play an important role also in Alzheimer’s disease. Some drugs that improve insulin sensitivity can also act in the brain to promote brain energy metabolism, neuronal survival, and synaptic plasticity. these drugs reduce neuroinflammation and might also increase neurogenesis and brain repair processes. Ongoing clinical trials are assessing their efficacy in preventing the progression of MCI and Alzheimer’s disease in humans. Randomized clinical trials are also needed to assess if improved diabetes control leads to a lower incidence of Alzheimer’s disease. Meanwhile, the dramatic increase in the prevalence of T2DM and Alzheimer’s disease worldwide implies that there are and will be a greater number of older, cognitively impaired patients, who have difficulty with aspects of diabetes self-management and are, therefore, at higher risk of adverse outcomes, such as hypoglycemia. Clinicians and health-care systems must carefully consider these challenges and envision adequate actions. ■

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Keywords: Alzheimer’s disease; antidiabetic drugs; cognitive impairment; dementia; type 2 diabetes